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42 gesichtete, geschützte Fragmente: Plagiat

[1.] Mag/Fragment 003 01 - Diskussion
Bearbeitet: 10. March 2014, 12:15 Graf Isolan
Erstellt: 8. March 2014, 16:37 (Hindemith)
BauernOpfer, Bienenstock and McDermott 2005, Fragment, Gesichtet, Mag, SMWFragment, Schutzlevel sysop

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Hindemith
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Quelle: Bienenstock and McDermott 2005
Seite(n): 22, Zeilen: 1ff
The bronchus-associated lymphoid tissue (BALT) constitutes organized lymphoid aggregates of T and B cell that are capable to respond against to inhaled antigens. BALT, located mostly at bifurcations of the bronchus in animals and humans, is already present in the fetus and develops rapidly following birth, especially in the presence of antigens. Humoral immune responses elicited by BALT are based primarily in immunoglobulin A secretion, locally and by BALT-derived B cells that have trafficked to distant mucosal sites. Similarly, located T cell responses have been noted. On the basis of these findings, the BALT can be thought of as functionally analogous to mucosal lymphoid aggregates in the intestine and is deemed a member of the common mucosal immunologic system (Bienenstock and McDermott, 2005). The bronchus-associated lymphoid tissue (BALT) and the nasal-associated lymphoid tissue (NALT) constitute organized lymphoid aggregates that are capable of T- and B-cell responses to inhaled antigens. BALT, located mostly at bifurcations of the bronchus in animals and humans, is present in the fetus and develops rapidly following birth, especially in the presence of antigens. Humoral immune responses elicited by BALT are primarily immunoglobulin A secretion both locally and by BALT-derived B cells that have trafficked to distant mucosal sites. Similarly located T-cell responses have been noted. On the basis of these findings, the BALT can be thought of as functionally analogous to mucosal lymphoid aggregates in the intestine and is deemed a member of the common mucosal immunologic system.
Anmerkungen

The source is given at the end, but it is not clear to the reader that the entire paragraph is taken from the source and that is has been taken more or less literally.

Sichter
(Hindemith), PlagProf:-)

[2.] Mag/Fragment 007 15 - Diskussion
Bearbeitet: 15. March 2014, 12:37 Graf Isolan
Erstellt: 10. March 2014, 19:34 (Graf Isolan)
Fragment, Gesichtet, Lipscomb and Masten 2002, Mag, SMWFragment, Schutzlevel sysop, Verschleierung

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Graf Isolan
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Untersuchte Arbeit:
Seite: 7, Zeilen: 15-31
Quelle: Lipscomb and Masten 2002
Seite(n): 116, Zeilen: left col. 36-46.48-49 - right col. 1-10.17-21
In the lung, DC reside within and beneath airway epithelium, in alveolar septae, in the connective tissue surrounding pulmonary veins and airway vessels, and with the lung capillaries of the lung parenchyma (Lipscomb et al., 1995). DC in the airway epithelium have an immature phenotype and exhibit a rapid turnover (Holt et al., 1994). DC that are resident within alveolar septae and in connective tissue surrounding vessels have a more mature phenotype than airway DC (Gong et al., 1992). In contrast to DC that are resident within the lung, in the vascular compartment circulating precursor DC are present (Suda et al., 1998). One role of lung DC is to provide protection against infectious agents by initiating immune response. An equally important role is to generate tolerance to inhaled allergens in normal noninflamed lungs. In this regard, immature DC continuously leave the peripheral blood and take over a surveillance position in lung tissue, avidly sampling the antigenic environment. In the steady state, lung DC likely remain relatively immature and constitutively migrate in low numbers into regional lymph nodes where they induce anergy, deletion of T cells, or a weak TH2-like response to air-borne antigens that is eventually downregulated (Stumbles et al., 1998). Active suppression of immature DC maturation by alveolar macrophages may explain why airway and [intraepithelial DC remain immature during their steady-state migration to lung-associated lymph nodes (Holt, 1993; Lipscomb et al., 1993).]

Gong JL, McCarthy KM, Telford J, Tamatani T, Miyasaka M, Schneeberger EE. Intraepithelial airway dendritic cells: a distinct subset of pulmonary dendritic cells obtained by microdissection. J Exp Med. 1992 Mar 1; 175 (3): 797-807.

Holt PG. Development of bronchus associated lymphoid tissue (BALT) in human lung disease: a normal host defence mechanism awaiting therapeutic exploitation? Thorax. 1993 Nov; 48 (11): 1097-8.

Holt PG. Pulmonary dendritic cell populations. Adv Exp Med Biol. 1993; 329: 557-62. Review.

Holt PG, Haining S, Nelson DJ, Sedgwick JD. Origin and steady-state turnover of class II MHC-bearing dendritic cells in the epithelium of the conducting airways. J Immunol. 1994 Jul 1; 153 (1): 256-61.

Lipscomb MF, Pollard AM, Yates JL. A role for TGF-beta in the suppression by murine bronchoalveolar cells of lung dendritic cell initiated immune responses. Reg Immunol. 1993 May-Aug; 5 (3-4): 151-7.

Lipscomb MF, Bice DE, Lyons CR, Schuyler MR, Wilkes D. The regulation of pulmonary immunity. Adv Immunol. 1995; 59: 369-455. Review.

Stumbles PA, Thomas JA, Pimm CL, Lee PT, Venaille TJ, Proksch S, Holt PG. Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity. J Exp Med. 1998 Dec 7; 188 (11): 2019-31.

Suda T, McCarthy K, Vu Q, McCormack J, Schneeberger EE. Dendritic cell precursors are enriched in the vascular compartment of the lung. Am J Respir Cell Mol Biol. 1998 Nov; 19 (5): 728-37.

In the lung, DCs reside within and beneath airway epithelium, in alveolar septae, in the connective tissue surrounding pulmonary veins and airway vessels, and within the lung capillaries of the lung parenchyma (reviewed in Ref. 202). DCs in the airway epithelium express an immature phenotype and exhibit a rapid turnover (142, 233). DCs residing within alveolar septae and in connective tissue surrounding vessels have a more mature phenotype than airway DCs (121). DCs residing within the lung vascular compartment represent circulating precursor DCs (336). [...] One role of lung DCs is to provide protection against infectious agents by initiating type 1 immune response. An equally important role is to generate tolerance to inhaled allergens in normal noninflamed lungs. In this regard, immature DCs continuously leave the peripheral blood and assume a surveillance position in lung tissue, avidly sampling the antigenic environment. In the steady state, lung DCs likely remain relatively immature and constituitively migrate in low numbers into regional lymph nodes where they induce either anergy, deletion of T cells, or a weak Th2-like response to air-borne antigens that eventually is downregulated (334). [...] Active suppression of immature DC maturation by alveolar macrophages may explain why airway and intraepithelial DCs remain immature during their steady-state migration to lung-associated lymph nodes (LALNs) (141, 203).

121. GONG JL, MCCARTHY KM, TELFORD J, TAMATANI T, MIYASAKA M, AND SCHNEEBERGER EE. Intraepithelial airway dendritic cells: a distinct subset of pulmonary dendritic cells obtained by microdissection. J Exp Med 175: 797–807 1992.

141. HOLT PG. Macrophage: dendritic cell interaction in regulation of IgE response in asthma. Clin Exp Allergy 23: 4–6, 1993.

142. HOLT PG, HAINING S, NELSON DJ, AND SEDGWICK JD. Origin and steady-state turnover of class II MHC-bearing dendritic cells in the epithelium of the conducting airways. J Immunol 153: 256–261, 1994.

202. LIPSCOMB MF, BICE DE, LYONS CR, SCHUYLER MR, AND WILKES D. The regulation of pulmonary immunity. Adv Immunol 59: 369–455, 1995.

203. LIPSCOMB MF, POLLARD AM, AND YATES JL. A role for TGF-beta in the suppression by murine bronchoalveolar cells of lung dendritic cell initiated immune responses. Reg Immunol 5: 151–157, 1993.

233. MCWILLIAM AS, NELSON D, THOMAS JA, AND HOLT PG. Rapid dendritic cell recruitment is a hallmark of the acute inflammatory response at mucosal surfaces. J Exp Med 179: 1331–1336, 1994.

334. STUMBLES PA, THOMAS JA, PIMM CL, LEE PT, VENAILLE TJ, PROKSCH S, AND HOLT PG. Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity. J Exp Med 188: 2019–2031, 1998.

336. SUDA T, MCCARTHY K, VU Q, MCCORMACK J, AND SCHNEEBERGER EE. Dendritic cell precursors are enriched in the vascular compartment of the lung. Am J Respir Cell Mol Biol 19: 728–737, 1998.

Anmerkungen

Largely identical, without any part of it marked as a citation. No source given.

Sichter
(Graf Isolan) Schumann

[3.] Mag/Fragment 008 01 - Diskussion
Bearbeitet: 15. March 2014, 12:45 Graf Isolan
Erstellt: 10. March 2014, 20:07 (Graf Isolan)
Fragment, Gesichtet, Lipscomb and Masten 2002, Mag, SMWFragment, Schutzlevel sysop, Verschleierung

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Graf Isolan
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Untersuchte Arbeit:
Seite: 8, Zeilen: 1-9
Quelle: Lipscomb and Masten 2002
Seite(n): 116, Zeilen: right col. 17-30
[Active suppression of immature DC maturation by alveolar macrophages may explain why airway and] intraepithelial DC remain immature during their steady-state migration to lung-associated lymph nodes (Holt, 1993; Lipscomb et al., 1993). Furthermore, autocrine production of IL-10 by immature DC can inhibit surface expression of MHC class-I and -II molecules and exert a generalized inhibitory effect on T cell proliferation (Stumbles et al., 1998). On exposure to inhaled allergens, the antigen may simply be insufficient in providing a danger signal to overcome suppression by alveolar macrophages and IL-10. However, if a danger signal is present at the tissue site, DC mature and migrate in greater number to draining lymph nodes to stimulate CD4+ T cell clonal expansion and differentiation.

Holt PG. Development of bronchus associated lymphoid tissue (BALT) in human lung disease: a normal host defence mechanism awaiting therapeutic exploitation? Thorax. 1993 Nov; 48 (11): 1097-8.

Holt PG. Pulmonary dendritic cell populations. Adv Exp Med Biol. 1993; 329: 557-62. Review.

Lipscomb MF, Pollard AM, Yates JL. A role for TGF-beta in the suppression by murine bronchoalveolar cells of lung dendritic cell initiated immune responses. Reg Immunol. 1993 May-Aug; 5 (3-4): 151-7.

Stumbles PA, Thomas JA, Pimm CL, Lee PT, Venaille TJ, Proksch S, Holt PG. Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity. J Exp Med. 1998 Dec 7; 188 (11): 2019-31.

Active suppression of immature DC maturation by alveolar macrophages may explain why airway and intraepithelial DCs remain immature during their steady-state migration to lung-associated lymph nodes (LALNs) (141, 203). Furthermore, autocrine production of IL-10 by immature DCs can inhibit surface expression of MHC class II and exert a generalized inhibitory effect on T cell proliferation (238, 334). On exposure to inhaled allergens, the antigen may simply be insufficient in providing a danger signal to overcome suppression by alveolar macrophages and IL-10. However, if a danger signal is present at the tissue site, DCs mature and migrate in greater numbers to the draining lymph nodes to stimulate CD4 T cell clonal expansion and differentiation.

141. HOLT PG. Macrophage: dendritic cell interaction in regulation of IgE response in asthma. Clin Exp Allergy 23: 4–6, 1993.

203. LIPSCOMB MF, POLLARD AM, AND YATES JL. A role for TGF-beta in the suppression by murine bronchoalveolar cells of lung dendritic cell initiated immune responses. Reg Immunol 5: 151–157, 1993.

238. MOORE KW, O’GARRA A, DE WAAL MALEFYT R, VIEIRA P, AND MOSMANN TR. Interleukin-10. Annu Rev Immunol 11: 165–190, 1993.

334. STUMBLES PA, THOMAS JA, PIMM CL, LEE PT, VENAILLE TJ, PROKSCH S, AND HOLT PG. Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity. J Exp Med 188: 2019–2031, 1998.

Anmerkungen

Largely identical, without any part of it marked as a citation. No source given.

Sichter
(Graf Isolan) Schumann

[4.] Mag/Fragment 008 11 - Diskussion
Bearbeitet: 14. March 2014, 10:40 WiseWoman
Erstellt: 9. March 2014, 15:34 (Hindemith)
Fragment, Gesichtet, Mag, SMWFragment, Schutzlevel sysop, Tschernig et al 1999, Verschleierung

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Untersuchte Arbeit:
Seite: 8, Zeilen: 11-12; 16-28
Quelle: Tschernig et al 1999
Seite(n): 66, 69, Zeilen: 66: l.col: 1-3, 9-19; 69: r.col: 13-20
Lymphocytes play a significant role in lung disorders, for example sarcoidosis, asthma, and rejection after transplantation (Berman et al., 1990). [...] Since the lung has no afferent lymphatic vessels, the blood is the starting point for lymphocyte immigration. Lymphocytes migrate to the lung vascular endothelium (marginal pool) and enter the interstitial lung tissue (interstitial pool), where the lymphocyte composition is different from blood and bronchoalveolar lavages (BAL) (Fliegert et al., 1996). In contrast to peripheral blood lymphocytes, mainly activated T cells are found in BAL of humans and mice (Curtis et al., 1995; Saltini et al., 1990). This immunological status confers lymphocytes appropriate defense mechanisms to such a vulnerable organ. The expression of adhesion molecules depends on the compartment from which the cells are recruited, indicating that local activation and expression of adhesion molecules is induced by the microenvironment. Possible candidates for such activators are dendritic cells and macrophages or components of the extracellular matrix (Holt, 1993; van Haarst et al., 1994).

Berman JS, Beer DJ, Theodore AC, Kornfeld H, Bernardo J, Center DM. Lymphocyte recruitment to the lung. Am Rev Respir Dis. 1990 Jul; 142 (1): 238-57. Review.

Curtis JL, Kim S, Scott PJ, Buechner-Maxwell VA. Adhesion receptor phenotypes of murine lung CD4+ T cells during the pulmonary immune response to sheep erythrocytes. Am J Respir Cell Mol Biol. 1995 May; 12 (5): 520-30.

Fliegert FG, Tschernig T, Pabst R. Comparison of lymphocyte subsets, monocytes, and NK cells in three different lung compartments and peripheral blood in the rat. Exp Lung Res. 1996 Nov-Dec; 22 (6): 677-90.

Holt PG. Development of bronchus associated lymphoid tissue (BALT) in human lung disease: a normal host defence mechanism awaiting therapeutic exploitation? Thorax. 1993 Nov; 48 (11): 1097-8.

Holt PG. Pulmonary dendritic cell populations. Adv Exp Med Biol. 1993; 329: 557-62. Review.

Saltini C, Kirby M, Trapnell BC, Tamura N, Crystal RG. Biased accumulation of T lymphocytes with "memory"-type CD45 leukocyte common antigen gene expression on the epithelial surface of the human lung. J Exp Med. 1990 Apr 1; 171 (4):1123-40.

van Haarst JM, Hoogsteden HC, de Wit HJ, Verhoeven GT, Havenith CE, Drexhage HA. Dendritic cells and their precursors isolated from human bronchoalveolar lavage: immunocytologic and functional properties. Am J Respir Cell Mol Biol. 1994 Sep; 11 (3): 344-50.

[page 66]

Lymphocytes play a significant role in lung disorders, e.g. sarcoidosis, asthma, and rejection after transplantation (for review see [1, 2]). [...] In contrast to the peripheral blood, mainly activated (CD4+, CD45Rlow and L-selectinlow) T-cells were found in the BAL of humans [4] and mice [5]. In humans only blood and BAL have been studied [6]. Since the lungs have no afferent lymphatics the blood is the starting point for lymphocyte immigration. Lymphocytes marginate to the lung vascular endothelium (marginal pool) and enter the interstitial lung tissue (interstitial pool), where the lymphocyte composition was different from blood and BAL when examined in healthy rats [7].

[page 69]

This immunological status is appropriate for such a vulnerable organ. The expression of adhesion molecules depends on the compartment from which the cells were extracted, leading to evidence that local activation and expression of adhesion molecules is induced by the microenvironment. Possible candidates for such activators are dendritic cells and macrophages or components of the extracellular matrix [21, 22].


1. Richeldi L, Franchi A, Rovatti E, Cossarizza A, duBois RM, Saltini C. Lymphocytes. In: Crystal RG, West JB, eds. The Lung. New York, Raven, 1996; pp. 803±820.

2. Berman JS, Beer DJ, Theodore AC, Kornfeld H, Bernardo J, Center DM. Lymphocyte recruitment to the lung. Am Rev Respir Dis 1990; 142: 238±257.

4. Saltini C, Kirby M, Trapnell BC, Tamura N, Crystal RG. Biased accumulation of T lymphocytes with "memory"- type CD45 leukocyte common antigen gene expression on the epithelial surface of the human lung. J Exp Med 1990; 171: 1123±1140.

5. Curtis JL, Kim S, Scott PJ, Buechner-Maxwell VA. Adhesion receptor phenotypes on murine lung CD4+ T cells during the pulmonary immune response to sheep erythrocytes. Am J Respir Cell Mol Biol 1995; 12: 520± 530.

6. Pabst R, Tschernig T. Lymphocytes in the lung: an often neglected cell. Anat Embryol 1995; 192: 293±299.

7. Fliegert F, Tschernig T, Pabst R. Comparison of lymphocyte subsets, monocytes, and NK cells in three different lung compartments and peripheral blood in the rat. Exp Lung Res 1996; 22: 677±690.

21. Holt PG. Regulation of antigen-presenting cell functions in lung and airway tissues. Eur Respir J 1993; 6: 120± 129.

22. van Haarst JMW, Hoogsteden HC, de Wit HJ, Verhoeven GT, Havenith CEG, Drexhage HA. Dendritic cells and their precursors isolated from human bronchoalveolar lavage: immunocytologic and functional properties. Am J Respir Cell Mol Biol 1994; 11: 344±350.

Anmerkungen

The source is not mentioned here.

Note, there are two publications "Holt, 1993" listed in the bibliography.

Sichter
(Hindemith) Schumann

[5.] Mag/Fragment 009 04 - Diskussion
Bearbeitet: 15. March 2014, 12:43 Graf Isolan
Erstellt: 5. March 2014, 07:10 (Hindemith)
BauernOpfer, Fragment, Gesichtet, Knight and Holgate 2003, Mag, SMWFragment, Schutzlevel sysop

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Quelle: Knight and Holgate 2003
Seite(n): 432, 433, Zeilen: 432: 12-13, last para - 433: l.col: 1ff
The epithelium constitutes the interface between the internal milieu and the external environment, and as such, it is the first point of contact for inhaled substances, in particular, respiratory viruses, airborne allergens, and environmental pollutants, as well as being a primary target for inhaled respiratory drugs (Folkerts et al., 1998; Gizycki et al., 1997).

At least eight morphologically distinct epithelial cell types are present in human respiratory epithelium, which can be classified in three different categories: basal, ciliated and secretory epithelial cells (Spina, 1998). Columnar ciliated epithelial cells are the predominant cell type within the airways, constituting more than 50% of all epithelial cells (Spina, 1998). The primary role of the ciliated apical surface is highlighted by the directional transport of mucus from the lung to the throat (Harkema et al., 1991). Mucus cells (goblet cells) are responsible for the control of the correct amount of mucus and the viscoelasticity of mucus for efficient mucociliary clearance by releasing acid mucins from their granules. These cells are thought to be capable of self-renewal and may also differentiate into ciliated epithelial cells (Evans et al., 1988; Harkema et al., 1991). Serous cells are also secreting cells and produce neutral mucin and a yet unidentified non-mucoid substance (Knight and Holgate, 2003). Basal cells are ubiquitous in the conducting epithelium, although the number of these cells decreases with airway size and the increasing thickness of the basal cell layer correlates with increasing size of the airway (Evans et al., 1988; Evans et al., 1990). Similar to the skin, the basal cell is thought to be the primary stem cell, giving rise to the mucus and ciliated epithelial cells. In smaller airways, where basal cells are sparse or absent, Clara cells perform the primary stem cell role.

In addition to their progenitor and structural roles, basal cells are also thought to secrete a number of bioactive molecules including neutral endopeptidase, 15-lipoxygenase products and cytokines (Knight and Holgate, 2003). In humans, Clara cells are located in large (bronchial) and small (bronchiolar) airways. The cells produce bronchiolar surfactant and are also characterized by agranular endoplasmic reticulum in the apical cytoplasm and granular endoplasmatic reticulum basally. In addition to their role in secretion, Clara cells are believed to metabolize xenobiotic [compounds by the action of p450 mono-oxygenases and may also produce specific antiproteases such as secretory leukocyte protease inhibitor (De Water et al., 1986).]


De Water R, Willems LN, Van Muijen GN, Franken C, Fransen JA, Dijkman JH, Kramps JA. Ultrastructural localization of bronchial antileukoprotease in central and peripheral human airways by a gold-labeling technique using monoclonal antibodies. Am Rev Respir Dis. 1986 May; 133 (5): 882-90.

Evans MJ, Plopper CG. The role of basal cells in adhesion of columnar epithelium to airway basement membrane. Am Rev Respir Dis. 1988 Aug; 138 (2): 481-3.

Evans MJ, Cox RA, Shami SG, Plopper CG. Junctional adhesion mechanisms in airway basal cells. Am J Respir Cell Mol Biol. 1990 Oct; 3 (4): 341-7.

Folkerts G, Nijkamp FP. Airway epithelium: more than just a barrier! Trends Pharmacol Sci. 1998 Aug; 19 (8): 334-41. Review.

Gizycki MJ, Adelroth E, Rogers AV, O'Byrne PM, Jeffery PK. Myofibroblast involvement in the allergen-induced late response in mild atopic asthma. Am J Respir Cell Mol Biol. 1997 Jun; 16 (6): 664-73.

Harkema JR, Hotchkiss JA. In vivo effects of endotoxin on nasal epithelial mucosubstances: quantitative histochemistry. Exp Lung Res. 1991 Jul-Aug; 17 (4): 743-61.

Knight DA, Holgate ST. The airway epithelium: structural and functional properties in health and disease. Respirology. 2003 Dec; 8 (4): 432-46. Review.

Spina D. Epithelium smooth muscle regulation and interactions. Am J Respir Crit Care Med. 1998 Nov; 158 (5Pt3): S141-5. Review.

[page 432]

However, it constitutes the interface between the internal milieu and the external environment as well as being a primary target for inhaled respiratory drugs. [...]

[...]

At least eight morphologically distinct epithelial cell types are present in human respiratory epithelium, although based on ultrastructural, functional and biochemical criteria these may be classified into three

[page 433]

categories: basal, ciliated and secretory.1 [...]

Columnar ciliated epithelial cells

Ciliated epithelial cells are the predominant cell type within the airways, accounting for over 50% of all epithelial cells.1 [...] Typically, ciliated epithelial cells possess up to 300 cilia/cell and numerous mitochondria immediately beneath the apical surface, highlighting the primary role of these cells, namely the directional transport of mucus from the lung to the throat.3

Mucous cells (goblet cells)

[...] Production of the correct amount of mucus and the viscoelasticity of mucus are important for efficient mucociliary clearance. [...] These cells are thought to be capable of self-renewal and may also differentiate into ciliated epithelial cells.7

Serous cells

[...] The chemical composition of the granules has not been extensively characterized, although the same cell-type in rat airways contains neutral mucin and an unidentified non-mucoid substance.

Basal cells

Basal cells are ubiquitous in the conducting epithelium, although the number of these cells decreases with airway size.7,9 There is a direct correlation between the thickness of the epithelium and the number of basal cells as well as the percentage of columnar cell attachment to the basement membrane via the basal cell. [...]

Similar to the skin, the basal cell is thought to be the primary stem cell, giving rise to the mucous and ciliated epithelial cells. [...] In smaller airways, where basal cells are sparse or absent, Clara cells perform the primary stem cell role.

In addition to their progenitor and structural roles, basal cells are also thought to secrete a number of bioactive molecules including neutral endopeptidase, 15-lipoxygenase products and cytokines.

Clara cells

In humans, Clara cells are located in large (bronchial) and small (bronchiolar) airways. The cells contain electron-dense granules, thought to produce bronchiolar surfactant and are also characterized by agranular endoplasmic reticulum in the apical cytoplasm and granular endoplasmic reticulum basally. In addition to their secretory role, Clara cells are believed to metabolize xenobiotic compounds by the action of p450 mono-oxygenases and may also produce specific antiproteases such as secretory leukocyte protease inhibitor.13


1 Spina D. Epithelium smooth muscle regulation and interactions. Am. J. Respir. Crit. Care Med. 1998; 158: S141–5.

3 Harkema JR, Mariassy A, St. George J, Hyde DM, Plopper CG. Epithelial cells of the conducting airways: a species comparison. In: Farmer SG, Hay DWP (eds). The Airway Epithelium: Physiology, Pathophysiology and Pharmacology. Marcel-Dekker, New York, 1991; 3–39.

7 Evans MJ, Plopper CG. The role of basal cells in adhesion of columnar epithelium to airway basement membrane. Am. Rev. Respir. Dis. 1988; 138: 481–3.

9 Evans MJ, Cox RA, Shami SG, Plopper CG. Junctional adhesion mechanisms in airway basal cells. Am. J. Respir. Cell. Mol. Biol. 1990; 3: 341–7.

13 De Water R, Willems LN, Van Muijen GN et al. Ultrastructural localization of bronchial antileukoprotease in central and peripheral human airways by a goldlabeling technique using monoclonal antibodies. Am. Rev. Respir. Dis. 1986; 133: 882–90.

Anmerkungen

The source is mentioned twice: once for the statement "Serous cells are also secreting cells and produce neutral mucin and a yet unidentified non-mucoid substance" and once for the statement "In addition to their progenitor and structural roles, basal cells are also thought to secrete a number of bioactive molecules including neutral endopeptidase, 15-lipoxygenase products and cytokines", but not for the rest of the page, which is a shortened and slightly adapted copy of the source, including references to the literature.

Sichter
(Hindemith) Schumann

[6.] Mag/Fragment 010 01 - Diskussion
Bearbeitet: 10. March 2014, 18:11 Graf Isolan
Erstellt: 5. March 2014, 07:57 (Hindemith)
BauernOpfer, Fragment, Gesichtet, Knight and Holgate 2003, Mag, SMWFragment, Schutzlevel sysop

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[In addition to their role in secretion, Clara cells are believed to metabolize xenobiotic] compounds by the action of p450 mono-oxygenases and may also produce specific antiproteases such as secretory leukocyte protease inhibitor (De Water et al., 1986). More recent evidence suggests that these cells play important role for stem cells, serving as a progenitor for both ciliated and mucus secreting cells (Hong et al., 2001).

The major function of the respiratory epithelium was once thought to be primarily that of a physical barrier, but recent studies clearly indicate that it is metabolically very active with the capacity to modulate a variety of inflammatory processes through the agency of an array of receptor-mediated events. On activation, it has the capacity to produce a number of proinflammatory cytokines, proinflammatory or regulatory mediators including arachidonic acid products, nitric oxide, endothelin-1, transforming growth factor (TGF)-ß, tumour necrosis factor (TNF)-α, and cytokines such as interleukin (IL)-1, IL-6 and IL-8 (Knight and Holgate, 2003).


De Water R, Willems LN, Van Muijen GN, Franken C, Fransen JA, Dijkman JH, Kramps JA. Ultrastructural localization of bronchial antileukoprotease in central and peripheral human airways by a gold-labeling technique using monoclonal antibodies. Am Rev Respir Dis. 1986 May; 133 (5): 882-90.

Hong KU, Reynolds SD, Giangreco A, Hurley CM, Stripp BR. Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion. Am J Respir Cell Mol Biol. 2001 Jun; 24 (6): 671-81.

Knight DA, Holgate ST. The airway epithelium: structural and functional properties in health and disease. Respirology. 2003 Dec; 8 (4): 432-46. Review.

[page 433]

In addition to their secretory role, Clara cells are believed to metabolize xenobiotic compounds by the action of p450 mono-oxygenases and may also produce specific antiproteases such as secretory leukocyte protease inhibitor.13 More recent evidence suggests that these cells play an important stem cell role, serving as a progenitor for both ciliated and mucus-secreting cells.14

[page 440]

The major function of the respiratory epithelium was once thought to be primarily that of a physical barrier, but recent studies clearly indicate that it is metabolically very active with the capacity to modulate a variety of inflammatory processes through the agency of an array of receptor-mediated events. On activation, it has the capacity to produce a number of pro-

[page 441]

inflammatory cytokines, pro-inflammatory or regulatory mediators including arachidonic acid products, nitric oxide, endothelin-1, TGF-β, TNFα, and cytokines such as IL-1, IL-6 and IL-8.


13 De Water R, Willems LN, Van Muijen GN et al. Ultrastructural localization of bronchial antileukoprotease in central and peripheral human airways by a goldlabeling technique using monoclonal antibodies. Am. Rev. Respir. Dis. 1986; 133: 882–90.

14 Hong KU, Reynolds SD, Giangreco A, Hurley CM, Stripp BR. Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion. Am. J. Respir. Cell Mol. Biol. 2001; 24: 671–81.

Anmerkungen

The source is given, but the reference to it does not indicate the extent of the borrowed text (which starts on the previous page), neither does it become clear that in large parts the source is cited literally.

Sichter
(Hindemith) Schumann

[7.] Mag/Fragment 011 02 - Diskussion
Bearbeitet: 10. March 2014, 12:03 Graf Isolan
Erstellt: 4. March 2014, 20:39 (Hindemith)
Chen et al 2004, Fragment, Gesichtet, Mag, SMWFragment, Schutzlevel sysop, Verschleierung

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Alveoli are the gas exchange units of the lung and the alveolar epithelium adapts to this functional role by developing two highly specialized alveolar epithelial cell types, which are morphologically and functionally different.[...] AECII consist of about 15% of the distal lung cells and occupy 5% of the alveolar surface (Crapo et al., 1978; Crapo et al., 1982; Haies et al., 1981). [...] AECII synthesize and secrete lung surfactant, a protein-lipid complex and surface-active material. Lung surfactant stabilizes alveoli by reducing the surface tension. [...] AECII also maintain the alveolar epithelium by cell proliferation and differentiation, minimize alveolar fluid by transport of sodium from the apical to the basolateral side, and alter the inflammatory process by secretion of growth factors and cytokines.

In contrast to AECII, AECI contribute 7% of total lung cells and cover more than 95% of the alveolar surface. This thin epithelium allows the easy diffusion of gases and forms a barrier against the indiscriminate leakage of fluid into alveolar spaces. It also regulates the exchange of physiologically important solutes and water between circulating blood and the alveolar space.

Alveoli are the gas exchange units of the lung. The alveolar epithelium adapts to this functional role by developing two highly specialized alveolar epithelial cells, cuboidal type II (AEC II) and squamous type I (AEC I). AEC II consist of about 15% of the distal lung cells and occupy 5% of the alveolar surface. AEC II synthesize and secrete lung surfactant, a protein-lipid complex and surface-active material. Lung surfactant stabilizes alveoli by reducing the surface tension. AEC II also maintain the alveolar epithelium by cell proliferation and differentiation, minimize alveolar fluid by transport of sodium from the apical to the basolateral side, and alter the inflammatory process by the secretion of growth factors and cytokines. [...]

AEC I contribute 7% of total lung cells and cover over 95% of the alveolar surface. This thin epithelium allows the easy diffusion of gases and forms a barrier against the indiscriminate leakage of fluid into alveolar spaces. It also regulates the exchange of physiologically important solutes and water between circulating blood and the alveolar space.

Anmerkungen

The source text has been taken without any attribution and enhanced with some additional detail (not documented and shown with "[...]").

Sichter
(Hindemith) Schumann

[8.] Mag/Fragment 012 01 - Diskussion
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The alveolar epithelium can be classified as a continuously renewing tissue since it comprises a population of alveolar type II epithelial cells that are characterized by almost unlimited potential to proliferate. It is still a matter of debate whether all AECII or only a small population act as the alveolar epithelial stem cell population (Uhal, 1997). The concept of AECII as stem cells of the adult alveolar epithelium was proposed by Kapanci and colleagues, and is widely accepted today (Kapanci et al., 1969). During ontogenesis, the AECII may derive from precursor cell common to AECII and Clara cells (Wuenschell et al., 1996). Furthermore AECII proliferate and differentiate to AECI to repair the damaged alveolar epithelium after lung injury or during fetal lung development, thus contributing to epithelial repair, whereas AECI are terminally differentiated, lack mitotic activity, and are easily injured. The programmed cell death or apoptosis is an important mechanism of cell removal or renewing of tissue. AECII are known to express the membrane receptor Fas (CD95, APO-1), the ligation of which may initiate the apoptotic cascade (Fine et al., 1997). This can be achieved by binding of Fas-ligand or the Fas-stimulating antibodies. There is some evidence that apoptosis of AECII is an integral mechanism of alveolar septal modelling in lung morphogenesis (Scavo et al., 1998; Schittny et al., 1998). Notably, apoptotic AECII appeared to be removed not only by alveolar macrophages but also by AECII cell neighbours (Fehrenbach et al., 2001).

Fehrenbach H. Alveolar epithelial type II cell: defender of the alveolus revisited. Respir Res. 2001; 2 (1): 33-46. Epub 2001 Jan 15. Review.

Fine A, Anderson NL, Rothstein TL, Williams MC, Gochuico BR. Fas expression in pulmonary alveolar type II cells. Am J Physiol. 1997 Jul; 273 (1Pt1): L64-71.

Kapanci Y, Weibel ER, Kaplan HP, Robinson FR. Pathogenesis and reversibility of the pulmonary lesions of oxygen toxicity in monkeys. II. Ultrastructural and morphometric studies. Lab Invest. 1969 Jan; 20 (1): 101-18.

Scavo LM, Ertsey R, Chapin CJ, Allen L, Kitterman JA. Apoptosis in the development of rat and human fetal lungs.Am J Respir Cell Mol Biol. 1998 Jan; 18 (1): 21-31.

Schittny JC, Djonov V, Fine A, Burri PH. Programmed cell death contributes to postnatal lung development. Am J Respir Cell Mol Biol. 1998 Jun; 18 (6): 786-93.

Uhal BD. Cell cycle kinetics in the alveolar epithelium. Am J Physiol. 1997 Jun; 272 (6Pt1): L1031-45. Review.

Wuenschell CW, Sunday ME, Singh G, Minoo P, Slavkin HC, Warburton D. Embryonic mouse lung epithelial progenitor cells co-express immunohistochemical markers of diverse mature cell lineages. J Histochem Cytochem. 1996 Feb; 44 (2): 113-23.

[page 33, Abstract]

AE2 cells proliferate, differentiate into AE1 cells, and remove apoptotic AE2 cells by phagocytosis, thus contributing to epithelial repair.

[page 38]

The alveolar epithelium can be classified as a continuously renewing tissue since it comprises a population of cells

[page 39]

(AE2) that are characterised by the almost unlimited potential to proliferate. [...] It is still a matter of debate whether all AE2 cells or only a subpopulation act as the alveolar epithelial stem cell population (for review, see [103]).

[...]

The concept of the AE2 cell as a stem cell of the adult alveolar epithelium was proposed by Kapanci and coworkers [108], and is widely accepted today (for review, see [103]). During ontogenesis, the AE2 cell may derive from a precursor cell common to AE2 and Clara cells [109].

[page 40]

One important mechanism of cell removal that was recognised almost a century ago [129] is programmed cell death or apoptosis [130]. [...] AE2 cells are known to express the membrane receptor Fas (CD95, APO-1), ligation of which may initiate the apoptotic cascade [134]. This can be achieved by binding of Fasligand or the Fas-stimulating antibodies. There is some evidence that apoptosis of AE2 cells is an integral mechanism of alveolar septal modelling in lung morphogenesis [135,136].

[...]

Notably, apoptotic AE2 cells (Fig. 6) appeared to be removed not only by alveolar macrophages but also by AE2 cell neighbours [138].


103. Uhal BD: Cell cycle kinetics in the alveolar epithelium. Am J Physiol 1997, 272:L1031–1045.

108. Kapanci Y, Weibel ER, Kaplan HP, Robinson FR: Pathogenesis and reversibility of the pulmonary lesions of oxygen toxicity in monkeys. II. Ultrastructural and morphometric studies. Lab Invest 1969, 20:101–117.

109. Wuenschell CW, Sunday ME, Singh G, Minoo P, Slavkin HC, Warburton D: Embryonic mouse lung epithelial progenitor cells coexpress immunohistochemical markers of diverse mature cell lineages. J Histochem Cytochem 1996, 44:113–123.

129. Gräper L: A new point of view regarding the physiological elimination of cells [in German]. Arch Zellforsch 1914, 12:373–394.

130. Rich T, Watson CJ, Wyllie A: Apoptosis: the germs of death. Nat Cell Biol 1999, 1:E69–71.

134. Fine A, Anderson NL, Rothstein TL, Williams MC, Gochuico BR: Fas expression in pulmonary alveolar type II cells. Am J Physiol 1997, 273:L64–71.

135. Scavo LM, Ertsey R, Chapin CJ, Allen L, Kitterman JA: Apoptosis in the development of rat and human fetal lungs. Am J Respir Cell Mol Biol 1998, 18:21–31.

136. Schittny JC, Djonov V, Fine A, Burri PH: Programmed cell death contributes to postnatal lung development. Am J Respir Cell Mol Biol 1998, 18:786–793.

138. Fehrenbach H, Kasper M, Koslowski R, Tan P, Schuh D, Müller M, Mason RJ: Alveolar epithelial type II cell apoptosis in vivo during resolution of keratinocyte growth factor-induced hyperplasia in the rat. Histochem Cell Biol 2000, 114:49–61.

Anmerkungen

On the last line the author gives "Fehrenbach et al., 2001" for the statement "Notably, apoptotic AECII appeared to be removed not only by alveolar macrophages but also by AECII cell neighbours". The author might either mean Fehrenbach et al. (2000), which is the reference for this statement in the source, or he means Fehrenbach (2001), which is the only publication with Fehrenbach as first author listed in the bibliography. In either case, it does not become clear to the reader that the whole passage is adapted from the source.

Sichter
(Hindemith), WiseWoman

[9.] Mag/Fragment 013 17 - Diskussion
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The best example for a cell-cell interaction between AECII and resident cells is the direct contact with AECI and during proliferation with AECII neighbours as well. These lateral cell-cell contacts within the alveolar epithelium are maintained by cell junction complex that includes gap junctions (Kasper et al, 1996). Additionally, AECII [have direct contact to fibroblasts at the basal membrane or with capillary endothelial cells (Marin et al., 1982).]

Kasper M, Traub O, Reimann T, Bjermer L, Grossmann H, Muller M, Wenzel KW Upregulation of gap junction protein connexin43 in alveolar epithelial cells of rats with radiation-induced pulmonary fibrosis. Histochem Cell Biol. 1996 Oct; 106 (4): 419-24.

Marin L, Dameron F, Relier JP. Changes in the cellular environment of differentiating type II pneumocytes. Quantitative study in the perinatal rat lung. Biol Neonate. 1982; 41 (3-4): 172-82.

Interaction with resident cells

First of all, the AE2 cell is in direct contact with AE1 cells and during proliferation with AE2 cell neighbours as well. These lateral cell-cell contacts within the alveolar epithelium are maintained by a cell junction complex that includes gap junctions [142]. The basal cell membrane is in close proximity to fibroblasts, in particular during the canalicular phase of lung morphogenesis, while modelling of the alveolar septum results in an increase in the spatial relationship of the AE2 cells with capillary endothelial cells of the adult lung [143].


142. Kasper M, Traub O, Reimann T, Bjermer L, Grossmann H, Müller M, Wenzel KW: Upregulation of gap junction protein connexin43 in alveolar epithelial cells of rats with radiationinduced pulmonary fibrosis. Histochem Cell Biol 1996, 106: 419–424.

143. Marin L, Dameron F, Relier JP: Changes in the cellular environment of differentiating type II pneumocytes. Quantitative study in the perinatal rat lung. Biol Neonate 1982, 41:172–182.

Anmerkungen

Following one reference to Fehrenbach for having termed type II epithelial cells "as integrative units of the alveolus", the author adopts over pp. 13-16 an uninterrupted review of some 30 articles from Fehrenbach without indicating this source.

Sichter
Hindemith

[10.] Mag/Fragment 014 01 - Diskussion
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[Additionally, AECII9] have direct contact to fibroblasts at the basal membrane or with capillary endothelial cells (Marin et al., 1982).

A strong evidence for a direct interaction of AECI and AECII was presented by Ashino and colleagues (Ashino et al., 2000). Mechanical stimulation of AECI is thought to result in Ca2+-oscillations, which were transmitted via intraepithelial gap junctions to AECII and modulate exocytosis rate of lamellar bodies. Direct inhibitory interactions between AECI and AECII have been postulated to suppress AECII proliferation. Loss of AECI during injury might then trigger the release of AECII from growth inhibition (Mason and McCormack, 1994). E-cadherin as a further candidate to mediate contact inhibition, has been localized to the basolateral membrane of AECII (Kasper et al., 1995; St. Croix et al., 1998).

But even an indirect cell-cell interaction for AECII to other AECII is possible by the negative feedback loop by which surfactant protein A (SP-A) upon release into the alveolar space inhibits surfactant exocytosis in vitro (Dobbs et al., 1987). Although AECII are equipped with membrane receptors for SP-A (Strayer et al., 1996), the in vivo relevance of this autocrine mechanism by which AECII may regulate their own action remains elusive, because mice that are deficient in SP-A did not show any defect in surfactant secretion nor any respiratory deficiency (Ikegami et al., 1998). Thus, some alternative mechanism must compensate the negative SP-A feedback loop. Another potential feedback mechanism that has been postulated is the inhibition of AECII proliferation via AECII derived transforming growth factor (TGF)-β in bleomycin-induced experimental lung fibrosis (Khali et al., 1994). A number of growth factors are released by AECII, which might act in an autocrine way via the corresponding receptors expressed by AECII.

As mentioned before, fibroblasts are in contact to AECII. This reciprocal cell-cell interaction is relevant to the modelling of alveolus during lung morphogenesis as well as during remodelling associated with alveolar repair following lung injury (Kasper et al., 1996; O´Reilly et al., 1997; Shannon, et al., 1997). Both direct and indirect cell-cell interactions have been reported.


Dobbs LG, Wright JR, Hawgood S, Gonzalez R, Venstrom K, Nellenbogen J. Pulmonary surfactant and its components inhibit secretion of phosphatidylcholine from cultured rat alveolar type II cells. Proc Natl Acad Sci U S A. 1987 Feb; 84 (4): 1010-4.

Ikegami M, Korfhagen TR, Whitsett JA, Bruno MD, Wert SE, Wada K, Jobe AH. Characteristics of surfactant from SP-A-deficient mice. Am J Physiol. 1998 Aug; 275 (2Pt1): L247-54.

Kasper M, Traub O, Reimann T, Bjermer L, Grossmann H, Muller M, Wenzel KW Upregulation of gap junction protein connexin43 in alveolar epithelial cells of rats with radiation-induced pulmonary fibrosis. Histochem Cell Biol. 1996 Oct; 106 (4): 419-24.

Kasper M, Huber O, Grossmann H, Rudolph B, Trankner C, Muller M. Immunocytochemical distribution of E-cadherin in normal and injured lung tissue of the rat. Histochem Cell Biol. 1995 Nov; 104 (5): 383-90.

Khalil N, O'Connor RN, Flanders KC, Shing W, Whitman CI. Regulation of type II alveolar epithelial cell proliferation by TGF-beta during bleomycin-induced lung injury in rats. Am J Physiol. 1994 Nov; 267 (5Pt1): L498-507.

Marin L, Dameron F, Relier JP. Changes in the cellular environment of differentiating type II pneumocytes. Quantitative study in the perinatal rat lung. Biol Neonate. 1982; 41 (3-4): 172-82.

Mason RJ, McCormack FX. Alveolar type II cell reactions in pathogenic states. In Lung surfactant:Basic research in the pathogenesis of lung disorders. Edited by Müller B, von WichertP. Basel; Karger, 1994: 194-204.

O'Reilly MA, Stripp BR, Pryhuber GS. Epithelial-mesenchymal interactions in the alteration of gene expression and morphology following lung injury. Microsc Res Tech. 1997 Sep 1; 38 (5): 473-9. Review.

Shannon JM, Deterding RR Epithelial-mesenchymal interactions in lung development. In Lung growth and development. Edited by Mc Donald JA. New York; Marcel Dekker, Inc., 1997: 81-118.

St Croix B, Sheehan C, Rak JW, Florenes VA, Slingerland JM, Kerbel RS. E-Cadherin-dependent growth suppression is mediated by the cyclin-dependent kinase inhibitor p27(KIP1). J Cell Biol. 1998 Jul 27; 142 (2): 557-71.

Strayer DS, Pinder R, Chander A. Receptor-mediated regulation of pulmonary surfactant secretion. Exp Cell Res. 1996 Jul 10; 226 (1): 90-7.

The basal cell membrane is in close proximity to fibroblasts, in particular during the canalicular phase of lung morphogenesis, while modelling of the alveolar septum results in an increase in the spatial relationship of the AE2 cells with capillary endothelial cells of the adult lung [143].

The in situ study of Ashino and co-workers [64] presented strong evidence of a direct interaction of AE1 and AE2 cells. Mechanical stimulation of AE1 cells is thought to result in [Ca2+]i-oscillations (see above), which are transmitted via interepithelial gap junctions to AE2 cells and modulate exocytosis rate of lamellar bodies [64]. Direct inhibitory interactions between AE1 and AE2 cells have been postulated to suppress AE2 cell proliferation [144].

Loss of AE1 cells during lung injury might then be the trigger to release AE2 cells from growth inhibition. Although E-cadherin, a candidate mediator of contact inhibition [145], has been localised to the basolateral membrane of adult human AE2 cells [146], experimental evidence for contact inhibition of AE2 cell proliferation by AE1 cells still remains to be presented.

The most intensely studied example of an indirect AE2–AE2 cell interaction is probably the negative feedback loop by which SP-A, released into the alveolar space, inhibits surfactant exocytosis in vitro [69]. Although AE2 cells are equipped with membrane receptors for SPA [70], the in vivo relevance of this autocrine mechanism by which AE2 cells may regulate their own action is still not convincing (as pointed out recently [52]). Since mice that are deficient for SP-A did not show any defect in surfactant secretion nor any respiratory deficiency [147], there must be some alternative mechanism compensating for the loss of a SP-A feedback loop, if present at all.

Another potential feedback mechanism that has been postulated is the inhibition of AE2 cell proliferation via AE2-cell-derived transforming growth factor (TGF)-b in bleomycin-induced experimental lung fibrosis [148]. A number of growth factors are released by AE2 cells, which might act in an autocrine way via the corresponding receptors expressed by AE2 cells (see Supplementary Table 2).

Fibroblasts

The interaction of AE2 cells with fibroblasts is probably the best studied reciprocal cell-cell relationship which is relevant to the modelling of alveoles during lung morphogenesis (for review see, eg, [149]) as well as during remodelling associated with alveolar repair following lung injury (for review see, eg, [123,150]). Both direct and indirect cell-cell interactions have been reported, in most instances from studies of cells grown in culture.


143. Marin L, Dameron F, Relier JP: Changes in the cellular environment of differentiating type II pneumocytes. Quantitative study in the perinatal rat lung. Biol Neonate 1982, 41:172–182.

64. Ashino Y, Ying X, Dobbs LG, Bhattacharya J: [Ca2+]i oscillations regulate type II cell exocytosis in the pulmonary alveolus. Am J Physiol Lung Cell Mol Physiol 2000, 279:L5–13.

144. Mason RJ, McCormack FX: Alveolar type II cell reactions in pathologic states. In Lung surfactant: Basic research in the pathogenesis of lung disorders. Edited by Müller B, von Wichert P. Basel; Karger, 1994:194–204.

145. St. Croix B, Sheehan C, Rak JW, Florenes VA, Slingerland JM, Kerbel RS: E-Cadherin-dependent growth suppression is mediated by the cyclin-dependent kinase inhibitor p27(KIP1). J Cell Biol 1998, 142:557–571.

146. Kasper M, Behrens J, Schuh D, Müller M: Distribution of E-cadherin and Ep-CAM in the human lung during development and after injury. Histochem Cell Biol 1995, 103:281–286.

69. Dobbs LG, Wright JR, Hawgood S, Gonzalez R, Venstrom K, Nellenbogen J: Pulmonary surfactant and its components inhibit secretion of phosphatidylcholine from cultured rat alveolar type II cells. Proc Natl Acad Sci U S A 1987, 84:1010–1014.

70. Strayer DS, Pinder R, Chander A: Receptor-mediated regulation of pulmonary surfactant secretion. Exp Cell Res 1996, 226:90–97.

52. Rooney SA: Regulation of surfactant secretion. In Lung surfactant: cellular and molecular processing. Edited by Rooney SA. Austin, Texas; RG Landes Company, 1998:139–163.

123. Kasper M, Haroske G: Alterations in the alveolar epithelium after injury leading to pulmonary fibrosis. Histol Histopathol 1996, 11:463–483.

150. O’Reilly MA, Stripp BR, Pryhuber GS: Epithelial-mesenchymal interactions in the alteration of gene expression and morphology following lung injury. Microsc Res Tech 1997, 38:473–479.

147. Ikegami M, Korfhagen TR, Whitsett JA, Bruno MD, Wert SE, Wada K, Jobe AH: Characteristics of surfactant from SP-Adeficient mice. Am J Physiol 1998, 275:L247–254.

148. Khalil N, O’Connor RN, Flanders KC, Shing W, Whitman CI: Regulation of type II alveolar epithelial cell proliferation by TGFbeta during bleomycin-induced lung injury in rats. Am J Physiol 1994, 267:L498–507.

149. Shannon JM, Deterding RR: Epithelial-mesenchymal interactions in lung development. In Lung growth and development. Edited by McDonald JA. New York; Marcel Dekker, Inc., 1997: 81–118.

Anmerkungen

In pp. 13-16, the author adopts an uninterrupted review of some 30 articles from Fehrenbach without indicating this source.

Sichter
Hindemith

[11.] Mag/Fragment 015 01 - Diskussion
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The interaction of alveolar epithelial and capillary endothelial cells is well examined. It was reported that from pulmonary endothelial cells conditioned medium stimulate fetal lung epithelial cell growth (Smith et al., 1986) and that endothelin-1 increases AECII surfactant secretion in vitro via a protein kinase C and Ca2+-mediated pathway (Sen et al., 1994). As a source of endothelin-1, endothelial cells are therefore principally competent to act in a paracrine manner on AECII, which were reported to express the endothelin receptor A (Markewitz et al., 1995). Furthermore, alveolar type II epithelial cells themselves may synthesize endothelin-1 and stimulate endogenous prostaglandin E2 synthesis in an autocrine fashion (Markewitz et al., 1995).

Recently, a very special mechanism of indirect intercellular communication between AECII and endothelial cells has been suggested. Stimulation of alveolar epithelial cells with tumour necrosis (TNF)-α was reported to increase epithelial Ca2+ influx and to activate epithelial cytoplasmic phospholipase A2, and results in basolateral release of arachidonic acid. Free arachidonic acid is thought to increase endothelial Ca2+ influx and expression of P-selectin (Kuebler et al., 2000), which is known to be crucial for initiation of leukocyte adherence. Thus, AECII could act as transducers of an inflammatory signal from the alveolus to the capillary bed to recruit granulocytes to the site of inflammation.

Alveolar macrophages are one of the mobile cell types that interact with AECII. Among the multitude of secretory products synthesized and released by alveolar macrophages (Kasper et al., 1996; Lohmann-Matthes et al., 1994) there are some factors that act as mitogens for AECII, such as hepatocyte growth factor (Mason et al., 1994) and heparin-binding epidermal growth factor (Leslie et al., 1997). Conversely, AECII were shown to express the chemokines RANTES and MCP-1, which chemotactically attract macrophages (O´Brien et al., 1998), as well as GM-CSF (Blau et al., 1994; Christensen et al., 1995), which in turn may stimulate macrophage growth (Worgall et al., 1999). Furthermore, SP-A released from AECII modulate macrophage functions such as oxygen radical release (Weissbach et al. 1994) and nitric oxide production (Stamme et al., 2000).

Interactions of AECII with leukocytes have just recently come into focus. AECII synthesize some cytokines affecting leukocytes, such as interleukin (IL)-6 or IL-8.

Little is known about the interaction of alveolar epithelial and capillary endothelial cells. Pulmonary endothelial cell conditioned medium was reported to stimulate foetal lung epithelial cell growth [156]. [...]

Endothelin-1 was observed to increase AE2 cell surfactant secretion in vitro via a protein kinase C and Ca2+-mediated pathway [158]. As a source of endothelin-1, endothelial cells are therefore principally competent to act in a paracrine manner on AE2 epithelial cells, which were reported to express the endothelin receptor A [159]. One has to take into account that AE2 cells themselves may synthesise endothelin-1 and stimulate endogenous prostaglandin E2 synthesis in an autocrine fashion [159].

Recently, a very special mechanism of indirect intercellular communication between AE2 cells and endothelial cells has been suggested based on in situ fluorescence imaging studies in alveoli of isolated perfused lungs [160]. Stimulation of alveolar epithelial cells with tumour necrosis factor (TNF)-a was reported to increase epithelial [Ca2+]; and to activate epithelial cytoplasmic phospholipase A2, and results in basolateral release of arachidonic acid. Free arachidonic acid is thought to increase endothelial [Ca2+]; and expression of P-selectin [160], which is known to be crucial for initiation of leukocyte adherence. Thus, AE2 cells may act as transducers of an inflammatory signal from the alveolus to the capillary bed to recruit granulocytes to the site of inflammation.

Interaction with mobile cells

Alveolar macrophages

Among the multitude of secretory products synthesised and released by alveolar macrophages (for reviews, see [123,161]) there are some factors that act as mitogens for AE2 cells, such as hepatocyte growth factor [162] and heparin-binding epidermal growth factor-like protein [163]. Conversely, AE2 cells were shown to express the chemokines RANTES and MCP-1, which chemotactically attract macrophages [164], as well as GM-CSF [165,166], which in turn may stimulate macrophage growth [167]. Furthermore, SP-A released from AE2 cells may modulate macrophage functions such as, oxygen radical release [168], and nitric oxide production [169]. One has to take into account, however, that there may be species-specific differences [162,163].

Leukocytes

Interactions of AE2 cells with leukocytes have just come into focus. AE2 cells may synthesise some cytokines affecting leukocytes, such as interleukin (IL)-6 or IL-8 (see Supplementary Table 2).


156. Smith SK, Giannopoulos G: Influence of pulmonary endothelial cells on fetal lung development. Pediatr Pulmonol 1985, 1: S53–S59.

158. Sen N, Grunstein MM, Chander A: Stimulation of lung surfactant secretion by endothelin-1 from rat alveolar type II cells. Am J Physiol 1994, 266:L255–262.

159. Markewitz BA, Kohan DE, Michael JR: Endothelin-1 synthesis, receptors, and signal transduction in alveolar epithelium: evidence for an autocrine role. Am J Physiol 1995, 268:L192–200.

160. Kuebler WM, Parthasarathi K, Wang PM, Bhattacharya J: A novel signalling mechanism between gas and blood compartments of the lung. J Clin Invest 2000, 105:905–913.

123. Kasper M, Haroske G: Alterations in the alveolar epithelium after injury leading to pulmonary fibrosis. Histol Histopathol 1996, 11:463–483.

161. Lohmann-Matthes ML, Steinmuller C, Franke-Ullmann G: Pulmonary macrophages. Eur Respir J 1994, 7:1678–1689.

162. Mason RJ, Leslie CC, McCormick-Shannon K, Deterding RR, Nakamura T, Rubin JS, Shannon JM: Hepatocyte growth factor is a growth factor for rat alveolar type II cells. Am J Respir Cell Mol Biol 1994, 11:561–567.

163. Leslie CC, McCormick-Shannon K, Shannon JM, Garrick B, Damm D, Abraham JA, Mason RJ: Heparin-binding EGF-like growth factor is a mitogen for rat alveolar type II cells. Am J Respir Cell Mol Biol 1997, 16:379–387.

164. O’Brien AD, Standiford TJ, Christensen PJ, Wilcoxen SE, Paine R, 3rd: Chemotaxis of alveolar macrophages in response to signals derived from alveolar epithelial cells. J Lab Clin Med 1998, 131:417–424.

165. Blau H, Riklis S, Kravtsov V, Kalina M: Secretion of cytokines by rat alveolar epithelial cells: possible regulatory role for SP-A. Am J Physiol 1994, 266:L148–155.

166. Christensen PJ, Armstrong LR, Fak JJ, Chen GH, McDonald RA, Toews GB, Paine R III: Regulation of rat pulmonary dendritic cell immunostimulatory activity by alveolar epithelial cellderived granulocyte macrophage colony- stimulating factor. Am J Respir Cell Mol Biol 1995, 13:426–433.

167. Worgall S, Singh R, Leopold PL, Kaner RJ, Hackett NR, Topf N, Moore MA, Crystal RG: Selective expansion of alveolar macrophages in vivo by adenovirus-mediated transfer of the murine granulocyte-macrophage colony-stimulating factor cDNA. Blood 1999, 93:655–666.

168. Weissbach S, Neuendank A, Pettersson M, Schaberg T, Pison U: Surfactant protein A modulates release of reactive oxygen species from alveolar macrophages. Am J Physiol 1994, 267: L660–666.

169. Stamme C, Walsh E, Wright JR: Surfactant protein A differentially regulates IFN-g- and LPS-induced nitrite production by rat alveolar macrophages. Am J Respir Cell Mol Biol 2000, 23: 772–779.

Anmerkungen

The author adopts on pp. 13-16 an uninterrupted review of some 30 articles from Fehrenbach without indicating this source. Continued from Fragment_014_01.

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[Via] these cytokines, AECII might be involved in the induction of differentiation of basophil, eosinphil, and neutrophil granulocytes and maintenance of inflammatory reactions. Recent data support the idea that AECII have an accessory function in T lymphocyte activation (Zissel et al., 2000). This has been suggested on the basis of the findings that the cells bear MHC class-II molecules (Schneeberger et al., 1986). Via these cytokines, AE2 cells might be involved in the induction of differentiation of basophil, eosinophil, and neutrophil granulocytes and maintenance of inflammatory reactions. Recent data support the idea that AE2 cells have an accessory function in T-lymphocyte activation [170]. This has been suggested on the basis of the finding that the cells bear receptors of MHC class II [171].

170. Zissel G, Ernst M, Rabe K, Papadopoulos T, Magnussen H, Schlaak M, Müller-Quernheim J: Human alveolar epithelial cells type II are capable of regulating T-cell activity. J Investig Med 2000, 48:66–75.

171. Schneeberger EE, DeFerrari M, Skoskiewicz MJ, Russell PS, Colvin RB: Induction of MHC-determined antigens in the lung by interferon-gamma. Lab Invest 1986, 55:138–144.

Anmerkungen

The author adopts on pp. 13-16 an uninterrupted review of some 30 articles from Fehrenbach without indicating this source. This is the final part.

After a short interruption, in which the author expands on Zissel and introduces a post-Fehrenbach (2005) article, the author continues to adopt two smaller text passages from Fehrenbach without indicating this source, ending on p. 17 line 7.

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Additionally, AECII were reported to inhibit lymphocyte proliferation in vitro without altering their activation state (Paine et al., 1991). Moreover, AECII derived TGF-β (Zissel et al., 2000) could indirectly inhibit T cell proliferation via blockade of activating factors, such as IL-2. In contrast, granulocyte macrophage-colony stimulating factor (GM-CSF) released at the basolateral surface of AECII could increase the potential of dendritic cells to induce T-cell proliferation (Christensen et al., 1995).

Christensen PJ, Armstrong LR, Fak JJ, Chen GH, McDonald RA, Toews GB, Paine R 3rd. Regulation of rat pulmonary dendritic cell immunostimulatory activity by alveolar epithelial cell-derived granulocyte macrophage colony-stimulating factor. Am J Respir Cell Mol Biol. 1995 Oct; 13 (4): 426-33.

Paine R 3rd, Mody CH, Chavis A, Spahr MA, Turka LA, Toews GB. Alveolar epithelial cells block lymphocyte proliferation in vitro without inhibiting activation. Am J Respir Cell Mol Biol. 1991 Sep; 5 (3): 221-9.

Zissel G, Ernst M, Rabe K, Papadopoulos T, Magnussen H, Schlaak M, Muller-Quernheim J. Human alveolar epithelial cells type II are capable of regulating T-cell activity. J Investig Med. 2000 Jan; 48 (1): 66-75.

AE2 cells were reported to inhibit lymphocyte proliferation in vitro without altering their activation state [172]. AE2-cell-derived TGF-β [170] may indirectly inhibit T-cell proliferation via blockade of activating factors, such as IL-2. In contrast, GM-CSF released at the basolateral surface of AE2 cells may increase the potential of dendritic cells to induce T-cell proliferation [166].

166. Christensen PJ, Armstrong LR, Fak JJ, Chen GH, McDonald RA, Toews GB, Paine R III: Regulation of rat pulmonary dendritic cell immunostimulatory activity by alveolar epithelial cellderived granulocyte macrophage colony- stimulating factor. Am J Respir Cell Mol Biol 1995, 13:426–433.

170. Zissel G, Ernst M, Rabe K, Papadopoulos T, Magnussen H, Schlaak M, Müller-Quernheim J: Human alveolar epithelial cells type II are capable of regulating T-cell activity. J Investig Med 2000, 48:66–75.

172. Paine R III, Mody CH, Chavis A, Spahr MA, Turka LA, Toews GB: Alveolar epithelial cells block lymphocyte proliferation in vitro without inhibiting activation. Am J Respir Cell Mol Biol 1991, 5:221–229.

Anmerkungen

The source is not mentioned here.

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(Hindemith) Schumann

[14.] Mag/Fragment 016 27 - Diskussion
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The surface-active agent was characterized in numerous biochemical studies of BAL material and is now known to be composed of ∼90% lipids (with ∼80-90% phospholipids) and of ∼10% proteins (Griese, 1999). Unlike most other lipid-rich components of cells and organs, the surfactant lipids are characterized by an [unusually high level of satured [sic] fatty acid chains, such as the predominant dipalmitoylphosphatidylcholines, which contribute substantially to the unique properties of pulmonary surfactant (van Golde et al., 1994).]

Griese M. Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J. 1999 Jun; 13 (6): 1455-76. Review.

van Golde LMG, BatenburgJJ, Robertson B The pulmonary surfactant system. News in Physiol Sciences 1994, 9:13-20.

This surface-active agent, termed surfactant, was characterised in numerous biochemical studies of bronchoalveolar lavage (BAL) material and is now known to be composed of ≈90% (mass) lipids (with ≈80-90% phospholipids) and of ≈10% proteins. Its composition may deviate greatly in pathologic states (for review, see eg [7]). Unlike most other lipid-rich components of cells and organs, the surfactant lipids are characterised by an unusually high level of saturated fatty acid chains, such as the predominant dipalmitoylphosphatidylcholines, which contribute substantially to the unique properties of pulmonary surfactant (for review, see eg [8]).

7. Griese M: Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J 1999, 13:1455–1476.

8. Van Golde LMG, Batenburg JJ, Robertson B: The pulmonary surfactant system. News in Physiol Sciences 1994, 9:13–20.

Anmerkungen

The source is not given. To be continued on the next page: Mag/Fragment_017_01

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(Hindemith) Schumann

[15.] Mag/Fragment 017 01 - Diskussion
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[Unlike most other lipid-rich components of cells and organs, the surfactant lipids are characterized by an] unusually high level of satured [sic] fatty acid chains, such as the predominant dipalmitoylphosphatidylcholines, which contribute substantially to the unique properties of pulmonary surfactant (van Golde et al., 1994). The protein fraction comprises a highly variable amount of serum proteins (Griese; 1999) and four apoproteins that are associated with surfactant and contribute to its specific function (Weaver and Whitsett, 1991).

Griese M. Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J. 1999 Jun; 13 (6): 1455-76. Review.

van Golde LMG, BatenburgJJ, Robertson B The pulmonary surfactant system. Newsin Physiol Sciences 1994, 9:13-20.

Weaver TE, Whitsett JA. Function and regulation of expression of pulmonary surfactant-associated proteins. Biochem J. 1991 Jan 15; 273 (Pt2): 249-64. Review.

Unlike most other lipid-rich components of cells and organs, the surfactant lipids are characterised by an unusually high level of saturated fatty acid chains, such as the predominant dipalmitoylphosphatidylcholines, which contribute substantially to the unique properties of pulmonary surfactant (for review, see eg [8]). The protein fraction comprises a highly variable amount of serum proteins (50–90% of protein) [7] and four apoproteins that are associated with surfactant and contribute to its specific functions [9].

7. Griese M: Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J 1999, 13:1455–1476.

8. Van Golde LMG, Batenburg JJ, Robertson B: The pulmonary surfactant system. News in Physiol Sciences 1994, 9:13–20.

9. Weaver TE, Whitsett JA: Function and regulation of pulmonary surfactant-associated proteins. Biochem J 1991, 273:249–264.

Anmerkungen

The source is not given.

The copied passage starts on the previous page: Mag/Fragment_016_27

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(Hindemith) Schumann

[16.] Mag/Fragment 017 08 - Diskussion
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SP-B is essential for the ability of surfactant to reduce surface tension (Nogee, 2004), and SP-C has recently been shown to bind lipopolysaccharide (LPS) (Augosto et al., 2002; Augosto et al., 2003). In the absence of surfactant, surface tension is extremely high at end expiration and tends to collapse the lung. This makes breathing difficult to the extent that respiration is frequently impossible without ventilatory support and surfactant replacement. A deficiency of surfactant – which can result in “Respiratory-Distress Syndrome (RDS)” – occurs when infants are born prematurely, before their surfactant biosynthetic machinery has matured. Treatment of these premature infants with exogenous surfactant replacement reduces mortality and morbidity, because of this disease (Wright, 2005).

Augusto LA, Li J, Synguelakis M, Johansson J, Chaby R. Structural basis for interactions between lung surfactant protein C and bacterial lipopolysaccharide. J Biol Chem. 2002 Jun 28; 277 (26): 23484-92. Epub 2002 Apr 29.

Augusto LA, Synguelakis M, Johansson J, Pedron T, Girard R, Chaby R. Interaction of pulmonary surfactant protein C with CD14 and lipopolysaccharide. Infect Immun. 2003 Jan; 71 (1): 61-7.

Nogee LM. Alterations in SP-B and SP-C expression in neonatal lung disease. Annu Rev Physiol. 2004; 66: 601-23. Review.

Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005 Jan; 5 (1): 58-68. Review.

SP-B is essential for the ability of surfactant to reduce surface tension3, and SP-C has recently been shown to bind lipopolysaccharide (LPS)4,5. In the absence of surfactant, surface tension is extremely high at end expiration and tends to collapse the lung. This makes breathing difficult to the extent that respiration is frequently impossible without ventilatory support and surfactant replacement. A deficiency of surfactant — which can result in RESPIRATORY-DISTRESS SYNDROME — occurs when infants are born prematurely, before their surfactant biosynthetic machinery has matured. Treatment of these babies with exogenous surfactant replacement (BOX 1) reduces mortality and morbidity due to this disease.

3. Nogee, L. M. Alterations in SP-B and SP-C expression in neonatal lung disease. Annu. Rev. Physiol. 66, 601–623 (2004).

4. Augusto, L. A. et al. Interaction of pulmonary surfactant protein C with CD14 and lipopolysaccharide. Infect. Immun. 71, 61–67 (2003).

5. Augusto, L. A., Li, J., Synguelakis, M., Johansson, J. & Chaby, R. Structural basis for interactions between lung surfactant protein C and bacterial lipopolysaccharide. J. Biol. Chem. 277, 23484–23492 (2002).

Anmerkungen

The source is given, but the extent of the copied text is not clear to the reader. Neither is it clear that the copy is almost literal. Also three references to the literature are taken from the source.

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(Hindemith) Schumann

[17.] Mag/Fragment 017 18 - Diskussion
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The other function of alveolar surfactant relies on the nature of SP-A and SP-D as collectins. Both proteins are able to bind to the surface of various pathogens, thus acting as opsonins to facilitate their elimination by alveolar macrophages. Therefore, alveolar surfactant is also responsible for host defence (Crouch, 2000; Pison et al., 1994; Wright, 1998).

Surfactant is synthesized by alveolar type II epithelial cells and released upon appropriate stimuli by exocytosis from special intracellular storage organelles termed lamellar bodies. Once released into the alveolar space, freshly secreted lamellar body material undergoes several steps of transformation that are necessary to establish the surface-active lining layer. Cyclic compression and expansion during ventilation result in a fraction of spent surfactant that will largely be recycled by AECII. Thus, single constituents of surfactant run through several cycles before being removed by alveolar macrophages and replaced by de novo synthesis (Fehrenbach, 2001).

Although the bronchiolar Clara cells and submucosal cells also synthesize and release the mature proteins SP-A, SP-B and SP-D (Kalina et al., 1992; Voorhout et al., 1992) the alveolar type II epithelial cell is the only type of pulmonary cell that [produces all surfactant components including phospholipids as well as all four surfactant proteins. The mature 3.5 -3.7kDa small SP-C is thought to be exclusively released by AECII cells (Beers et al., 1994; Phelps and Floros et al., 1991).]


Beers MF, Kim CY, Dodia C, Fisher AB. Localization, synthesis, and processing of surfactant protein SP-C in rat lung analyzed by epitope-specific antipeptide antibodies. J Biol Chem. 1994 Aug 12; 269 (32): 20318-28.

Crouch EC. Surfactant protein-D and pulmonary host defense. Respir Res. 2000; 1 (2): 93-108. Epub 2000 Aug 25. Review.

Fehrenbach H. Alveolar epithelial type II cell: defender of the alveolus revisited. Respir Res. 2001; 2 (1): 33-46. Epub 2001 Jan 15. Review.

Kalina M, Mason RJ, Shannon JM. Surfactant protein C is expressed in alveolar type II cells but not in Clara cells of rat lung. Am J Respir Cell Mol Biol. 1992 Jun; 6 (6): 594-600.

Phelps DS, Floros J. Localization of pulmonary surfactant proteins using immunohistochemistry and tissue in situ hybridization. Exp Lung Res. 1991 Nov-Dec; 17 (6): 985-95.

Pison U, Max M, Neuendank A, Weissbach S, Pietschmann S. Host defence capacities of pulmonary surfactant: evidence for 'non-surfactant' functions of the surfactant system. Eur J Clin Invest. 1994 Sep; 24 (9): 586-99. Review.

Voorhout WF, Veenendaal T, Kuroki Y, Ogasawara Y, van Golde LM, Geuze HJ. Immunocytochemical localization of surfactant protein D (SP-D) in type II cells, Clara cells, and alveolar macrophages of rat lung. J Histochem Cytochem. 1992 Oct; 40 (10): 1589-97.

Wright JR. Host defense functions of surfactant In Lung surfactant:cellular and molecular processing. Edited by Ronney SA. Austin, Texas; R. G. Landes Company, 1998: 191-214.

Another function of alveolar surfactant postulated by Macklin [1], host defence, has attracted major scientific interest in recent years (for reviews, see [32,33]). This function of surfactant relies on the nature of SP-A and SPD as collectins. Both proteins are able to bind to the surface of various pathogens, thus acting as opsonins to facilitate their elimination by alveolar macrophages [32–34]. [...]

[...] It is synthesised by the AE2 cells and released upon appropriate stimuli by exocytosis from special intracellular storage organelles termed lamellar bodies. Once released into the alveolar space, freshly secreted lamellar body material undergoes several steps of transformation that are necessary to establish the surface-active lining layer. Cyclic compression and expansion during ventilation result in a fraction of spent surfactant that will largely be recycled by the AE2 cells. Thus, single constituents of surfactant may run through several cycles before being removed by alveolar macrophages and replaced by de novo synthesis (for comprehensive review, see [11]).

Synthesis

Although the bronchiolar Clara cells synthesise and release the mature proteins SP-A, SP-B, and SP-D (Fig. 2a) [37,38], the AE2 cell is the only type of pulmonary cell that produces all the surfactant components (phospholipids [Fig. 3] as well as all four surfactant proteins). The mature 3.5–3.7 kDa small SP-C (Fig. 2b) is thought to be released by AE2 cells only [39,40].


1. Macklin CC: The pulmonary alveolar mucoid film and the pneumonocytes. Lancet 1954, 29:1099–1104.

11. Rooney SA: Lung surfactant: cellular and molecular processing. Austin, Texas, RG Landes Company, 1998.

32. Pison U, Max M, Neuendank A, Weissbach S, Pietschmann S: Host defence capacities of pulmonary surfactant: evidence for ‘non- surfactant’ functions of the surfactant system. Eur J Clin Invest 1994, 24:586–599.

33. Wright JR: Host defense functions of surfactant. In Lung surfactant: cellular and molecular processing. Edited by Rooney SA. Austin, Texas; R. G. Landes Company, 1998:191–214.

34. Crouch EC: Surfactant protein-D and pulmonary host defense. Respir Res 2000, 1:93–108.

37. Kalina M, Mason RJ, Shannon JM: Surfactant protein C is expressed in alveolar type II cells but not in Clara cells of rat lung. Am J Respir Cell Mol Biol 1992, 6:594–600.

38. Voorhout WF, Veenendaal T, Kuroki Y, Ogasawara Y, van Golde LM, Geuze HJ: Immunocytochemical localization of surfactant protein D (SP-D) in type II cells, Clara cells, and alveolar macrophages of rat lung. J Histochem Cytochem 1992, 40: 1589–1597.

39. Phelps DS, Floros J: Localization of pulmonary surfactant proteins using immunohistochemistry and tissue in situ hybridization. Exp Lung Res 1991, 17:985–995.

40. Beers MF, Kim CY, Dodia C, Fisher AB: Localization, synthesis, and processing of surfactant protein SP-C in rat lung analyzed by epitope-specific antipeptide antibodies. J Biol Chem 1994, 269:20318–20328.

Anmerkungen

The source is mentioned on the last line of the second paragraph. It is not clear to the reader that the preceding two as well as the following two paragraphs are taken from the source almost literally, together with several references to the literature.

To be continued on the next page: Mag/Fragment_018_01

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[Although the bronchiolar Clara cells and submucosal cells also synthesize and release the mature proteins SP-A, SP-B and SP-D (Kalina et al., 1992; Voorhout et al., 1992) the alveolar type II epithelial cell is the only type of pulmonary cell that] produces all surfactant components including phospholipids as well as all four surfactant proteins. The mature 3.5-3.7 kDa small SP-C is thought to be exclusively released by AECII cells (Beers et al., 1994; Phelps and Floros et al., 1991).

About 85% of the secreted surfactant is taken up again, metabolised and re-secreted by AECII. Re-uptake and recycling have been demonstrated for all surfactant lipids and for all four surfactant proteins. The degradation of surfactant is accomplished by alveolar macrophages with only minimal contribution (Herbein et al., 2000; Nicholas, 1996; Young et al., 1993).


Beers MF, Kim CY, Dodia C, Fisher AB. Localization, synthesis, and processing of surfactant protein SP-C in rat lung analyzed by epitope-specific antipeptide antibodies. J Biol Chem. 1994 Aug 12; 269 (32): 20318-28.

Herbein JF, Savov J, Wright JR. Binding and uptake of surfactant protein D by freshly isolated rat alveolar type II cells. Am J Physiol Lung Cell Mol Physiol. 2000 Apr; 278 (4): L830-9.

Kalina M, Mason RJ, Shannon JM. Surfactant protein C is expressed in alveolar type II cells but not in Clara cells of rat lung. Am J Respir Cell Mol Biol. 1992 Jun; 6 (6): 594-600.

Nicholas TE. Pulmonary surfactant: no mere paint on the alveolar wall. Respirology. 1996 Dec; 1 (4): 247-57. Review.

Phelps DS, Floros J. Localization of pulmonary surfactant proteins using immunohistochemistry and tissue in situ hybridization. Exp Lung Res. 1991 Nov-Dec; 17 (6): 985-95.

Voorhout WF, Veenendaal T, Kuroki Y, Ogasawara Y, van Golde LM, Geuze HJ. Immunocytochemical localization of surfactant protein D (SP-D) in type II cells, Clara cells, and alveolar macrophages of rat lung. J Histochem Cytochem. 1992 Oct; 40 (10): 1589-97.

Young SL, Fram EK, Larson E, Wright JR. Recycling of surfactant lipid and apoprotein-A studied by electron microscopic autoradiography. Am J Physiol. 1993 Jul; 265 (1Pt1): L19-26.

[page 35]

Synthesis

Although the bronchiolar Clara cells synthesise and release the mature proteins SP-A, SP-B, and SP-D (Fig. 2a) [37,38], the AE2 cell is the only type of pulmonary cell that produces all the surfactant components (phospholipids [Fig. 3] as well as all four surfactant proteins). The mature 3.5-3.7 kDa small SP-C (Fig. 2b) is thought to be released by AE2 cells only [39,40].

[page 38]

Today it is established that most of the secreted surfactant — estimated at about 85% [24] — is taken up again, metabolised and re-secreted by the AE2 cells. Re-uptake and recycling have been demonstrated for surfactant lipids [58] and all four surfactant proteins [51,58,96,97]. [...]

The degradation of surfactant is accomplished by the alveolar macrophages with only minimal contribution, if any, from AE2 cells.


24. Nicholas TE: Pulmonary surfactant: no mere paint on the alveolar wall. Respirology 1996, 1:247–257.

37. Kalina M, Mason RJ, Shannon JM: Surfactant protein C is expressed in alveolar type II cells but not in Clara cells of rat lung. Am J Respir Cell Mol Biol 1992, 6:594–600.

38. Voorhout WF, Veenendaal T, Kuroki Y, Ogasawara Y, van Golde LM, Geuze HJ: Immunocytochemical localization of surfactant protein D (SP-D) in type II cells, Clara cells, and alveolar macrophages of rat lung. J Histochem Cytochem 1992, 40: 1589–1597.

39. Phelps DS, Floros J: Localization of pulmonary surfactant proteins using immunohistochemistry and tissue in situ hybridization. Exp Lung Res 1991, 17:985–995.

40. Beers MF, Kim CY, Dodia C, Fisher AB: Localization, synthesis, and processing of surfactant protein SP-C in rat lung analyzed by epitope-specific antipeptide antibodies. J Biol Chem 1994, 269:20318–20328.

51. Herbein JF, Savov J, Wright JR: Binding and uptake of surfactant protein D by freshly isolated rat alveolar type II cells. Am J Physiol 2000, 278:L830–839.

58. Young SL, Fram EK, Larson E, Wright JR: Recycling of surfactant lipid and apoprotein-A studied by electron microscopic autoradiography. Am J Physiol 1993, 265:L19–L26.

96. Breslin JS, Weaver TE: Binding, uptake, and localization of surfactant protein B in isolated rat alveolar type II cells. Am J Physiol 1992, 262:L699–707.

97. Pinto RA, Wright JR, Lesikar D, Benson BJ, Clements JA: Uptake of pulmonary surfactant protein C into adult rat lung lamellar bodies. J Appl Physiol 1993, 74:1005–1011.

Anmerkungen

The source is mentioned further up on the previous page, but without any indication that the here documented passage might have been taken from it. See Mag/Fragment_017_18.

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(Hindemith) Schumann

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2.3.1 Immunoregulatory functions of surfactant proteins

As mentioned above, the host defence functions of surfactant are primarily mediated by SP-A and SP-D, which are members of the collectin family of proteins. SP-A and SP-D have been also localized to non-pulmonary sites, including the trachea, brain, testes, salivary glands, lachrymal glands, heart, prostate, kidney, pancreas and the female urogenital tract (Leth-Larsen et al., 2004; Lin et al., 2000; Madsen et al., 2000; Rubio et al., 1995), although it is not yet clear whether all of these organs express sufficient amounts of protein for it to be physiologically effective.

Among their well-established role as opsonins, SP-A and SP-D also have functions in initiating parturition, facilitating clearance of apoptotic cells and directly killing bacteria.

2.3.2 Collectin structure

In addition to the two lung collectins SP-A and SP-D, serum collectins have been identified in humans (mannose-binding lectin, MBL) and in bovidae (conglutinin, CL-43 and CL-46) (Hansen and Holmskov, 2002).

SP-A and SP-D are synthesized as primary translation products of approximately 26-36kDa and 43kDa, respectively (figure 3). The collagen-like domain is N-terminal to a coiled-coil structure that precedes the C-terminal lectin domain. The lectin domains mediate the interaction of collectins with a wide varity of pathogens. The collagen domains vary greatly in length (Holmskov et al., 2003).

The host-defence functions of surfactant are primarily mediated by SP-A and SP-D, which are members of the collectin family of proteins.

[P. 59] [...]

SP-A and SP-D have been localized to non-pulmonary sites, including the trachea, brain, testes, salivary glands, lachrymal glands, heart, prostate, kidney, pancreas and the female urogenital tract11–14, although it is not yet clear whether all of these organs express sufficient amounts of protein for it to be physiologically effective. [...] An emphasis is placed on recent studies showing that, in addition to their well-established role as opsonins, SP-A and SP-D also have novel functions in initiating parturition, facilitating clearance of apoptotic cells and directly killing bacteria.

Collectin structure

In addition to the two lung collectins SP-A and SP-D (FIG. 2), serum collectins have been identified in humans (mannose-binding lectin,MBL) and in bovidae (conglutinin, CL-43 and CL-46)15. [...] SP-A and SP-D are synthesized as primary translation products of approximately 26–36 kDa and 43 kDa, respectively. The collagen-like domain is N-terminal to a coiled-coil structure that precedes the lectin domain. The collagen domains vary greatly in length, ranging from 19 Gly-X-Y triplets in MBL to 59 in human SP-D18. --- 11. Rubio, S. et al. Pulmonary surfactant protein A (SP-A) is expressed by epithelial cells of small and large intestine. J. Biol. Chem. 270, 12162–12169 (1995).

12. Lin, Z. et al. Both human SP-A1 and SP–A2 genes are expressed in small and large intestine. Am. J. Respir. Crit. Care Med. 161, A43 (2000).

13. Madsen, J. et al. Localization of lung surfactant protein D on mucosal surfaces in human tissue. J. Immunol. 164, 5866–5870 (2000).

14. Leth-Larsen, R., Floridon, C., Nielsen, O. & Holmskov, U. Surfactant protein D in the female genital tract. Mol. Hum. Reprod. 10, 149–154 (2004).

15. Hansen, S. & Holmskov, U. Lung surfactant protein D (SP-D) and the molecular diverted descendants: conglutinin, CL-43 and CL-46. Immunobiology 205, 498–517 (2002).

18. Holmskov, U., Thiel, S. & Jensenius, J. C. Collectins and ficolins: humoral lectins of the innate immune defense. Annu. Rev. Immunol. 21, 547–578 (2003).

Anmerkungen

The source is not indicated. The references are identical. Heading 2.3.1 is identical with the title of Wright 2005.

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For example, both surfactant proteins, SP-A and SP-D, bind to mannose and glucose but bind only poorly to galactose (Haagsman et al., 1987; Lim et al.; 1994; Persson et al., 1990). The high affinity of the collectins for clustered oligosaccharides is thought to be important for their ability to distinguish non-self from self, as most carbohydrates in animals are terminated by sugars, such as galactose or sialic acid, that are poorly recognized by the collectins.

Haagsman HP, Hawgood S, Sargeant T, Buckley D, White RT, Drickamer K, Benson BJ. The major lung surfactant protein, SP 28-36, is a calcium-dependent, carbohydrate-binding protein. J Biol Chem. 1987 Oct 15; 262 (29):13877-80.

Lim BL, Wang JY, Holmskov U, Hoppe HJ, Reid KB. Expression of the carbohydrate recognition domain of lung surfactant protein D and demonstration of its binding to lipopolysaccharides of gram-negative bacteria. Biochem Biophys Res Commun. 1994 Aug 15; 202 (3):1674-80.

Persson A, Chang D, Crouch E. Surfactant protein D is a divalent cation-dependent carbohydrate-binding protein. J Biol Chem. 1990 Apr 5; 265 (10): 5755-60.

For example, both SP-A and SP-D bind to mannose and glucose but bind poorly to galactose23–25. [...] However, the high affinity of the collectins for clustered oligosaccharides is thought to be important for their ability to distinguish non-self from self, as most carbohydrates in animals are terminated by sugars, such as galatose [sic] or sialic acid, that are poorly recognized by the collectins.

23. Haagsman, H. P. et al. The major lung surfactant protein, SP 28–36, is a calcium-dependent, carbohydrate-binding protein. J. Biol. Chem. 262, 13877–13880 (1987). This paper was the first to report that SP-A is a member of the collectin family of collagenous C-type lectins.

24. Persson, A., Chang, D. & Crouch, E. Surfactant protein D is a divalent cation-dependent carbohydrate-binding protein. J. Biol. Chem. 265, 5755–5760 (1990).

25. Lim, B. L., Wang, J. Y., Holmskov, U., Hoppe, H. J. & Reid, K. B. Expression of the carbohydrate recognition domain of lung surfactant protein D and demonstration of its binding to lipopolysaccharides of Gram-negative bacteria. Biochem. Biophys. Res. Commun. 202, 1674–1680 (1994).

Anmerkungen

The remainder of the text on this page is copied from Wright with minor adaptations. Wright is indicated as source in the preceding sentence.

In this fragment, Mag adopts Wright’s summary of the findings of three other papers, using Wright’s words, without acknowledging Wright as source.

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[21.] Mag/Fragment 020 02 - Diskussion
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Fragment, Gesichtet, Mag, SMWFragment, Schutzlevel sysop, Verschleierung, Wright 2005

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Surfactant proteins A and D bind to a variety of bacteria, viruses, allergens and apoptotic cells and thereby function as opsonins to enhance the uptake of these cells and particles. Binding of the collectins to pathogens occurs by various mechanisms. Some pathogens are aggregated by SP-A and/or SP-D and were phagocytized by immune cells like macrophages. SP-A and SP-D also have direct effects on immune cells and modulate the production of cytokines and inflammatory mediators.

Numerous studies have reported that SP-A mediates cellular functions through C1q receptors (Ferguson et al., 1999; Malholtra et al., 1994), including C1qR (also known as CD93) (Nepomuceno et al., 1997; Steinberger et al., 2002) and calreticulin (Malhotra et al., 1990; Malholtra et al., 1993). SP-A and SP-D are able to bind Calreticulin, which in turn binds to CD91. CD91 is a component of the binding complex (Gardai et al., 2003).

The binding of SP-A and/or SP-D to the signal-inhibitory regulatory protein-α (SIRP-α) modulates cellular functions in a similar way like the binding complex of surfactant proteins with the CD91–calreticulin complex. In the absence of a pathogen, SP-A binds through its lectin domain to SIRP-α, whereas in the presence of a foreign organism or cell debris, to which the lectin domain of SP-A binds, the free collagen-like region activates immune cells through CD91–calreticulin. Importantly, engagement of the different receptors elicits different responses. Upon binding of SP-A to SIRP-α, the inflammatory-mediator production is inhibited. By contrast, SP-A enhances inflammatory mediator like tumour-necrosis factor (TNF), CXCL12 and CCL2 production through its binding to the CD91-calreticulin complex. Therefore, SP-A and SP-D both are able to enhance and inhibit inflammatory-mediator production to modulate the regulation of immune cells.

Another receptor that binds surfactant protein A was identified by Chroneos and colleagues and termed SP-R210 (Chroneos et al., 1996). Blocking of this receptor with specific antibodies leads to a loss of SP-A mediated functions, including inhibition of lymphocyte proliferation (Borron et al., 1998), enhanced uptake of bacteria by macrophages (Weikert et al., 1997) and mycobacterial killing by a nitric-oxide-dependent pathway (Weikert et al., 2000). Nevertheless, the molecular identity of SP-R210 is still unclear.


Borron P, McCormack FX, Elhalwagi BM, Chroneos ZC, Lewis JF, Zhu S, Wright JR, Shepherd VL, Possmayer F, Inchley K, Fraher LJ. Surfactant protein A inhibits T cell proliferation via its collagen-like tail and a 210-kDa receptor. Am J Physiol. 1998 Oct; 275 (4 Pt 1): L679-86.

Borron PJ, Crouch EC, Lewis JF, Wright JR, Possmayer F, Fraher LJ. Recombinant rat surfactant-associated protein D inhibits human T lymphocyte proliferation and IL-2 production. J Immunol. 1998 Nov 1; 161 (9): 4599-603.

Chroneos ZC, Abdolrasulnia R, Whitsett JA, Rice WR, Shepherd VL. Purification of a cell-surface receptor for surfactant protein A. J Biol Chem. 1996 Jul 5; 271 (27): 16375-83.

Ferguson JS, Voelker DR, McCormack FX, Schlesinger LS. Surfactant protein D binds to Mycobacterium tuberculosis bacilli and lipoarabinomannan via carbohydrate-lectin interactions resulting in reduced phagocytosis of the bacteria by macrophages. J Immunol. 1999 Jul 1; 163 (1): 312-21.

Gardai SJ, Xiao YQ, Dickinson M, Nick JA, Voelker DR, Greene KE, Henson PM. By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell. 2003 Oct 3; 115 (1): 13-23.

Malhotra R, Thiel S, Reid KB, Sim RB. Human leukocyte C1q receptor binds other soluble proteins with collagen domains. J Exp Med. 1990 Sep 1; 172 (3): 955-9.

Malhotra R, Willis AC, Jensenius JC, Jackson J, Sim RB. Structure and homology of human C1q receptor (collectin receptor). Immunology. 1993 Mar; 78 (3): 341-8.

Malhotra R, Haurum JS, Thiel S, Sim RB. Binding of human collectins (SP-A and MBP) to influenza virus. Biochem J. 1994 Dec 1; 304 (Pt2): 455-61.

Nepomuceno RR, Henschen-Edman AH, Burgess WH, Tenner AJ. cDNA cloning and primary structure analysis of C1qR(P), the human C1q/MBL/SPA receptor that mediates enhanced phagocytosis in vitro. Immunity. 1997 Feb; 6 (2): 119-29.

Steinberger P, Szekeres A, Wille S, Stockl J, Selenko N, Prager E, Staffler G, Madic O, Stockinger H, Knapp W. Identification of human CD93 as the phagocytic C1q receptor (C1qRp) by expression cloning. J Leukoc Biol. 2002 Jan; 71 (1): 133-40.

Weikert LF, Edwards K, Chroneos ZC, Hager C, Hoffman L, Shepherd VL. SP-A enhances uptake of bacillus Calmette-Guerin by macrophages through a specific SP-A receptor. Am J Physiol. 1997 May; 272 (5Pt1): L989-95.

Weikert LF, Lopez JP, Abdolrasulnia R, Chroneos ZC, Shepherd VL. Surfactant protein A enhances mycobacterial killing by rat macrophages through a nitric oxide-dependent pathway. Am J Physiol Lung Cell Mol Physiol. 2000 Aug; 279 (2): L216-23.

[page 60]

Numerous studies have reported that SP-A mediates cellular functions through C1q receptors37,38, including C1qR (also known as CD93)39,40 and calreticulin41,42. [...] However, recent studies have confirmed that calreticulin binds SP-A and SP-D and have shown that CD91 is a component of the binding complex43. [...] Gardai and co-workers43 recently reported that SP-A and SP-D also modulate cellular functions through signal-inhibitory regulatory protein-α (SIRP-α), as well as the CD91-calreticulin complex. [...] For example, in the absence of a pathogen, SP-A binds through its lectin domain to SIRP-α. In the presence of a foreign organism or cell debris, to which the lectin domain of SP-A binds, the free collagen-like region activates immune cells through CD91–calreticulin. Importantly, engagement of the different receptors elicits different responses. When SP-A binds SIRP-α, inflammatory-mediator production is inhibited. By contrast, SP-A enhances inflammatory mediator (for example, tumour-necrosis factor (TNF),

[page 61]

CXCL12 and CCL2) production through the CD91–calreticulin complex. This model provides at least a partial explanation for the apparently conflicting reports that SP-A and SP-D both enhance and inhibit inflammatory-mediator production and provides important information about mechanisms by which specific collectin responses might be mediated.

SP-R210 was identified more than eight years ago as an SP-A receptor45. SP-R210 was purified by SP-A affinity chromatography, and a SP-R210-specific antibody was shown to block SP-A-mediated functions, including inhibition of lymphocyte proliferation46, enhanced uptake of bacteria by macrophages47 and mycobacterial killing by a nitric-oxide-dependent pathway48. However, the molecular identity of SP-R210 has not yet been established.

[...]

Figure 3 Functions of SP-A and SP-D. Surfactant protein A (SP-A) and SP-D bind to a variety of bacteria, viruses, allergens and apoptotic cells and thereby function as opsonins to enhance the uptake of these cells and particles. Binding of the collectins to pathogens occurs by various mechanisms. Some pathogens are aggregated by SP-A and/or SP-D. SP-A and SP-D also have direct effects on immune cells and modulate the production of cytokines and inflammatory mediators.


37. Tenner, A. J. Membrane receptors for soluble defense collagens. Curr. Opin. Immunol. 11, 34–41 (1999).

38. Malhotra, R., Lu, J., Holmskov, U. & Sim, R. B. Collectins, collectin receptors and the lectin pathway of complement activation. Clin. Exp. Immunol. 97, 4–9 (1994).

39. Nepomuceno, R. R., Henschen-Edman, A. H., Burgess, W. H. & Tenner, A. J. cDNA cloning and primary structure analysis of C1aRp, the human C1q/MBL/SPA receptor that mediates enhanced phagocytosis in vitro. Immunity 6, 119–129 (1997).

40. Steinberger, P. et al. Identification of human CD93 as the phagocytic C1q receptor (C1qRp) by expression cloning. J. Leukoc. Biol. 71, 133–140 (2002).

41. Malhotra, R., Willis, A., Jensenius, J., Jackson, J. & Sim, R. Structure and homology of human C1q receptor (collectin receptor). Immunology 78, 341–348 (1993).

42. Malhotra, R., Thiel, S., Reid, K. B. & Sim, R. B. Human leukocyte C1q receptor binds other soluble proteins with collagen domains. J. Exp. Med. 172, 955–959 (1990).

43. Gardai, S. J. et al. By binding SIRPα or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell 115, 13–23 (2003).
This is a compelling study showing that SP-A and SP-D bind two distinct receptors: SIRP-α and CD91–calreticulin.

45. Chroneos, Z. C., Abdolrasulnia, R., Whitsett, J. A., Rice, W. R. & Shepherd, V. L. Purification of a cell-surface receptor for surfactant protein A. J. Biol. Chem. 271, 16375–16383 (1996).
This paper was the first to report the characterization of an SP-A receptor.

46. Borron, P. et al. Surfactant protein A inhibits T cell proliferation via its collagen-like tail and a 210-kDa receptor. Am. J. Physiol. Lung Cell. Mol. Physiol. 275, L679–L686 (1998).

47. Weikert, L. F. et al. SP-A enhances uptake of bacillus Calmette-Guerin by macrophages through a specific SP-A receptor. Am. J. Physiol. Lung Cell. Mol. Physiol. 272, L989–L995 (1997).

48. Weikert, L. F., Lopez, J. P., Abdolrasulnia, R., Chroneos, Z. C. & Shepherd, V. L. Surfactant protein A enhances mycobacterial killing by rat macrophages through a nitric oxide-dependent pathway. Am. J. Physiol. Lung Cell. Mol. Physiol. 279, L216–L223 (2000).

Anmerkungen

Mag adopts Wright's literary review without indicating Wright as the source.

Note: there are two references "Borron et al. (1998)" in the bibliography.

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Glycoprotein 340 (gp340) is also discussed as a protein that binds SP-D through its CRD (Holmskov et al., 1997). Because of its localisation at the cell surface of alveolar macrophages, gp340 was suggested to be a SP-D receptor. It is identical to salivary agglutinin, a high-molecular-weight component of saliva that binds Streptococcus mutans, a bacterium that causes dental caries (Prakobphol et al., 2000). This putative receptor gp340 has no transmembrane domain so that it is suggested that it could interact with an adaptor molecule on the surface of the cell (Wright, 2005).

Additionally, a family of conserved cellular receptors that recognize pathogen-associated molecular patterns (PAMP) are discussed as binding-partners for SP-A and SP-D. This family of Toll-like receptors (TLRs) is activated by ligands like flagellin and CpG-containing DNA from bacteria, peptidoglycan from Gram-positive bacteria, LPS from Gram-negative bacteria, RNA from viruses and zymosan from yeast (Takeda et al., 2003). All these activation mechanisms end up in a series of conserved responses that culminate in inflammation and the production of inflammatory cytokines, such as TNF and interleukin-1β. The SP-A dependent binding to TLR4 results in an activation of the nuclear factor κB (NF-κB) signalling pathway and upregulation of cytokine synthesis (Guillot et al., 2002), whereas interaction of SP-A with TLR2 attenuates stimulation of TLR2 signalling and also stimulation of TNF secretion induced by zymosan or peptidoglycan (Sato et al., 2003).

In addition to phagocytosis, SP-A and SP-D have also the ability to regulate the production of inflammatory mediators by immune cells in a context-dependent manner. One example shows that inflammatory mediators, such as TNF, are both up- and downregulated by SP-A and SP-D (Crouch and Wright, 2001). The release of TNF that is induced by LPS or intact bacteria is inhibited by SP-A (Hickling et al., 1998; McIntosh et al., 1996; Rosseau et al., 1999). In contrast, SP-A enhances TNF production either when alone (Kremlev et al., 1994, Kremlev et al., 1997) or in presence of “rough” LPS (Sano et al., 1999).

A further effect of surfactant proteins SP-A and SP-D is the enhanced uptake of apoptotic cells by alveolar macrophages in vitro (Schagat, et al., 2001), which could be even shown for lungs of naïve mice in the case of SP-D (Vandivier et al., 2002).


Crouch E, Wright JR. Surfactant proteins a and d and pulmonary host defense. Annu Rev Physiol. 2001; 63: 521-54. Review.

Guillot L, Balloy V, McCormack FX, Golenbock DT, Chignard M, Si-Tahar M. Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. J Immunol. 2002 Jun 15; 168 (12): 5989-92.

Hickling TP, Sim RB, Malhotra R. Induction of TNF-alpha release from human buffy coat cells by Pseudomonas aeruginosa is reduced by lung surfactant protein A. FEBS Lett. 1998 Oct 16; 437 (1-2): 65-9.

Holmskov U, Lawson P, Teisner B, Tornoe I, Willis AC, Morgan C, Koch C, Reid KB. Isolation and characterization of a new member of the scavenger receptor superfamily, glycoprotein-340 (gp-340), as a lung surfactant protein-D binding molecule. J Biol Chem. 1997 May 23; 272 (21): 13743-9.

Kremlev SG, Phelps DS. Surfactant protein A stimulation of inflammatory cytokine and immunoglobulin production. Am J Physiol. 1994 Dec; 267 (6Pt1): L712-9.

Kremlev SG, Umstead TM, Phelps DS. Surfactant protein A regulates cytokine production in the monocytic cell line THP-1. Am J Physiol. 1997 May; 272 (5Pt1): L996-1004.

McIntosh JC, Mervin-Blake S, Conner E, Wright JR. Surfactant protein A protects growing cells and reduces TNF-alpha activity from LPS-stimulated macrophages. Am J Physiol. 1996 Aug; 271 (2Pt1): L310-9.

Prakobphol A, Xu F, Hoang VM, Larsson T, Bergstrom J, Johansson I, Frangsmyr L, Holmskov U, Leffler H, Nilsson C, Boren T, Wright JR, Stromberg N, Fisher SJ. Salivary agglutinin, which binds Streptococcus mutans and Helicobacter pylori, is the lung scavenger receptor cysteine-rich protein gp-340. J Biol Chem. 2000 Dec 22; 275 (51): 39860-6.

Rosseau S, Hammerl P, Maus U, Gunther A, Seeger W, Grimminger F, Lohmeyer J. Surfactant protein A down-regulates proinflammatory cytokine production evoked by Candida albicans in human alveolar macrophages and monocytes. J Immunol. 1999 Oct 15; 163 (8): 4495-502.

Sano H, Sohma H, Muta T, Nomura S, Voelker DR, Kuroki Y. Pulmonary surfactant protein A modulates the cellular response to smooth and rough lipopolysaccharides by interaction with CD14. J Immunol. 1999 Jul 1; 163 (1):387-95.

Schagat TL, Wofford JA, Wright JR. Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils. J Immunol. 2001 Feb 15; 166 (4): 2727-33.

Sato M, Sano H, Iwaki D, Kudo K, Konishi M, Takahashi H, Takahashi T, Imaizumi H, Asai Y, Kuroki Y. Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-kappa B activation and TNF-alpha secretion are down-regulated by lung collectin surfactant protein A. J Immunol. 2003 Jul 1; 171 (1): 417-25.

Takeda K, Takeuchi O, Akira S. Recognition of lipopeptides by Toll-like receptors. J Endotoxin Res. 2002; 8 (6): 459-63.

Vandivier RW, Ogden CA, Fadok VA, Hoffmann PR, Brown KK, Botto M, Walport MJ, Fisher JH, Henson PM, Greene KE. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J Immunol. 2002 Oct 1; 169 (7): 3978-86.

Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005 Jan; 5 (1): 58-68. Review.

Glycoprotein 340 (gp340) was initially identified as a protein that binds the CRD of SP-D49. Because of its location at the cell surface of alveolar macrophages, gp340 was suggested to be an SP-D receptor. It was subsequently shown to be identical to salivary agglutinin, a high-molecular-weight component of saliva that binds Streptococcus mutans, a bacterium that causes dental caries50. gp340 does not have a transmembrane domain, and its identity as an SP-D receptor remains unclear. The possibility that gp340 could interact with an adaptor molecule on the surface of the cell has not yet been investigated.

Other recent studies have reported that SP-A and SP-D bind to Toll-like receptors (TLRs) — a family of conserved cellular receptors that recognize pathogenassociated molecular patterns, including flagellin and CpG-containing DNA from bacteria, peptidoglycan from Gram-positive bacteria, LPS from Gram-negative bacteria, RNA from viruses and zymosan from yeast51. Activation of TLRs by these ligands initiates a conserved series of responses that culminate in inflammation and the production of inflammatory cytokines, such as TNF and interleukin-1β (IL-1β). Guillot and co-workers52 observed a TLR4-dependent SP-A activation of the nuclear factor-κB (NF-κB)-signalling pathway and upregulation of cytokine synthesis in TLR4-transfected Chinese hamster ovary cells. Such a response was lacking in the TLR4-deficient mice. In addition, Murakami and colleagues53 reported that SP-A directly binds TLR2. By contrast, the interaction of SP-A with TLR2 attenuates stimulation of TLR2 signalling and also stimulation of TNF secretion induced by zymosan or peptidoglycan. [...]

[page 62]

Collectins regulate multiple cellular responses in addition to phagocytosis. SP-A and SP-D also regulate the production of inflammatory mediators by immune cells in a context-dependent manner. Several reports show that inflammatory mediators, such as TNF, are both upregulated and downregulated27 by SP-A and SP-D. For example, SP-A inhibits62–64 the release of TNF that is induced by LPS or intact bacteria; by contrast, SP-A enhances TNF production either when alone65,66 or in the presence of ‘rough’LPS67. [...]

[page 63]

Recent studies have shown that both SP-A and SP-D enhance the uptake of apoptotic cells by alveolar macrophages in vitro79. Vandivier and colleagues80 showed that SP-A, SP-D and C1q all enhanced apoptotic-cell uptake by mouse and human alveolar macrophages in vitro, but only SP-D altered apoptotic-cell clearance from naive mouse lung80.


27. Crouch, E. & Wright, J. R. Surfactant proteins A and D and pulmonary host defense. Annu. Rev. Physiol. 63, 521–554 (2001).

49. Holmskov, U. et al. Isolation and characterization of a new member of the scavenger receptor superfamily, glycoprotein-340 (gp-340), as a lung surfactant protein-D binding molecule. J. Biol. Chem. 272, 13743–13749 (1997).

50. Prakobphol, A. et al. Salivary agglutinin, which binds Streptococcus mutans and Helicobacter pylori, is the lung scavenger receptor cysteine-rich protein gp-340. J. Biol. Chem. 275, 39860– 39866 (2000).

51. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

52. Guillot, L. et al. The immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. J. Immunol. 168, 5989–5992 (2002).

53. Sato, M. et al. Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-κB activation and TNF-á secretion are down-regulated by lung collectin surfactant protein A. J. Immunol. 171, 417–425 (2003).

62. Rosseau, S. et al. Surfactant protein A down-regulates proinflammatory cytokine production evoked by Candida albicans in human alveolar macrophages and monocytes. J. Immunol. 163, 4495–4502 (1999).

63. McIntosh, J. C., Mervin-Blake, S., Conner, E. & Wright, J. R. Surfactant protein A protects growing cells and reduces TNF-α activity from LPS-stimulated macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 271, L310–L319 (1996).

64. Hickling, T. P., Sim, R. B. & Malhotra, R. Induction of TNF-α release from human buffy coat cells by Pseudomonas aeruginosa is reduced by lung surfactant protein A. FEBS Lett. 437, 65–69 (1998).

65. Kremlev, S. G., Umstead, T. M. & Phelps, D. S. Surfactant protein A regulates cytokine production in the monocytic cell line THP-1. Am. J. Physiol. Lung Cell. Mol. Physiol. 272, L996–L1004 (1997).

66. Kremlev, S. G. & Phelps, D. S. Surfactant protein A stimulation of inflammatory cytokine and immunoglobulin production. Am. J. Physiol. Lung Cell. Mol. Physiol. 267, L712–L719 (1994).

67. Sano, H. et al. Pulmonary surfactant protein A modulates the cellular response to smooth and rough lipopolysaccharides by interaction with CD14. J. Immunol. 163, 387–395 (1999).

79. Schagat, T. L., Wofford, J. A. & Wright, J. R. Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils. J. Immunol. 166, 2727–2733 (2001). The ability of SP-A to enhance phagocytosis of apoptotic cells was first reported in this publication.

80. Vandivier, R. W. et al. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J. Immunol. 169, 3978–3986 (2002).

Anmerkungen

The source is given for the statement: "This putative receptor gp340 has no transmembrane domain so that it is suggested that it could interact with an adaptor molecule on the surface of the cell", but not for the rest of the page which also follows the source very closely and gives the same references to the literature.

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(Hindemith), PlagProf:-)

[23.] Mag/Fragment 022 01 - Diskussion
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Through the carbohydrate-recognition domains (CRD) and the collagen-like regions it is possible for SP-A and SP-D, as well as MBL, to bind DNA from a variety of origins, including mice and bacteria (Palaniyar et al., 2004). SP-D effectively binds and aggregates alveolar macrophages DNA and it enhances the uptake of DNA by human monocytic cells (Palaniyar et al., 2003). Binding of the collectins to cell-surface DNA might be one mechanism by which they mediate enhanced phagocytosis of apoptotic cells.

Uptake of apoptotic cells by macrophages results in release of anti-inflammatory mediators, such as transforming growth factors-β (TGF-β), IL-10 and prostaglandin E2 (Fadok et al., 1998). This response is in contrast to the release of pro-inflammatory cytokines that occurs when phagocytes ingest microorganisms. In addition to enhancing the uptake of apoptotic cells, SP-A also enhances the release of TGF-β by macrophages (Reidy and Wright, 2003), indicating that SP-A can promote resolution of inflammation at several levels of the apoptotic-cell clearance process and that surfactant proteins can indirectly induce anti-inflammatory responses by phagocytes.

As discussed above, surfactant is linked to innate immunity. However, surfactant is also linked to adaptive immunity in the lung by modulating functions of both dendritic cells and T cells.

It has been shown that SP-A and SP-D have different effects on DC functions. The uptake and presentation of antigens is enhanced by SP-D (Brinker et al., 2001), but only SP-A can inhibit maturation of DC, as assessed by cell-surface marker expression, and functional activity, such as phagocytosis and chemotaxis (Brinker et al., 2003).

The proliferation of T cells stimulated with plant lectins, CD3-specific antibodies or phorbol esters is inhibited by SP-A and SP-D. It has been suggested that the inhibition of IL-2 production might mediate this process (Borron et al., 1996; Borron et al, 1998). In addition, both the collagen-like region and the CRD of SP-A have been implicated in the inhibition of lymphocyte function, probably due to inhibition of calcium signalling (Borron et al., 2002). These data indicate that SP-D and SP-A might provide an important link between innate and adaptive immunity, by modulation of both DC and T cell functions.


Borron P, Veldhuizen RA, Lewis JF, Possmayer F, Caveney A, Inchley K, McFadden RG, Fraher LJ. Surfactant associated protein-A inhibits human lymphocyte proliferation and IL-2 production. Am J Respir Cell Mol Biol. 1996 Jul; 15 (1): 115-21.

Borron P, McCormack FX, Elhalwagi BM, Chroneos ZC, Lewis JF, Zhu S, Wright JR, Shepherd VL, Possmayer F, Inchley K, Fraher LJ. Surfactant protein A inhibits T cell proliferation via its collagen-like tail and a 210-kDa receptor. Am J Physiol. 1998 Oct; 275 (4 Pt 1): L679-86.

Borron PJ, Crouch EC, Lewis JF, Wright JR, Possmayer F, Fraher LJ. Recombinant rat surfactant-associated protein D inhibits human T lymphocyte proliferation and IL-2 production. J Immunol. 1998 Nov 1; 161 (9): 4599-603.

Borron PJ, Mostaghel EA, Doyle C, Walsh ES, McHeyzer-Williams MG, Wright JR. Pulmonary surfactant proteins A and D directly suppress CD3+/CD4+ cell function: evidence for two shared mechanisms. J Immunol. 2002 Nov 15; 169 (10): 5844-50.

Brinker KG, Martin E, Borron P, Mostaghel E, Doyle C, Harding CV, Wright JR. Surfactant protein D enhances bacterial antigen presentation by bone marrow-derived dendritic cells. Am J Physiol Lung Cell Mol Physiol. 2001 Dec; 281 (6): L1453-63.

Brinker KG, Garner H, Wright JR. Surfactant protein A modulates the differentiation of murine bone marrow-derived dendritic cells. Am J Physiol Lung Cell Mol Physiol. 2003 Jan; 284 (1): L232-41. Epub 2002 Sep 13.

Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998 Feb 15; 101 (4): 890-8.

Palaniyar N, Clark H, Nadesalingam J, Hawgood S, Reid KB. Surfactant protein D binds genomic DNA and apoptotic cells, and enhances their clearance, in vivo. Ann N Y Acad Sci. 2003 Dec; 1010: 471-5.

Palaniyar N, Nadesalingam J, Clark H, Shih MJ, Dodds AW, Reid KB. Nucleic acid is a novel ligand for innate, immune pattern recognition collectins surfactant proteins A and D and mannose-binding lectin. J Biol Chem. 2004 Jul 30; 279 (31): 32728-36. Epub 2004 May 15.

Reidy MF, Wright JR. Surfactant protein A enhances apoptotic cell uptake and TGF-beta1 release by inflammatory alveolar macrophages. Am J Physiol Lung Cell Mol Physiol. 2003 Oct; 285 (4): L854-61. Epub 2003 Jun 6.

SP-A and SP-D, as well as MBL, bind DNA from a variety of origins, including mice and bacteria82. Binding occurs through both the CRDs and the collagen-like regions. SP-D effectively binds and aggregates alveolarmacrophage DNA83, and it enhances the uptake of DNA by human monocytic cells84. Binding of the collectins to cell-surface DNA might be one mechanism by which they mediate enhanced phagocytosis of apoptotic cells.

A consequence of apoptotic-body uptake by a phagocyte is induction of an anti-inflammatory response by the phagocyte. For example, macrophage uptake of apoptotic cells results in release of antiinflammatory mediators, such as transforming growth factor-β (TGF-β), IL-10 and prostaglandin E2 (REF. 85)[sic]. This response is in contrast to the release of proinflammatory cytokines that occurs when phagocytes ingest a microorganism. In addition to enhancing the uptake of apoptotic cells, SP-A also enhanced the release of TGF-β by macrophages86, indicating that SP-A can promote resolution of inflammation at several levels of the apoptotic-cell clearance process.

Surfactant links innate and adaptive immunity

Recent studies have provided support for the concept that surfactant might have a role in linking innate and adaptive immunity in the lung by modulating functions of both DCs and T cells. [...]

Recent studies have shown that SP-A and SP-D have different effects on DC functions. For example, SP-D enhances the uptake and presentation of a model antigen expressed by Escherichia coli95. SP-A, but not SP-D, inhibits maturation of DCs, as assessed by cell-surface marker expression, and functional activity, such as phagocytosis and chemotaxis96.

[...] Subsequent studies by Borron and colleagues99,100 showed that SP-A and SP-D inhibit proliferation of T cells that have been stimulated with plant lectins, CD3-specific antibodies or phorbol esters, by a process that is thought to be mediated (at least, in part) by inhibition of IL-2 production. In addition, both the collagen-like region46 and the CRD101 of SP-A have been implicated in the inhibition of lymphocyte function, probably owing to inhibition of calcium signalling102.

[...]

As noted by Shepherd55 in an invited commentary, these studies indicate that SP-D and SP-A might provide an important link between innate and adaptive immunity, by modulation of DC and T-cell functions (FIG. 5).


46. Borron, P. et al. Surfactant protein A inhibits T cell proliferation via its collagen-like tail and a 210-kDa receptor. Am. J. Physiol. Lung Cell. Mol. Physiol. 275, L679–L686 (1998).

82. Palaniyar, N. et al. Nucleic acid is a novel ligand for innate immune pattern recognition collectins surfactant proteins A and D and mannose-binding lectin. J. Biol. Chem. 279, 32728–32736 (2004).

83. Palaniyar, N., Clark, H., Nadesalingam, J., Hawgood, S. & Reid, K. B. Surfactant protein D binds genomic DNA and apoptotic cells, and enhances their clearance, in vivo. Ann. NY Acad. Sci. 1010, 471–475 (2003).

84. Palaniyar, N., Nadesalingam, J. & Reid, K. B. Innate immune collectins bind nucleic acids and enhance DNA clearance in vitro. Ann. NY Acad. Sci. 1010, 467–470 (2003).

85. Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998).

86. Reidy, M. F. & Wright, J. R. Surfactant protein A enhances apoptotic cell uptake and TGF-β1 release by inflammatory alveolar macrophages. Am. J. Physiol. Lung Cell Mol. Physiol. 285, L854–L861 (2003).

95. Brinker, K. G. et al. Surfactant protein D enhances bacterial antigen presentation by bone marrow-derived dendritic cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 281, L1453– L1463 (2001).

96. Brinker, K. G., Garner, H. & Wright, J. R. Surfactant protein A modulates the differentiation of murine bone marrow-derived dendritic cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 284, L232–L241 (2003).

99. Borron, P. et al. Surfactant associated protein-A inhibits human lymphocyte proliferation and IL-2 production. Am. J. Respir. Cell Mol. Biol. 15, 115–121 (1996).

100. Borron, P. J. et al. Recombinant rat surfactant-associated protein D inhibits human T lymphocyte proliferation and IL-2 production. J. Immunol. 161, 4599–4603 (1998).

101. Wang, J. Y., Shieh, C. C., You, P. F., Lei, H. Y. & Reid, K. B. Inhibitory effect of pulmonary surfactant proteins A and D on allergen-induced lymphocyte proliferation and histamine release in children with asthma. Am. J. Respir. Crit. Care Med. 158, 510–518 (1998).

102. Borron, P. J. et al. Pulmonary surfactant proteins A and D directly suppress CD3+/CD4+ cell function: evidence for two shared mechanisms. J. Immunol. 169, 5844–5850 (2002).

Anmerkungen

The source is not given here. Continuation of Fragment_020_08.

Note: there are two publications "Borron et al. 1998" listed in the bibliography.

Sichter
(Hindemith), PlagProf:-)

[24.] Mag/Fragment 024 01 - Diskussion
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3 Autoimmunity

The concept of autoimmunity was first predicted by Paul Ehrlich at the beginning of the twentieth century, and he described it as “horror autotoxicus”. His experiments led him to conclude that the immune system is normally focused on responding to foreign materials and has an inbuilt tendency to avoid attacking self tissues. But when this process is disturbed, the immune system can attack self tissues resulting in autoimmune diseases.

Autoimmunity

The concept of autoimmunity was first predicted by Nobel Laureate Paul Ehrlich at the start of the twentieth century, and he described it as 'horror autotoxicus'. His experiments led him to conclude that the immune system is normally focused on responding to foreign materials and has an inbuilt tendency to avoid attacking self tissues. But when this process goes wrong, the immune system can attack self tissues resulting in autoimmune disease.

Anmerkungen

No source is indicated.

Sichter
Schumann

[25.] Mag/Fragment 024 08 - Diskussion
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Autoimmune diseases occur in up to 3-5% of the population (Jacobson et al., 1997). Many of these diseases are classified according to what organs and tissues are targeted by the damaging immune responses. There is an autoimmune disease specific for nearly every organ in the body, usually involving responses to an antigen expressed only in that specific organ. In other autoimmune diseases, such as systemic lupus erythematous [sic] (SLE), no particular cell type seems to be targeted; rather, the response seems to be directed against antigens that are widely expressed throughout the host. Nevertheless these diseases are antigen-specific; moreover, recognition of widely expressed antigens sometimes results unexpectedly in selective manifestations of the organ (Mathews et al., 1983; Yeaman et al., 1988). Autoimmune organ damage can be mediated by T cells, as in multiple sclerosis (MS) and type 1 diabetes (Steinman, 1996) and, furthermore, CD4+ and/or CD8+ T cells can have crucial roles (Haskins and McDuffie, 1990; Hutchings et al., 1992). In these diseases, autoantibodies are also produced and serve as markers of the antigen-specific T-cell responses, for example, antibodies to insulin or other pancreatic islet-cell antigens in type 1 diabetes (Yu et al., 1996). In other diseases, damage is actually mediated by autoantibodies and requires CD4+ T-helper cells. For example, nearly all SLE patients have elevated levels of autoantibodies to nuclear antigens.

Haskins K, McDuffie M. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science. 1990 Sep 21; 249 (4975):1433-6.

Hutchings PR, Cooke A, Dawe K, Champion BR, Geysen M, Valerio R, Roitt IM. A thyroxine-containing peptide can induce murine experimental autoimmune thyroiditis. J Exp Med. 1992 Mar 1; 175 (3): 869-72.

Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997 Sep; 84 (3): 223-43. Review.

Mathews MB, Bernstein RM. Myositis autoantibody inhibits histidyl-tRNA synthetase: a model for autoimmunity. Nature. 1983 Jul 14-20; 304 (5922): 177-9.

Steinman L. A few autoreactive cells in an autoimmune infiltrate control a vast population of nonspecific cells: a tale of smart bombs and the infantry. Proc Natl Acad Sci U S A. 1996 Mar 19; 93 (6): 2253-6. Review.

Yeaman SJ, Fussey SP, Danner DJ, James OF, Mutimer DJ, Bassendine MF. Primary biliary cirrhosis: identification of two major M2 mitochondrial autoantigens. Lancet. 1988 May 14; 1 (8594): 1067-70.

Yu L, Rewers M, Gianani R, Kawasaki E, Zhang Y, Verge C, Chase P, Klingensmith G, Erlich H, Norris J, Eisenbarth GS. Antiislet autoantibodies usually develop sequentially rather than simultaneously. J Clin Endocrinol Metab. 1996 Dec; 81 (12): 4264-7.

Autoimmune diseases occur in up to 3–5% of the general population1 (Table 1). Many of these diseases are classified according to what organs and tissues are targeted by the damaging immune response (Table 1). There is an autoimmune disease specific for nearly every organ in the body, involving, usually, response to an antigen expressed only in that organ. In other autoimmune diseases, such as systemic lupus erythematosus (SLE), no particular cell type seems to be targeted; rather, the response seems to be directed against antigens that are widely expressed throughout the host (Table 1). Nevertheless these diseases are antigen-specific; in addition, recognition of widely expressed antigens sometimes results unexpectedly in organ selective manifestations2–4.

Autoimmune organ damage can be mediated by T cells, as in multiple sclerosis (MS) and type 1 diabetes5, and CD4+ and/or CD8+ T cells can have crucial roles6–8. In these diseases, autoantibodies are also produced and serve as markers of the antigen-specific T-cell responses, for example, as antibodies to insulin or other pancreatic islet-cell antigens in type 1 diabetes9. In other diseases, damage is actually mediated by autoantibodies and requires CD4+ T-helper cells. For example, nearly all SLE patients have elevated levels of antibodies to nuclear antigens [...]


1. Jacobson, D.L., Gange, S.J., Rose, N.R. & Graham, N.M. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol. 84, 223–243 (1997).

2. Mathews, M.B. & Bernstein, R.M. Myositis autoantibody inhibits histidyltRNA synthetase: A model for autoimmunity. Nature 304, 177–179 (1983).

3. Yeaman, S.J. et al. Primary biliary cirrhosis: Identification of two major M2 mitochondrial autoantigens. Lancet 1, 1067–1070 (1988).

4. Matsumoto, I., Staub, A., Benoist, C. & Mathis, D. Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science 286, 1732–1735 (1999).

5. Steinman, L. Multiple sclerosis: A coordinated immunological attack against myelin in the central nervous system. Cell 85, 299–302 (1996).

6. Hutchings, P., O’Reilly, L., Parish, N.M., Waldmann, H. & Cooke, A. The use of a non-depleting anti-CD4 monoclonal antibody to re-establish tolerance to β cells in NOD mice. Eur J. Immunol. 22, 1913–1918 (1992).

7. Wong, F.S., Visintin, I., Wen, L., Flavell, R.A. & Janeway, C.A. Jr. CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells. J. Exp. Med. 183, 67–76 (1996).

8. Haskins, K. & McDuffie, M. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 249, 1433–1436 (1990).

9. Yu, L. et al. Antiislet autoantibodies usually develop sequentially rather than simultaneously. J. Clin. Endocrinol. Metab. 81, 4264–4267 (1996).

Anmerkungen

The source is given on the next page as reference for a table, but without any indication that the passage here documented is taken from it as well including most references to the literature.

Sichter
(Hindemith) Schumann

[26.] Mag/Fragment 027 13 - Diskussion
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Regulatory T cells may be defined as CD4+ T cells that inhibit immunopathology or autoimmune disease in vivo. Specifically, Treg cells include those able to suppress naïve T cell proliferation in vitro and to control CD4+ or CD8+ T cell numbers in vivo, in lymphopenic hosts. Two major Treg populations have been described so far, [...] Treg cells may be defined as CD4+ T cells that inhibit immunopathology or autoimmune disease in vivo. Specifically, Treg cells include those able to suppress naive T-cell proliferation in vitro and to control CD4+ or CD8+ T-cell numbers in vivo, in lymphopenic hosts. Two major Treg populations have been described so far, [...].
Anmerkungen

The source is not mentioned here.

Sichter
(Hindemith) Schumann

[27.] Mag/Fragment 027 21 - Diskussion
Bearbeitet: 10. March 2014, 13:25 Hindemith
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The two subsets of regulatory T cells might function in different immunological settings, depending on the context of antigen exposure, the nature of the inflammatory response and the T cell receptor (TCR) repertoires of the individual cells. The natural Treg cells are probably most effective at suppressing autoreactive T cell responses locally, in non-inflammatory settings – circumstances in which antigen specific, self limiting reactions are required to achieve a fine homeostatic balance. In contrast, during self-damaging inflammatory reactions to microbes or transplanted tissue, or settings (for example inflammatory bowel disease), adaptive Treg cells might be induced to suppress the pathological immune responses. The two TReg-cell subsets might function in different immunological settings, depending on the context of antigen exposure, the nature of the inflammatory response and the TCR repertoires of the individual cells. We argue that natural TReg cells would be most effective at suppressing autoreactive T-cell responses locally, in non-inflammatory settings — circumstances in which antigen-specific, self-limiting reactions are required to achieve a fine homeostatic balance. By contrast, during self-damaging inflammatory reactions to microbes or transplanted tissue, or in settings of inflammatory autoimmune disease that are more similar to the infectious setting (for example, inflammatory bowel disease), adaptive TReg cells might be induced to suppress the pathological immune responses.
Anmerkungen

No indication of the source.

Sichter
Schumann

[28.] Mag/Fragment 028 01 - Diskussion
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4.1 Naturally occurring CD4+CD25+ regulatory T cells

The CD4+CD25+ regulatory T cells are currently the focus of intensive research and were first described in the early 1970s by Gershon and colleagues (Gershon et al., 1974). These cells represent 5-10% of the CD4+ T lymphocytes in healthy adult mice and humans and are thought to perform a specialized role in controlling both the innate and the adaptive immune system. Although easily identified and isolated from unmanipulated mice and humans on the basis of CD25 expression, this chain of the IL-2(R) receptor is also expressed on activated T cells (Maloy et al., 2003; Sakaguchi et al., 2001; Shevach, 2002). So far, no characteristic stable surface marker has been assigned to Treg cells. Additional markers expressed by these cells include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (Read et al., 2000; Takahashi et al., 2000) and glucocorticoid induced tumor necrosis factor receptor (TNFSR18) (McHugh et al., 2002; Shimizu et al., 2002), which were initially implicated in the mechanism of Treg action. However, both of these molecules are also expressed by nonregulatory T cells after activation. Various groups identified the forkhead/winged helix transcription factor Foxp3 as a marker for both CD25+ Treg cells and CD25- cell that have regulatory activity (Fontenot et al., 2003; Hori et al., 2003).


Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003 Apr; 4 (4): 330-6. Epub 2003 Mar 3.

Gershon RK, Lance EM, Kondo K Immuno-regulatory role of spleen localizing thymocytes. J Immunol. 1974 Feb; 112 (2): 546-54.

Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003 Feb 14; 299 (5609): 1057-61. Epub 2003 Jan 9.

Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med. 2003 Jan 6; 197 (1): 111-9.

McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, Byrne MC. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity. 2002 Feb; 16 (2): 311-23.

Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000 Jul 17; 192 (2): 295-302.

Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001 Aug; 182: 18-32. Review.

Sakaguchi S, Takahashi T, Yamazaki S, Kuniyasu Y, Itoh M, Sakaguchi N, Shimizu J. Immunologic self tolerance maintained by T-cell-mediated control of self-reactive T cells: implications for autoimmunity and tumor immunity. Microbes Infect. 2001 Sep; 3 (11): 911-8. Review.

Shevach EM. CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol. 2002 Jun; 2 (6): 389-400. Review.

Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol. 2002 Feb; 3 (2): 135-42. Epub 2002 Jan 22.

Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000 Jul 17; 192 (2): 303-10.

[page 801]

Naturally occurring CD4+CD25+ Treg cells

The CD4+CD25+ T cell subset is currently the focus of intensive research. These cells represent 5-10% of the CD4+ T lymphocytes in healthy adult mice and humans and are thought to perform a specialized role in controlling both the innate and the adaptive immune system2,3,17. Although easily identified and isolated from unmanipulated mice and humans on the basis of CD25 expression, this chain of the IL-2R is also expressed on activated T cells2,3,17. Thus far, no characteristic stable surface marker has been ascribed to Treg cells. Additional markers expressed by these cells include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)18,19 and glucocorticoid-induced tumor necrosis factor receptor20,21, which were initially

[page 802]

implicated in the mechanism of Tregaction. However, both of these molecules are also expressed by nonregulatory T cells, after activation. [...]

The forkhead/winged helix transcription factor Foxp3 was shown to be specifically expressed by CD25+ Treg cells, as well as by CD25- T cells with regulatory activity23–25.


2. Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 182, 18–32 (2001).

3. Shevach, E.M. CD4+ CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2, 389–400 (2002).

17. Maloy, K.J. et al. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003).

18. Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).

19. Takahashi, T. et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303–310 (2000).

20. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3, 135–142 (2002).

21. McHugh, R.S. et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311–323 (2002).

23. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

24. Khattri, R., Cox, T., Yasayko, S.A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).

25. Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

Anmerkungen

The source is not mentioned here, although the entire passage including references to the literature is taken from it (apart from a minor historical note at the beginning).

Note: there are two entries "Sakaguchi et al. 2001" in the bibliography of the thesis.

Sichter
(Hindemith) Schumann

[29.] Mag/Fragment 028 23 - Diskussion
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The resident regulatory cells that develop in the thymus are generated in a burst of activity during the early stages of fetal and neonatal T cell development (Sakaguchi et al., 2001). They are polyclonal on the basis of diverse TCR usage (Shevach, 2002), and they are potentially capable of recognizing diverse self-antigens.

The promiscuous gene expression of many self tissue-specific proteins in the medullar epithelial cells of the thymus is described as a potential mechanism to ensure central tolerance to peripheral self-antigens, because this self-antigen expression in the thymus might lead, among other things, to the deletion of immature autoreactive T cells (Derbinski et al., 2001). However, it is possible that these self proteins are expressed at low levels and, additionally, by only some of the epithelial [cells, making clonal deletion a rather ineffective means of inducing tolerance to peripheral antigens.]

[page 253]

The resident regulatory cells that develop in the thymus are generated in a burst of activity during the early stages of fetal and neonatal T-cell

[page 254]

development7. They are polyclonal on the basis of diverse TCR usage3, and they are potentially capable of recognizing diverse self-antigens. Kyewski and colleagues8, have shown that messenger RNA transcripts encoding many tissue-specific proteins are expressed by ‘islands’of medullary epithelial cells in the thymus. It has been proposed that this promiscuous gene expression might be a mechanism to ensure central tolerance to peripheral self-antigens. Self-antigens that are expressed by these medullary epithelial cells in the thymus might delete immature self-reactive T cells. However, it is probable that these self-proteins are expressed at low levels and by only some of the epithelial cells, making clonal deletion a rather ineffective means of inducing tolerance to peripheral antigens.


7. Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity and transplantation tolerance. Immunol. Rev. 182, 18–32 (2001).

3. Shevach, E. M. CD4+CD25+ suppressor T cells: more questions than answers. Nature Rev. Immunol. 2, 389–400 (2002)

8. Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nature Immunol. 2, 1032–1039 (2001).

Anmerkungen

The source is not indicated. Continued on the next page.

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Schumann

[30.] Mag/Fragment 029 01 - Diskussion
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[However, it is possible that these self proteins are expressed at low levels and, additionally, by only some of the epithelial] cells, making clonal deletion a rather ineffective means of inducing tolerance to peripheral antigens. An alternative mechanism of inducing self tolerance in the thymus might be the localized antigen presentation, resulting in a more robust regulation of autoreactivity. Once generated, the thymic Treg cells are exported in the peripheral tissues, where they may function normally to prevent the activation of other, self reactive T cells that have the potential of developing into effector cells (Salomon et al., 2000).

These regulatory T cells were described as a “normal” population of suppressor cells, because they are always present in normal individuals and carry out their regulatory function during normal surveillance of self-antigens. Furthermore, because of their development in the thymus, the natural regulatory T cells are expected to be specific for self-antigens.

Recent studies indicate that CD28 controls both thymic development and peripheral homeostasis of natural Treg cells. Ligation of CD28 is expected to act at two stages during Treg cell development (Boden et al., 2003). In addition, once the natural Treg cells emerge from the thymus, costimulation through CD28 is required to maintain a stable pool of these cells in the periphery by promoting their self renewal through homeostatic proliferation and by supporting their survival (Boden et al., 2003; Salomon et al., 2000). The development and maintenance functions of CD28 are not mediated through IL-2. It is possible that signalling through CD28 stimulates the production of a response to an yet unknown cytokine that functions as a growth and survival factor of these cells. The absence of CD80/CD86 or CD28 results in a reduction of the number of regulatory cells in peripheral lymphoid tissues and an unexpected exacerbation of natural Treg cells, which plays an important role controlling autoimmunity (Lenschow et al., 1996; Salomon et al., 2000).

However, it is probable that these self-proteins are expressed at low levels and by only some of the epithelial cells, making clonal deletion a rather ineffective means of inducing tolerance to peripheral antigens. An alternative mechanism of inducing self-tolerance in the thymus might be the generation of TReg cells in response to this localized antigen presentation, resulting in a more robust regulation of autoreactivity. Once generated, the thymic TReg cells are exported to peripheral tissues, where it is proposed that they function normally to prevent the activation of other, self-reactive T cells that have the potential of developing into effector cells9. [...] We refer to these regulatory cells as a ‘natural’ population, because they are always present in normal individuals and carry out their regulatory function during normal surveillance of self-antigens. Furthermore, because these TReg cells develop in the thymus, they are likely to be specific for self-antigens. [...]

Recent studies indicate that CD28 controls both thymic development and peripheral homeostasis of the natural TReg cells. Ligation of CD28 is likely to act at two stages during TReg-cell development13. Strong antigenic signals are required for the generation of natural TReg cells in the thymus14; therefore, a combination of TCR ligation and maximal co-stimulation might be required for these cells to develop from their immature precursors. In addition, once the natural TReg cells emerge from the thymus, co-stimulation through CD28 is required to maintain a stable pool of the cells in the periphery by promoting their self-renewal through homeostatic proliferation and by supporting their survival9,13. The development and maintenance functions of CD28 are not mediated through interleukin-2 (IL-2), IL-15 or its receptor (IL-15R), the anti-apoptotic molecule BCL-XL or OX40 (Q. Tang and J.A.B., unpublished observations). It is possible that signals through CD28 stimulate the production of and responses to an as yet unknown cytokine(s) that functions as a growth and survival factor for these cells. [...] The absence of CD80/CD86 or CD28 results in a reduction of the number of regulatory cells in peripheral lymphoid tissues and an unexpected exacerbation of autoimmunity owing to the absence of natural TReg cells, which are essential to control autoimmunity9,15.


9. Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).

13. Boden, E., Tang, Q., Bour-Jordan, H. & Bluestone, J. A. in Novartis Foundation Symposium 252. Generation and Effector Functions of Regulatory Lymphocytes (Wiley, Europe) (in the press).

14. Bensinger, S. J., Bandeira, A., Jordan, M. S., Caton, A. J. & Laufer, T. M. Major histocompatibility complex class-IIpositive cortical epithelium mediates the selection of CD4+CD25+ immunoregulatory T cells. J. Exp. Med. 194, 427–438 (2001).

15. Lenschow, D. et al. CD28/B7 regulation of TH1 and TH2 subsets in the development of autoimmune diabetes. Immunity 5, 285–293 (1996).

Anmerkungen

No indication of the source.

Sichter
Schumann

[31.] Mag/Fragment 030 01 - Diskussion
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4.2 Adaptive regulatory T cells

These cells are generated from mature T cell populations under certain conditions of antigenic stimulation, and they can be induced ex vivo by culturing mature CD4+ T cells with antigen or polyclonal activators in the presence of immunosuppressive cytokines, namely IL-10 (Barrat et al., 2002; Levings et al., 2001). Similar to natural Treg cells, adaptive Treg cells originate from thymus, but they might be derived from classical T cell subsets or natural Treg cells. The level of expression of CD25 by adaptive Treg cell is variable, depending on the disease setting and the site of regulatory activity. Of note, adaptive Treg cells function in vivo in a cytokine dependent manner (Barrat et al., 2002; Chatenoud et al., 1997; Maloy and Powrie, 2001), so that these regulatory T cells are distinguished from natural Treg cells not by their origin (the thymus), but by their requirement for further differentiation as a consequence of exposure to antigen in a distinct immunological context.


Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF, de Waal-Malefyt R, Coffman RL, Hawrylowicz CM, O'Garra A. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med. 2002 Mar 4; 195 (5): 603-16.

Chatenoud L, Primo J, Bach JF. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol. 1997 Mar 15 ; 158 (6): 2947-54.

Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt R, Roncarolo MG. IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol. 2001 May 1; 166 (9): 5530-9.

Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol. 2001 Sep; 2 (9): 816-22. Review.

Adaptive regulatory T cells. Additional populations of regulatory cells have been described in many settings of immunity18–21.These cells are generated from mature T-cell populations under certain conditions of antigenic stimulation, and they can be induced ex vivo by culturing mature CD4T+ T cells with antigen or polyclonal activators in the presence of immunosuppressive cytokines, notably IL-10 (REFS 5,22). Similar to natural TReg cells, adaptive TReg cells originate from the thymus, but they might be derived from classical T-cell subsets or natural TReg cells. The level of expression of CD25 by adaptive TReg cells is variable, depending on the disease setting and the site of regulatory activity23. Of note, adaptive TReg cells function in vivo in a cytokine-dependent manner5,6,18. So, we propose that adaptive TReg cells are distinguished from natural TReg cells not by their origin (the thymus), but rather by their requirement for further differentiation as a consequence of exposure to antigen in a distinct immunological context.

5. Barrat, F. J. et al. In vitro generation of interleukin-10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (TH1)- and TH2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002).

22. Levings, M. K., Sangregorio, R. & Roncarolo, M.-G. Human CD25+CD4+ T cells suppress naive and memory T-cell proliferation and can be expanded in vitro without loss of suppressor function. J. Exp. Med. 193, 1295–1302 (2001).

6. Chatenoud, L., Primo, J. & Bach, J. F. CD3 antibodyinduced dominant self-tolerance in overtly diabetic NOD mice. J. Immunol. 158, 2947–2954 (1997).

18. Maloy, K. J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nature Immunol. 2, 816–822 (2001).

Anmerkungen

No mention of the source. Directly followed by Fragment_030_13.

Sichter
Schumann

[32.] Mag/Fragment 030 13 - Diskussion
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Several different in vitro protocols have been described over the past few years that result in the generation of suppressor T cells. The activation of mouse or human CD4+ T cells in vitro in the presence of IL-10 has been shown to result in the generation of T cell clones with a cytokine profile different from that of T helper 1 (TH1) or T helper 2 (TH2) cells. Functionally, these T cell clones have inhibitory effects on antigen specific activation of naïve T cells that are mediated partially by IL-10 and TGF-β, and were termed T regulatory 1 (TR1) cells (Groux et al., 1997). A related approach for the generation of suppressor T cells in vitro involves the stimulation of naïve T cells with immature (im)DC. Surprisingly, although these cells produce IL-10, their suppressor phenotype resembles that of CD25+ T cells, as it is contact dependent, antigen non-specific and APC-independent. Immature DC are the ideal population to prime regulatory T cells as they are deficient in costimulatory molecules, and priming with antigen-imDC complexes might even be able to downregulate pre-existing antigen specific immune responses (Dhodapkar et al., 2001). Exposure to TGF-β has also been reported to facilitate the differentiation/expansion of suppressor T cell populations in vitro (Yamagiwa et al.; 2001).

Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med. 2001 Jan 15; 193 (2): 233-8.

Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997 Oct 16; 389 (6652): 737-42.

Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA. A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol. 2001 Jun 15; 166 (12): 7282-9.

Several different in vitro protocols have been described over the past few years that result in the generation of suppressor T cells (FIG. 1). The activation of human or mouse CD4+ T cells in vitro in the presence of IL-10 has been shown to result in the generation of T-cell clones with a cytokine profile that is different from that of T helper 1 (TH1) or TH2 cells.[...] Functionally, these T-cell clones have inhibitory effects on the antigen-specific activation of naive autologous T cells that are mediated partially by IL-10 and TGF-β. These new T cells were termed T regulatory 1 (TR1) cells67. [...]

A related approach for the generation of suppressor T cells in vitro involves the stimulation of naive T cells with iDCs. [...] Surprisingly, although these cells produced IL-10, their suppressor phenotype resembled that of CD25+ T cells, as it was contact-dependent, antigen non-specific and APC-independent. [...] Immature DCs are the ideal population to prime regulatory T cells as they are deficient in co-stimulatory molecules, and priming with antigen–iDC complexes might even be able to downregulate pre-existing antigen-specific immune responses70.

Exposure to TGF-β has also been reported to facilitate the differentiation/expansion of suppressor T-cell populations in vitro. [...]71


67. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific TD-cell responses and prevents colitis. Nature 389, 737–742 (1997). The first definition of the TR1 population of regulatory T cells.

70. Dhodapkar, M. V., Steinman, R. M., Krasovsky, J., Munz, C. & Bhardwaj, N. Antigen-specific inhibition of effector T-cell function in humans after injection of immature dendritic cells. J. Exp. Med. 193, 233–238 (2001).

71. Yamagiwa, S., Gray, J. D., Hashimoto, S. & Horwitz, D. A. A role of TGF-β in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J. Immunol. 166, 7282–7289 (2001).

Anmerkungen

The source is not mentioned here although the text is identical up to marginal adaptations. Also the references to the literature are the same.

Sichter
(Hindemith), PlagProf:-)

[33.] Mag/Fragment 030 29 - Diskussion
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Another possibility to induce regulatory T cells is antigen exposure by certain routes, including intranasal or oral administration. This strategy seems to induce selectively the appearance of T cells with this regulatory phenotype (Chen et al., 1994). For example, antigen exposure by certain routes, including intranasal or oral administration, seems to induce selectively the appearance of T cells with this regulatory phenotype21.

21. Chen, Y., Kuchroo, V. K., Inobe, J.-I., Hafler, D. A. & Weiner, H. L. Regulatory T-cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240 (1994).

Anmerkungen

A short fragment, following directly after Fragment 030 13. Could alternatively be rated as "Keine Wertung".

Sichter
(PlagProf:-)) Schumann

[34.] Mag/Fragment 031 01 - Diskussion
Bearbeitet: 10. March 2014, 12:23 Graf Isolan
Erstellt: 5. March 2014, 07:22 (PlagProf:-))
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Moreover, in contrast to natural Treg cell, which are fully functional at the time of thymic export as a consequence of strong TCR engagement, the development of adaptive Treg cells in the periphery might be triggered by low-affinity antigen or altered TCR signal transduction. These antigen-stimulated adaptive Treg cells are not functional without activation by further exposure to antigens – such as during infection, organ transplantation under cover of certain immunomodulatory therapies, or ectopic expression of non-self-antigens (Apostolou et al., 2002; Belkaid et al., 2002; Fuss et al., 2002; Kingsley et al., 2002; Powrie, 2003). Concerning the antigen specificity of adaptive Treg cells, it is interesting to speculate that these cells have a diverse repertoire, which might be expanded as a consequence of fortuitous cross-reactivities with foreign proteins. It is possible that the TCR repertoire of adaptive Treg cells is self-antigen specific, but that these cells are triggered in an inflammatory environment to promote bystander suppression through the production of suppressive cytokines.

It is important to note that unlike natural Treg cells, adaptive Treg cells might not require costimulation through CD28 for their development or function (Taylor et al., 2002). Interestingly, IL-2 might promote the development and function of both types of Treg cells, on the basis of studies showing the total absence of Treg cells in IL-2 receptor-deficient mice (Malek et al., 2002; Furtado et al., 2002).

4.3 Mechanism of suppression

In addition to potential differences in terms of TCR repertoire and differentiation state, it is proposed that natural and adaptive subsets of Treg cells differ in their mechanism of action. Adaptive Treg cells mediate their inhibitory activities by producing immunosuppressive cytokines, such as TGF-ß and IL-10 (Kingsley et al., 2002; Nakamura et al., 2001). In contrast, natural Treg cells, at least in vitro, function by a cytokine-independent mechanism, which presumably involves direct interactions with responding T cells or antigen-presenting cells (Shevach, 2002). This contact-dependent mechanism of suppression has been shown most convincingly by CD4+CD25+ natural Treg cells employed in in vitro models of suppression, whereas cytokine-mediated suppression has been best established for peripheral adaptive Treg [cells in vivo.]

[page 254]

Moreover, in contrast to natural TReg cells, which are fully functional at the time of thymic export as a consequence of strong TCR engagement, the development of adaptive TReg cells in the periphery might be triggered by low-affinity antigen or altered TCR signal transduction. [...] These antigen-stimulated adaptive TReg cells are not functional without activation by further exposure to antigens — such as during infection, organ transplantation under the cover of certain immunomodulatory therapies, or ectopic expression of non-self antigens19,26–29. What remains unclear is the antigen specificity of the adaptive TReg cells. Given that they often seem to develop in the context of infection or organ transplantation, it is interesting to speculate that adaptive TReg cells have a diverse repertoire, which is perhaps

[page 255]

expanded as a consequence of fortuitous cross-reactivities with foreign proteins. However, as foreign-antigen-specific TReg cells have been described only rarely, it remains possible that the TCR repertoire of adaptive TReg-cell populations (in particular, the CD4+CD25+ subset) is self-antigen specific, but that these cells are triggered in an inflammatory environment to promote bystander suppression through the production of suppressive cytokines (see below). [...] However, it is important to note that unlike natural TReg cells, adaptive TReg cells might not require co-stimulation through CD28 for their development or function. [...] Interestingly, IL-2 might promote the development and function of both types of TReg cell, on the basis of studies showing the total absence of TReg cells in IL-2R-deficient mice11,31.

Mechanisms of suppression

In addition to potential differences in terms of TCR repertoire and differentiation state, we propose that the natural and adaptive subsets of TReg cells differ in their mechanism of action. Many studies have indicated that what we term adaptive TReg cells mediate their inhibitory activities by producing immunosuppressive cytokines, such as transforming growth factor-β (TGF-β) and IL-10 (REFS 19,32; L. Chatenoud, personal communication). By contrast, natural TReg cells, at least in vitro, function by a cytokine-independent mechanism, which presumably involves direct interactions with responding T cells or antigenpresenting cells3. This contact-dependent mechanism of suppression has been shown most convincingly by CD4+CD25+ natural TReg cells tested in in vitro models of suppression, whereas cytokine-mediated suppression has been best established for peripheral adaptive TReg cells in vivo33.


19. Kingsley, C. I., Karim, M., Bushell, A. R. & Wood, K. J. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J. Immunol. 168, 1080–1086 (2002).

26. Apostolou, I., Sarukhan, A., Klein, L. & von Boehmer, H. Origin of regulatory T cells with known specificity for antigen. Nature Immunol. 3, 756–763 (2002).

27. Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. M. & Sacks, D. L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002).

28. Fuss, I. J., Boirivant, M., Lacy, B. & Strober, W. The interrelated roles of TGF-β and IL-10 in the regulation of experimental colitis. J. Immunol. 168, 900–908 (2002).

29. Powrie, F. in Novartis Foundation Symposium 252. Generation and Effector Functions of Regulatory Lymphocytes (Wiley, Europe) (in the press).

11. Malek, T. R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ- deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).

31. Furtado, G. C., de Lafaille, M. A., Kutchukhidze, N. & Lafaille, J. J. Interleukin-2 signaling is required for CD4+ regulatory T-cell function. J. Exp. Med. 196, 851–857 (2002).

19. Kingsley, C. I., Karim, M., Bushell, A. R. & Wood, K. J. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J. Immunol. 168, 1080–1086 (2002).

32. Nakamura, K., Kitani, A. & Strober, W. Cell contactdependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor-β. J. Exp. Med. 194, 629–644 (2001).

33. Bach, J. F. & Chatenoud, L. Tolerance to islet autoantigens and type I diabetes. Annu. Rev. Immunol. 19, 131–161 (2001).

Anmerkungen

No indication of the source.

Sichter
Schumann

[35.] Mag/Fragment 032 01 - Diskussion
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[This contact-dependent mechanism of suppression has been shown most convincingly by CD4+CD25+ natural Treg cells employed in in vitro models of suppression, whereas cytokine-mediated suppression has been best established for peripheral adaptive Treg] cells in vivo. However, the adaptive Treg cell subset, although it suppresses in a cytokine-dependent manner, might still require direct cell-cell contact to initiate the suppressive cascade.

32a diss Mag.png

Figure 6: Two classes of regulatory T cells can be envisioned. a In this hypothetical model, the natural regulatory T (Treg) cells (blue) suppress immune response in a contact-dependent manner and function in general homeostasis to block the actions of autoimmune T cells (red) in noninflammatory settings. b The adaptive Treg cell subset enhances the robust nature of suppression in an inflammatory milieu. Importantly, adaptive Treg cells can develop either CD4+CD25+ natural Treg cells (blue striped) or by altering the activity of T helper (TH) cells (red striped). APC, antigen presenting cell; interleukin (IL)-10, transforming growth factor (TGF)-β, regulatory T cell (Treg) (adapted from Bluestone and Abbas, 2003).

This contact-dependent mechanism of suppression has been shown most convincingly by CD4+CD25+ natural TReg cells tested in in vitro models of suppression, whereas cytokine-mediated suppression has been best established for peripheral adaptive TReg cells in vivo33. However, the adaptive TReg-cell subset, although it suppresses in a cytokine-dependent manner, might still require direct cell-cell contact to initiate the suppressive cascade.

32a source Mag.png

Figure 1 Two classes of regulatory T cells can be envisioned. a In this hypothetical model, the natural regulatory T (TReg) cells (blue) suppress immune responses in a contact-dependent manner and function in general homeostasis to block the actions of autoimmune T cells (red) in non-inflammatory settings. b The adaptive TReg-cell subset enhances the robust nature of suppression in an inflammatory milieu. Importantly, adaptive TReg cells can develop either from CD4+CD25+ natural TReg cells (blue striped) or by altering the activity of T helper (TH) cells (red striped). APC, antigen-presenting cell; IL-10, interleukin-10; TGF-β, transforming growth factor-β.


33. Bach, J. F. & Chatenoud, L. Tolerance to islet autoantigens and type I diabetes. Annu. Rev. Immunol. 19, 131–161 (2001).

Anmerkungen

At the end of the caption one finds "adapted from Bluestone and Abbas, 2003".

Sichter
(Hindemith) Schumann

[36.] Mag/Fragment 055 13 - Diskussion
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Already 1977 Mason and Williams developed the concept of the alveolar type II epithelial cell (AECII) as a defender of the alveolus (Mason and Williams, 1977). AECII may act as immunoregulatory cells and can interact with resident and mobile cells, either directly by membrane contact or indirectly via cytokines/growth factors and their receptors. Thus alveolar type II epithelial cells represent an integrative unit of immune responses within the alveolus.

Mason RJ, Williams MC. Type II alveolar cell. Defender of the alveolus. Am Rev Respir Dis. 1977 Jun; 115 (6Pt2): 81-91.

In 1977, Mason and Williams developed the concept of the alveolar epithelial type II (AE2) cell as a defender of the alveolus. [...] AE2 cells may act as immunoregulatory cells. AE2 cells interact with resident and mobile cells, either directly by membrane contact or indirectly via cytokines/growth factors and their receptors, thus representing an integrative unit within the alveolus.
Anmerkungen

The source is not mentioned.

Sichter
(Hindemith) Schumann

[37.] Mag/Fragment 057 03 - Diskussion
Bearbeitet: 10. March 2014, 12:20 Graf Isolan
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Alveolar type II epithelial cells (AECII) are critical for normal lung development, homeostasis, and repair after injury. AECII produce pulmonary surfactant lipids and proteins required for reducing alveolar surface tension (Finkelstein et al., 1983; Shannon et al., 2001). As essential progenitors for type I epithelial cells, they are also critical for normal alveolar development and tissue remodelling after injury (Adamson and Bowdenet [sic], 1974; Adamson and Bowden, 1975). The ability to investigate organogenesis and disease progression by overexpressing and deleting genes in mice, particularly genes expressed by alveolar type II epithelial cells, has recently favoured the use of mouse models in pulmonary research.

Although mice are advantageous for manipulating genes, they have not been useful for isolating alveolar type II epithelial cells for ex vivo study so far. In contrast, rat and rabbit AECII have successfully been isolated using velocity centrifugation through a gradient of albumin (Dobbs and Mason, 1979 and Finkelstein et al., 1983). Isolation of mouse AECII by this method has been less successful.


Adamson IY, Bowden DH. The pathogenesis of bloemycin-induced pulmonary fibrosis in mice. Am J Pathol. 1974 Nov; 77 (2):185-97.

Adamson IY, Bowden DH. The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen. Lab Invest. 1974 Jan; 30 (1): 35-42.

Adamson IY, Bowden DH. Derivation of type 1 epithelium from type 2 cells in the developing rat lung. Lab Invest. 1975 Jun; 32 (6): 736-45.

Dobbs LG, Mason RJ. Pulmonary alveolar type II cells isolated from rats. Release of phosphatidylcholine in response to beta-adrenergic stimulation. J Clin Invest. 1979 Mar; 63 (3): 378-87.

Finkelstein JN, Maniscalco WM, Shapiro DL. Properties of freshly isolated type II alveolar epithelial cells. Biochim Biophys Acta. 1983 Jun 2; 762 (3): 398-404.

Shannon JM, Pan T, Nielsen LD, Edeen KE, Mason RJ. Lung fibroblasts improve differentiation of rat type II cells in primary culture. Am J Respir Cell Mol Biol. 2001 Mar; 24 (3): 235-44.

ALVEOLAR TYPE II epithelial cells are critical for normal lung development, homeostasis, and repair after injury. Type II cells produce pulmonary surfactant lipids and proteins required for reducing alveolar surface tension (10, 29, 30). As essential progenitors for type I epithelial cells, they are also critical for normal alveolar development and tissue remodeling after injury (1, 2). [...] The ability to investigate organogenesis and disease progression by overexpressing and deleting genes in mice, particularly genes expressed by type II cells, has recently favored the use of mice in pulmonary research (27).

Although mice are advantageous for manipulating genes, they have not been useful for isolating type II cells for ex vivo study. In contrast, rat and rabbit type II cells have successfully been isolated using velocity centrifugation through a gradient of albumin (8, 10). Isolation of mouse type II cells by this method has been less successful, because airway Clara cells, which are extremely abundant in mice, frequently contaminate the preparations (7, 18).


1. Adamson IY and Bowden DH. The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen. Lab Invest 30: 35–42, 1974.

2. Adamson IYR and Bowden DH. Derivation of type 1 epithelium from type 2 cells in the developing rat lung. Lab Invest 32: 736–745, 1975.

7. Dobbs LG. Isolation and culture of alveolar type II cells. Am J Physiol Lung Cell Mol Physiol 258: L134–L147, 1990.

8. Dobbs LG and Mason RJ. Pulmonary alveolar type II cells isolated from rats. Release of phosphatidylcholine in response to β-adrenergic stimulation. J Clin Invest 63: 378–387, 1979.

10. Finkelstein JN, Maniscalco WM, and Shapiro DL. Properties of freshly isolated type II alveolar epithelial cells. Biochim Biophys Acta 762: 398–404, 1983.

18. Kumar RK, Li W, and O’Grady R. Maintenance of differentiated phenotype by mouse type 2 pneumocytes in serum-free primary culture. Exp Lung Res 21: 79–94, 1995.

27. Perl AK and Whitsett JA. Molecular mechanisms controlling lung morphogenesis. Clin Genet 56: 14–27, 1999.

29. Rice WR, Conkright JJ, Na CL, Ikegami M, Shannon JM, and Weaver TE. Maintenance of the mouse type II cell phenotype in vitro. Am J Physiol Lung Cell Mol Physiol 283: L256–L264, 2002.

30. Shannon JM, Jennings SD, and Nielsen LD. Modulation of alveolar type II cell differentiated function in vitro. Am J Physiol Lung Cell Mol Physiol 262: L427–L436, 1992.

31. Shannon JM, Pan T, Nielsen LD, Edeen KE, and Mason RJ. Lung fibroblasts improve differentiation of rat type II cells in primary culture. Am J Respir Cell Mol Biol 24: 235–244, 2001.

Anmerkungen

Nothing has been marked as a citation.

Note that there are two references "Adamson and Bowden (1974)" in the bibliography.

Note also that Mag gives the reference Shannon et al 2001 when Roper et al. actually give Shannon et al. 1974. Shannon et al. 2001 can be found in Roper's bibliography directly below Shannon et al. 1974.

Sichter
(Graf Isolan), Hindemith

[38.] Mag/Fragment 079 11 - Diskussion
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Untersuchte Arbeit:
Seite: 79, Zeilen: 11-16
Quelle: Wright 2005
Seite(n): 58, Zeilen: left col. 23-28; right col. 26-28
Pulmonary surfactant was initially identified as a lipoprotein complex that reduces surface tension at the air–liquid interface of the lung (Clements, 1957; Pattle, 1955). This definition has been reassessed in light of recent studies that show that surfactant also functions in pulmonary host defence and that surfactant proteins are expressed also in non-pulmonary sites. The host defence functions of surfactant are primarily mediated by SP-A and SP-D, which are members of the collectin family of [proteins.]

Clements JA. Surface tension of lung extracts. Proc Soc Exp Biol Med. 1957 May; 95 (1): 170-2.

Pattle RE. Properties, function and origin of the alveolar lining layer. Nature. 1955 Jun 25; 175 (4469): 1125-6.

Pulmonary surfactant was initially identified as a lipoprotein complex that reduces surface tension at the air–liquid interface of the lung1,2.This definition has been reassessed in light of recent studies that show that surfactant also functions in pulmonary host defence and that surfactant proteins are expressed in non-pulmonary sites. [...]

The host-defence functions of surfactant are primarily mediated by SP-A and SP-D, which are members of the collectin family of proteins.


1. Pattle, R. E. Properties, function and origin of the lining layer. Nature 175, 1125–1126 (1955).

2. Clements, J. A. Surface tension of lung extracts. Proc. Soc. Exp. Biol. Med. 95, 170–172 (1957).

Anmerkungen

Though nearly identical nothing has been marked as a citation.

Sichter
(Graf Isolan) Schumann

[39.] Mag/Fragment 080 01 - Diskussion
Bearbeitet: 10. March 2014, 12:18 Graf Isolan
Erstellt: 4. March 2014, 21:56 (Graf Isolan)
BauernOpfer, Fragment, Gesichtet, Mag, SMWFragment, Schutzlevel sysop, Wright 2005

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An emphasis is placed on recent studies showing that, in addition to their well-established role as opsonsins [sic], SP-A and SP-D also have novel functions in initiating parturition, facilitating clearance of apoptotic cells and directly killing bacteria. Furthermore, immunoregulatory functions of the surfactant proteins A und D on T cells are discussed (Wright, 2005).

Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005 Jan; 5 (1): 58-68. Review.

In this review, the structure and immunoregulatory functions of the surfactant proteins SP-A and SP-D are discussed. An emphasis is placed on recent studies showing that, in addition to their well-established role as opsonins, SP-A and SP-D also have novel functions in initiating parturition, facilitating clearance of apoptotic cells and directly killing bacteria.
Anmerkungen

The source is named at the end. Nevertheless: nothing has been marked as a citation.

Sichter
(Graf Isolan) Schumann

[40.] Mag/Fragment 086 05 - Diskussion
Bearbeitet: 16. March 2014, 17:02 Hindemith
Erstellt: 11. March 2014, 01:15 (Graf Isolan)
BauernOpfer, Boyton and Openshaw 2002, Fragment, Gesichtet, Mag, SMWFragment, Schutzlevel sysop

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Quelle: Boyton and Openshaw 2002
Seite(n): 1, Zeilen: 8-16 (abstract)
The respiratory tract is a fragile tissue with architecture that is finely designed for gas exchange. Due to this main function the lung is exposed to numerous pathogens and other harmful air pollutions and developed many mechanisms to prevent infectious and inflammations. In the first line of defence are structural mechanisms coming from barriers such as epithelial cell layers, mucus and cilia, which avoid the invasion of pathogens or antigens. A battery of mediators that constitute the innate response including lactoferin, lysozyme, collectins and defensins is followed. Activation of these molecules can lead directly to lysis of pathogens, or to destruction through opsonisation or the recruitment of inflammatory cells (Boyton et al., 2002).

Boyton RJ, Openshaw PJ. Pulmonary defences to acute respiratory infection. Br Med Bull. 2002; 61:1-12. Review.

The immune response to respiratory infection must, therefore, be rapid and efficient. However, the respiratory tract is a fragile tissue with architecture that is finely designed for gas exchange, so that the price of excessive or inappropriate inflammatory responses may itself be very high. The first line of defence comes from barriers such as mucus and cilia, followed by a battery of mediators that constitute the innate response. These include lactoferrin, lysozyme, collectins and defensins. Activation of these molecules can lead directly to lysis of pathogens, or to destruction through opsonisation or the recruitment of inflammatory cells.
Anmerkungen

Found in the chapter "Discussion" of the thesis. No part has been marked as a citation and for the reader it is not transparent to what extent the source has been used.

Sichter
(Graf Isolan), Hindemith

[41.] Mag/Fragment 090 16 - Diskussion
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Erstellt: 4. March 2014, 22:37 (Hindemith)
Fragment, Gesichtet, Herrath and Harrison 2003, Mag, SMWFragment, Schutzlevel sysop, Verschleierung

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Quelle: Herrath and Harrison 2003
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Therefore, physiological regulatory functions cannot be distinguished easily from effects that are caused by homeostatic proliferation and clonal expansion of transferred cells (Bach, 2003; Barthlott et al., 2003).

Bach JF. Regulatory T cells under scrutiny. Nat Rev Immunol. 2003 Mar;3(3):189-98. Review. Erratum in: Nat Rev Immunol. 2003 Jun; 3 (6): 509.

Bach JF., Chair's introduction. Generation and effector functions of regulatory lymphocytes. Novartis Found Symp. 2003; 252: 1-5; discussion 106-14. Review.

Barthlott T, Kassiotis G, Stockinger B. T cell regulation as a side effect of homeostasis and competition. J Exp Med. 2003 Feb 17;197 (4): 451-60.

[...] and therefore physiological regulatory functions cannot be distinguished easily from effects that are caused by homeostatic proliferation and the clonal expansion of the transferred cells (see the reviews by J. F. Bach in this issue45 and by B. Stockinger and colleagues46)

45. Bach, J. F. Regulatory T cells under scrutiny. Nature Rev. Immunol. 3, 189–198 (2003).

46. Kassiotis, G., Garcia, S., Simpson, E. & Stockinger, B. Impairment of immunological memory in the absence of MHC despite survival of memory T cells. Nature Immunol. 3, 244–250 (2002).

Anmerkungen

The source is not given.

Note: there are two references "Bach, 2003" listed in the bibliography.

Sichter
(Hindemith) Schumann

[42.] Mag/Fragment 093 20 - Diskussion
Bearbeitet: 16. March 2014, 21:38 WiseWoman
Erstellt: 7. March 2014, 01:29 (Hindemith)
BauernOpfer, Fragment, Gesichtet, Mag, Moyron-Quiroz et al 2004, SMWFragment, Schutzlevel sysop

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The role of BALT in mouse and humans are controversialy [sic] discussed and it is reported that infection or inflammation triggers the organization of lymphoid structures in the lung of both species (Chvatchko et al., 1996; Delventhal et al., 1992; Tschernig and Pabst, 2000). These structures do not fit the classical definition of BALT, as they are not formed independently of antigen (Bienenstock and Johnston, 1976; Plesch et al., 1983). Because the inducible BALT (iBALT) appears in the lung only after infection or inflammation, it is generally assumed that iBALT is simply an accumulation of effector cells that were initially primed in conventional lymphoid organs. The neo-formation of iBALT is caused by inflammatory responses, which directly promote the recruitment, priming and expansion of antigen-specific lymphocytes (Moyron-Quiroz et al., 2004).

Bienenstock J, Johnston N. A morphologic study of rabbit bronchial lymphoid aggregates and lymphoepithelium. Lab Invest. 1976 Oct; 35 (4): 343-8.

'Chvatchko Y, Kosco-Vilbois MH, Herren S, Lefort J, Bonnefoy JY. Germinal center formation and local immunoglobulin E (IgE) production in the lung after an airway antigenic challenge. J Exp Med. 1996 Dec 1; 184 (6): 2353-60.

Delventhal S, Brandis A, Ostertag H, Pabst R. Low incidence of bronchus-associated lymphoid tissue (BALT) in chronically inflamed human lungs. Virchows Arch B Cell Pathol Incl Mol Pathol. 1992; 62 (4): 271-4.

Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, Hartson L, Sprague F, Goodrich S, Woodland DL, Lund FE, Randall TD. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med. 2004 Sep; 10 (9): 927-34. Epub 2004 Aug 15.

Plesch BE, Gamelkoorn GJ, van de Ende M. Development of bronchus associated lymphoid tissue (BALT) in the rat, with special reference to T- and B-cells. Dev Comp Immunol. 1983 Winter; 7 (1): 179-88.

Tschernig T, Pabst R. Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases. Pathobiology. 2000 Jan-Feb; 68 (1): 1-8. Review.

Although the presence of BALT in mouse and human lungs is controversial, there are reports that infection or inflammation triggers the organization of lymphoid structures in the lungs of both species18–21. These structures do not fit the classical definition of BALT, as they are not formed independently of antigen22,23. Because inducible BALT (iBALT) appears in the lung only after infection or inflammation, it is generally assumed that iBALT is simply an accumulation of effector cells that were initially primed in conventional lymphoid organs; however, it is also possible that inflammatory responses directly trigger the neo-formation of iBALT, which promotes the recruitment, priming and expansion of antigen-specific lymphocytes in situ.

18. Delventhal, S., Hensel, A., Petzoldt, K. & Pabst, R. Effects of microbial stimulation on the number, size and activity of bronchus-associated lymphoid tissue (BALT) structures in the pig. Int. J. Exp. Path. 73, 351–357 (1992).

19. Tshering, [sic] T. & Pabst, R. Bronchus associated lymphoid tissue (BALT) is not present in normal adult lung but in different diseases. Pathobiol. 68, 1–8 (2000).

20. Chvatchko, Y., Kosco-Vilbois, M.H., Herren, S., Lefort, J. & Bonnefoy, J.-Y. Germinal center formation and local immunoglobulin E (IgE) production in the lung after an airway antigenic challenge. J. Exp. Med. 184, 2353–2360 (1996).

21. Chin, R.K. et al. Lymphotoxin pathway directs thymic Aire expression. Nat. Immunol. 4, 1121–1127 (2003).

22. Bienenstock, J. & Johnston, N. A morphologic study of rabbit bronchial lymphoid aggregates and lymphoepithelium. Lab. Invest. 35, 343–348 (1976).

23. Plesch, B.E.C., van der Brugge-Gamelkoorn, G.J. & van de Ende, M.B. Development of bronchus associated lymphoid tissue (BALT) in the rat, with special reference to T and B cells. Dev. Comp. Immunol. 7, 79–84 (1983).

Anmerkungen

The source is given for the last part of the passage. It is also given just before the passage documented here, but that refers to the preceding paragraph. It is, however, not clear to the reader that also the parts for which other literature is referenced are taken from the source and that the source is being followed more or less literally.

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(Hindemith), WiseWoman

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