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Cytokine induction by circulating immune complexes and signs of in-vivo complement activation in systemic lupus erythematosus are associated with the occurrence of anti-Sjögren's syndrome A antibodies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Autoimmunitet)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Autoimmunitet)
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2007 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 147, no 3, 513-520 p.Article in journal (Refereed) Published
Abstract [en]

Circulating immune complexes (IC) and levels of IC-induced cytokines have been correlated with complement activation and autoantibody profiles in systemic lupus erythematosus (SLE). SLE sera were analysed concerning levels of immune complexes (IC), classical complement function and different antinuclear and anti-C-reactive protein (CRP) autoantibodies. Blood mononuclear cells from healthy donors were stimulated with isolated IC and production of interleukin (IL)-10, IL-6 and IL-12p40 was measured. Functional experiments revealed that increased levels of IC-induced cytokines were associated with both increased classical complement activation and the occurrence of anti-Sjögren's syndrome A (SSA) and anti-SSB but not other autoantibodies. Biochemical measurement of circulating IC showed that the degree of complement activation and the occurrence of anti-SSA were synergistically associated with levels of circulating IC in SLE sera, as complement activation was a prerequisite for the enhancing effect of anti-SSA. Anti-CRP was associated with complement activation, but not with other autoantibodies. Our results indicate that anti-SSA and possibly anti-SSB antibodies influence IC formation and subsequent IC-induced cytokine induction, and that they thereby participate in the inflammatory process in active SLE.

Place, publisher, year, edition, pages
2007. Vol. 147, no 3, 513-520 p.
Keyword [en]
Complement, Cytokines, Immune complex, Systemic lupus erythematosus
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-14037DOI: 10.1111/j.1365-2249.2006.03313.xISI: 000243928900016PubMedID: 17302901OAI: oai:DiVA.org:uu-14037DiVA: diva2:41807
Available from: 2008-01-28 Created: 2008-01-28 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Functional Role of Immune Complexes in Rheumatic and Parasitic Diseases
Open this publication in new window or tab >>Functional Role of Immune Complexes in Rheumatic and Parasitic Diseases
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Immune complexes (IC) have key pathological roles in both autoimmune and infectious diseases. In this thesis functional mechanisms behind IC-driven inflammation in rheumatic diseases and tropical infections have been studied, with special focus on the contribution of autoantibodies and cytokine-inducing properties of IC. In the autoimmune disease SLE, increased levels of IC-induced cytokines were associated with both increased classical complement activation and the occurrence of the autoantibodies anti-SSA and anti-SSB, both directed against RNA-associated antigens. In addition, complement activation and anti-SSA synergistically predisposed to higher levels of IC in sera. In the following study it was demonstrated that also other autoantibodies against RNA-associated autoantigens were more enriched than anti-dsDNA in SLE IC.

Sudanese Visceral Leishmaniasis (VL) patients had elevated IC levels, and precipitated IC induced higher levels of GM-CSF, IL10, IL6 and IL1RA than control IC. Levels of IC were especially prominent in severely ill patients receiving antimony treatment, and a parallel association with IC induction of GM-CSF was demonstrated. Leishmania-infected patients were often rheumatoid factor (RF) positive and a substantial number displayed reactivity towards cyclic citrullinated peptide (CCP) antigens. Contrary to what was seen in Sudanese RA sera, the CCP reactivity was not restricted to citrulline but reacted equally well with arginine-containing control peptides. Levels of anti-CCP among VL patients were not due to cross-reactions with, or CCP-reactivity bound to IC.

I have demonstrated that IC are associated with the presence of autoantibodies in both SLE and in Leishmania infection. In SLE, autoantibodies against RNA-associated antigens were more prone to form circulating IC than anti-dsDNA. In Leishmania infection false reactivity against the CCP-autoantigen correlated to IC levels although the IC themselves did not contain such reactivity. In both diseases higher IC levels were associated with a more active disease, and purified IC induced key cytokines in disease pathogeneses.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 636
National Category
Immunology in the medical area
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-139529 (URN)978-91-554-7981-7 (ISBN)
Public defence
2011-02-17, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-01-27 Created: 2010-12-28 Last updated: 2011-03-11Bibliographically approved
2. Immune Complex Regulated Cytokine Production in Rheumatic and Lymphoproliferative Diseases
Open this publication in new window or tab >>Immune Complex Regulated Cytokine Production in Rheumatic and Lymphoproliferative Diseases
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Immune complexes (ICs) are produced during normal immune responses and facilitate clearance of foreign antigens. ICs not efficiently cleared from the circulation can cause tissue damage. This might happen if ICs are formed with autoantibodies and autoantigens. Well described effects of ICs are neutralization of antigen, classical complement activation or FcR-mediated phagocytosis, whereas cytokine inducing effects of ICs in human clinical settings are less well described. I have investigated cytokine-inducing properties in vitro of ICs from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and cryoglobulinemia in association with lymphoproliferative diseases.

Cryoglobulin (CG)-induced cytokine production varied with changes in temperature and ionic strength in parallel to CG precipitation. IgG CG-induced cytokine production was also mediated via FcγIIa on monocytes. Blockade of the complement system, resembling the in vivo situation of complement consumption in CG-associated diseases, increased IgG CG induced IL-10 and decreased TNF-α production. This represents hitherto not described mechanisms for CG-associated inflammation.

ICs from SLE patients induced IL-10 and IL-6 production from PBMC cultures via FcγRIIa. Occurrence of anti-SSA autoantibodies and signs of in vivo complement activation contributed to increased levels of circulating ICs in SLE patients, corresponding to increased amounts of IC-induced IL-10 in vitro. This represents a possible vicious cycle that might perpetuate antibody dependent pathology in SLE, and put anti-SSA in a new pathological context.

RF-associated ICs from RA joints and ICs formed with antibodies against collagen type II from RA serum induced pro-inflammatory cytokine production from monocytes via FcγRIIa, showing how specific autoantibodies might induce or perpetuate joint inflammation in RA.

I have described how ICs can induce significant amounts of pathophysiologically important monocyte-derived cytokines in three major IC-dependent diseases. Blockade of FcγRIIa and suppression of monocytes/macrophages might be a means of reducing pathogenic IC-induced cytokine production in these diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 218
Keyword
Immunology, Immune complex, Cytokines, Rheumatic diseases, Lymphoproliferative diseases, Immunologi
Identifiers
urn:nbn:se:uu:diva-7446 (URN)978-91-554-6780-6 (ISBN)
Public defence
2007-02-09, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-01-19 Created: 2007-01-19 Last updated: 2011-02-15Bibliographically approved

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Mathsson, LindaÅhlin, ErikRönnelid, Johan

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