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High synovial expression of the inhibitory Fc gamma RIIb in rheumatoid arthritis
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology.
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2007 (English)In: Arthritis Research & Therapy, ISSN 1478-6362, Vol. 9, no 3, R51- p.Article in journal (Refereed) Published
Abstract [en]

Activating Fc gamma receptors (FcγRs) have been identified as having important roles in the inflammatory joint reaction in rheumatoid arthritis (RA) and murine models of arthritis. However, the role of the inhibitory FcγRIIb in the regulation of the synovial inflammation in RA is less known. Here we have investigated synovial tissue from RA patients using a novel monoclonal antibody (GB3) specific for the FcγRIIb isoform. FcγRIIb was abundantly expressed in synovia of RA patients, in sharp contrast to the absence or weak staining of FcγRIIb in synovial biopsies from healthy volunteers. In addition, the expression of FcγRI, FcγRII and FcγRIII was analyzed in synovia obtained from early and late stages of RA. Compared with healthy synovia, which expressed FcγRII, FcγRIII but not FcγRI, all activating FcγRs were expressed and significantly up-regulated in RA, regardless of disease duration. Macrophages were one of the major cell types in the RA synovium expressing FcγRIIb and the activating FcγRs. Anti-inflammatory treatment with glucocorticoids reduced FcγR expression in arthritic joints, particularly that of FcγRI. This study demonstrates for the first time that RA patients do not fail to up-regulate FcγRIIb upon synovial inflammation, but suggests that the balance between expression of the inhibitory FcγRIIb and activating FcγRs may be in favour of the latter throughout the disease course. Anti-inflammatory drugs that target activating FcγRs may represent valuable therapeutics in this disease.

Place, publisher, year, edition, pages
2007. Vol. 9, no 3, R51- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-12874DOI: 10.1186/ar2206ISI: 000248809300016PubMedID: 17521421OAI: oai:DiVA.org:uu-12874DiVA: diva2:40644
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2011-01-27Bibliographically approved
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 611
fc gamma receptors, rheumatoid arthritis, antibodies, mast cells, mast cell
National Category
Research subject
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)
Available from: 2009-03-27 Created: 2009-03-05 Last updated: 2011-01-27Bibliographically approved

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