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Surface-bound anti-type II collagen-containing immune complexes induce production of tumor necrosis factor α, interleukin-1β, and interleukin-8 from peripheral blood mononuclear cells via FcγRIIa: A potential pathophysiologic mechanism for humoral anti-type II collagen immunity in arthritis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. 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. 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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Autoimmunitet)
2006 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, no 6, 1759-1771 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Type II collagen (CII) is a major component of hyaline cartilage, and antibodies against CII are found in a subgroup of patients with rheumatoid arthritis. We undertook this study to investigate whether and how antibodies directed against CII can form solid-phase immune complexes (ICs) with cytokine-inducing properties in a model theoretically resembling the situation in the inflamed joint, in which CII is exposed for interaction with anti-CII antibodies during periods of inflammation. METHODS: Sixty-five arthritis patients with varying levels of anti-native CII antibodies and 10 healthy controls were evaluated concerning anti-CII and cytokines induced in a solid-phase IC model. Monocytes were either depleted or enriched to define responder cells. Antibodies blocking Fc gamma receptors (Fc gammaR) were used to define the responsible T cell surface receptors. RESULTS: ICs containing anti-CII from arthritis patients induced the production of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and IL-8. We found a close correlation between enzyme-linked immunosorbent assay optical density values and induction of TNFalpha (r = 0.862, P < 0.0001), IL-1beta (r = 0.839, P < 0.0001), and IL-8 (r = 0.547, P < 0.0001). The anti-CII-containing IC density threshold needed for cytokine induction differed among peripheral blood mononuclear cell donors. Anti-CII-containing IC-induced cytokine production was almost totally abolished (>99%) after monocyte depletion, and receptor blocking studies showed significant decreases in the production of TNFalpha, IL-1beta, and IL-8 after blocking Fc gammaRIIa, but not after blocking Fc gammaRIII. CONCLUSION: These findings represent a possible mechanism for perpetuation of joint inflammation in the subgroup of arthritis patients with high levels of anti-CII. Blockade of Fc gammaRIIa and suppression of synovial macrophages are conceivable treatment options in such patients.

Place, publisher, year, edition, pages
2006. Vol. 54, no 6, 1759-1771 p.
Keyword [en]
Adult, Aged, Aged; 80 and over, Antigen-Antibody Complex/*immunology, Antigens; CD/*physiology, Arthritis/*immunology, Collagen Type II/*immunology, Enzyme-Linked Immunosorbent Assay, Female, Humans, Interleukin-1/*biosynthesis, Interleukin-8/*biosynthesis, Male, Middle Aged, Monocytes/immunology/*metabolism, Receptors; IgG/*physiology, Research Support; Non-U.S. Gov't, Tumor Necrosis Factor-alpha/*biosynthesis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95382DOI: 10.1002/art.21892PubMedID: 16736518OAI: oai:DiVA.org:uu-95382DiVA: diva2:169567
Available from: 2007-01-19 Created: 2007-01-19 Last updated: 2017-12-14Bibliographically approved
In thesis
1. 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
2. Anti-Collagen Type II Autoantibodies in an Acute Phenotype of Early Rheumatoid Arthritis
Open this publication in new window or tab >>Anti-Collagen Type II Autoantibodies in an Acute Phenotype of Early Rheumatoid Arthritis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is an autoimmune disease with systemic inflammatory features that primarily affects small peripheral joints. Type II collagen (CII), is the most abundant collagen type in joint cartilage. Antibodies against CII (anti-CII) are found in a subpopulation of RA patients. Anti-CII can form surface-bound immune complexes (IC) in inflamed joints, which might intensify joint inflammation and destruction. In this thesis I have studied the functional effects of surface-bound anti-CII–containing IC in vitro and correlated the results to clinical parameters.

Anti-CII IC induced TNF-α, IL-1β and IL-8 production from monocytes via FcγRIIa. Anti-CII levels were dichotomously distributed in RA patients where a small outlier group (3.3%) with very high anti-CII levels showed in vitro induction of pro-inflammatory cytokines by anti-CII-containing IC. These patients also had a distinct phenotype with elevated laboratory signs of inflammation and increased radiological erosions at the time of diagnosis.

In another in vitro model, co-cultured macrophages and RA synovial fibroblasts stimulated with anti-CII IC induced the production of matrix metalloproteinases (MMP)-1 and MMP-8, enzymes responsible for the initial cleavage of CII during cartilage degradation. This was mediated via production of TNF-α and IL-1β, and especially anti-CII IC-induced IL-1β sup-ported the production of MMP-1. The presence of anti-CII antibodies in patients with early synovitis was not predictive for future RA development.

In summary, I have shown how anti-CII-containing IC may explain part of the early pathogenesis and can define a distinct clinical phenotype in RA patients with high levels of anti-CII.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 444
National Category
Immunology in the medical area
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-100483 (URN)978-91-554-7486-7 (ISBN)
Public defence
2009-05-13, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjöldsv. 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-04-22 Created: 2009-04-01 Last updated: 2010-05-28Bibliographically approved

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Mullazehi, MohammedMathsson, LindaRönnelid, Johan

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