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On the immunopathogenesis of systemic lupus erythematosus - Immune complexes, type I interferon system, complement system and platelets

Lood, Christian LU (2012) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2012:32.
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disorder characterized by inflammation in several organ systems. SLE patients have an impaired ability to clear dying cells which leads to the exposure of several nuclear antigens which might break self tolerance. Autoantibodies directed against the nuclear antigens will form large immune complexes (ICs) which are central in the immunopathogenesis of SLE. Through activation of the complement system, ICs mediate tissue destruction, and through interaction with immune cells ICs induce large amounts of pro-inflammatory cytokines, including IFN-alpha. Furthermore, ICs might activate platelets and thus be involved in the development of cardiovascular diseases which is increased in... (More)
Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disorder characterized by inflammation in several organ systems. SLE patients have an impaired ability to clear dying cells which leads to the exposure of several nuclear antigens which might break self tolerance. Autoantibodies directed against the nuclear antigens will form large immune complexes (ICs) which are central in the immunopathogenesis of SLE. Through activation of the complement system, ICs mediate tissue destruction, and through interaction with immune cells ICs induce large amounts of pro-inflammatory cytokines, including IFN-alpha. Furthermore, ICs might activate platelets and thus be involved in the development of cardiovascular diseases which is increased in SLE patients.



In this thesis I have investigated the immunopathogenesis of SLE with an emphasis on ICs, type I interferon (IFN) system, complement system and platelets. In the first papers we studied the plasmacytoid dendritic cell (pDC) and properties regulating their IFN-alpha producing ability, a central cytokine in the SLE pathogenesis. We found that C1q, a component of the classical pathway of the complement system, could regulate the type I interferon production by pDCs (Paper I). Furthermore, pDCs were able to produce a pro-inflammatory protein, S100A8/A9, which is increased in SLE patients (Paper II). Next we observed that the complement system and type I IFN system affect the platelets. Platelets isolated from SLE patients were more activated, had a type I IFN signature (Paper III), as well as complement deposition on the cell surface (Paper IV). Both the type I IFN signature and the complement deposition were associated with cardiovascular disease and venous thrombosis. In the final paper we found that EndoS, a bacterial endoglycosidase, abolished all pro-inflammatory properties of ICs isolated from SLE patients (Paper V). Thus, we suggest that EndoS has the potential to be developed as a new therapy against SLE considering its potent IC-modulating effects.



In summary, this thesis confirms a central role of immune complexes and their subsequent pro-inflammatory effects in the immunopathogenesis of SLE and development of cardiovascular disease and venous thrombosis. (Less)
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author
supervisor
opponent
  • Professor Mevorach, Dror, Division of Medicine, Center of Research in Rhematology, Hadassah University Hospital Eink-Karem, Jerusalem, Israel
organization
publishing date
type
Thesis
publication status
published
subject
keywords
systemic lupus erythematosus, autoimmunity, rheumatology, immunology, cardiovascular disease
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2012:32
pages
84 pages
publisher
Section of Rheumatology, Dept of Clinical Sciences, Lund
defense location
BMC D15, Belfragesalen
defense date
2012-05-16 09:00
ISSN
1652-8220
ISBN
978-91-86871-94-9
language
English
LU publication?
yes
id
7512a15d-37bd-42fd-acdf-8387158a8444 (old id 2440350)
date added to LUP
2012-04-18 08:05:23
date last changed
2016-09-19 08:44:48
@phdthesis{7512a15d-37bd-42fd-acdf-8387158a8444,
  abstract     = {Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disorder characterized by inflammation in several organ systems. SLE patients have an impaired ability to clear dying cells which leads to the exposure of several nuclear antigens which might break self tolerance. Autoantibodies directed against the nuclear antigens will form large immune complexes (ICs) which are central in the immunopathogenesis of SLE. Through activation of the complement system, ICs mediate tissue destruction, and through interaction with immune cells ICs induce large amounts of pro-inflammatory cytokines, including IFN-alpha. Furthermore, ICs might activate platelets and thus be involved in the development of cardiovascular diseases which is increased in SLE patients.<br/><br>
<br/><br>
In this thesis I have investigated the immunopathogenesis of SLE with an emphasis on ICs, type I interferon (IFN) system, complement system and platelets. In the first papers we studied the plasmacytoid dendritic cell (pDC) and properties regulating their IFN-alpha producing ability, a central cytokine in the SLE pathogenesis. We found that C1q, a component of the classical pathway of the complement system, could regulate the type I interferon production by pDCs (Paper I). Furthermore, pDCs were able to produce a pro-inflammatory protein, S100A8/A9, which is increased in SLE patients (Paper II). Next we observed that the complement system and type I IFN system affect the platelets. Platelets isolated from SLE patients were more activated, had a type I IFN signature (Paper III), as well as complement deposition on the cell surface (Paper IV). Both the type I IFN signature and the complement deposition were associated with cardiovascular disease and venous thrombosis. In the final paper we found that EndoS, a bacterial endoglycosidase, abolished all pro-inflammatory properties of ICs isolated from SLE patients (Paper V). Thus, we suggest that EndoS has the potential to be developed as a new therapy against SLE considering its potent IC-modulating effects.<br/><br>
<br/><br>
In summary, this thesis confirms a central role of immune complexes and their subsequent pro-inflammatory effects in the immunopathogenesis of SLE and development of cardiovascular disease and venous thrombosis.},
  author       = {Lood, Christian},
  isbn         = {978-91-86871-94-9},
  issn         = {1652-8220},
  keyword      = {systemic lupus erythematosus,autoimmunity,rheumatology,immunology,cardiovascular disease},
  language     = {eng},
  pages        = {84},
  publisher    = {Section of Rheumatology, Dept of Clinical Sciences, Lund},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {On the immunopathogenesis of systemic lupus erythematosus - Immune complexes, type I interferon system, complement system and platelets},
  volume       = {2012:32},
  year         = {2012},
}