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

Christian Lood

Research output: ThesisDoctoral Thesis (compilation)

254 Downloads (Pure)

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.

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.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Rheumatology
Supervisors/Advisors
  • Bengtsson, Anders, Supervisor
  • Truedsson, Lennart, Supervisor
  • Sturfelt, Gunnar, Supervisor
Award date2012 May 16
Publisher
ISBN (Print)978-91-86871-94-9
Publication statusPublished - 2012

Bibliographical note

Defence details

Date: 2012-05-16
Time: 09:00
Place: BMC D15, Belfragesalen

External reviewer(s)

Name: Mevorach, Dror
Title: Professor
Affiliation: Division of Medicine, Center of Research in Rhematology, Hadassah University Hospital Eink-Karem, Jerusalem, Israel

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Subject classification (UKÄ)

  • Rheumatology and Autoimmunity

Free keywords

  • systemic lupus erythematosus
  • autoimmunity
  • rheumatology
  • immunology
  • cardiovascular disease

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