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Reduced IgG1-immune complex binding and low TNF production characterize monocytes in rheumatoid arthritis and correlates with disease status
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. (Sandra Kleinau)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. (Sandra Kleinau)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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(English)Manuscript (Other academic)
Keyword [en]
Rheumatoid arthritis, Fc gamma receptors, IgG-immune complexes, monocytes
Research subject
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-98881OAI: oai:DiVA.org:uu-98881DiVA: diva2:201464
Available from: 2009-03-04 Created: 2009-03-04 Last updated: 2010-01-14
In thesis
1. The Role of Fc gamma Receptors and Mast Cell Chymase in Autoimmune Arthritis
Open this publication in new window or tab >>The Role of Fc gamma Receptors and Mast Cell Chymase in Autoimmune Arthritis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In autoimmune diseases such as rheumatoid arthritis (RA), self-reactive antibodies are present at high levels, which contributes to disease pathogenesis. The antibodies mediate their effect predominantly by binding to Fc gamma receptors (FcγR) on various leukocytes, such as monocytes, macrophages and mast cells, where FcγR ligation leads to cell activation. In this thesis the role of FcγR in RA was investigated. We could, for the first time, demonstrate an increased expression of the inhibitory FcγRIIb in RA synovial tissue, while this receptor as well as FcγRI were almost absent in healthy synovial tissue. The enhanced FcγRI expression in RA synovia was reduced by one intraarticular injection of glucocorticoids, indicating that FcγRI participates in the joint inflammation. Interestingly, RA patients with an ongoing joint inflammation exhibited blood monocytes with immune compromised features, such as decreased FcγR binding of IgG1-IC and reduced TNF production. These effects were associated with high levels of auto-antibodies in the patients, implying that the monocyte FcγR are saturated with IgG. In order to investigate whether soluble FcγR could be used as a therapy in arthritis, we injected human soluble FcγR into mice with collagen-induced arthritis (CIA). The soluble FcγR reduced the levels of pathogenic IgG anti-collagen type II (CII) antibodies, arthritis severity and pro-inflammatory cytokines. Thus, suggesting that soluble FcγR may represent a novel therapeutic agent in RA.

We also studied the disease-aggravating role of mast cells in arthritis by investigating mouse mast cell protease-4 (mMCP-4) in CIA. We found that mMCP-4 deficient mice displayed a reduced IgG anti-CII response and reduced arthritis severity. This indicates a role for mMCP-4 in adaptive immunity.

In conclusion, these data demonstrate that IgG occupancy of FcγR and mast cell secretion of mMCP-4 play vital roles in the development of autoimmune arthritis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 611
Keyword
fc gamma receptors, rheumatoid arthritis, antibodies, mast cells, mast cell
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-98921 (URN)978-91-554-7446-1 (ISBN)
Public defence
2009-04-17, C10:305, BMC, Husargatan 3, Box 596, 751 24, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-03-27 Created: 2009-03-05 Last updated: 2011-01-27Bibliographically approved

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