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Amelioration of collagen-induced arthritis by human recombinant soluble FcγRIIb
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. (Sandra Kleinau)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. (Sandra Kleinau)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. (Sandra Kleinau)
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2008 (English)In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 127, no 2, 225-233 p.Article in journal (Refereed) Published
Abstract [en]

Immune complex (IC) binding to Fc gamma receptors (FcγRs) is central for inflammatory reactions seen in autoimmune diseases. Consequently, a therapeutic agent with a possibility to interfere with binding of pathogenic IC to FcγRs would be valuable in autoimmune disorders such as rheumatoid arthritis (RA). Here we have explored the therapeutic effect of a recombinant solublehuman FcγRIIb (sFcγRIIb) protein in collagen-induced arthritis (CIA). In vitro studies of the sFcγRIIb demonstrated binding to mouse IgG, suggesting that sFcγRIIb can absorb pathogenic IgG anticollagen type II (CII) IC in vivo. Hence, administration of sFcγRIIb significantly reduced CIA severity compared to control treated mice. The sFcγRIIb treated mice had significantly less IgG anti-CII antibodies in serum and lowermRNA levels of inflammatory cytokines compared to controlmice. In conclusion, sFcγRIIb treatment ameliorates CIA by reducing IC-stimulated inflammation and joint swelling. This suggests that recombinant sFcγRIIb may be useful as therapeutic agent in RA.

Place, publisher, year, edition, pages
2008. Vol. 127, no 2, 225-233 p.
Keyword [en]
Fc gamma receptors, Collagen-induced arthritis, Mice, Autoimmunity, Therapy, Antibody, Rheumatology, Cytokines
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-98880DOI: 10.1016/j.clim.2008.02.002ISI: 000255231100015PubMedID: 18346938OAI: oai:DiVA.org:uu-98880DiVA: diva2:201459
Available from: 2009-03-04 Created: 2009-03-04 Last updated: 2017-12-13Bibliographically 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.
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
2. B cells in Autoimmunity: Studies of Complement Receptor 1 & 2 and FcγRIIb in Autoimmune Arthritis
Open this publication in new window or tab >>B cells in Autoimmunity: Studies of Complement Receptor 1 & 2 and FcγRIIb in Autoimmune Arthritis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

B cells are normally regulated to prevent activation against self-proteins through tolerance mechanisms.  However, occasionally there is a break in tolerance and B cells can become self-reactive, which might lead to the development of autoimmune disease. The activation of self-reactive B cells is regulated by receptors on the B cell surface, such as Fc gamma receptor IIb (FcγRIIb), complement receptor type 1 (CR1), and CR type 2 (CR2).

In this thesis I have studied the role of FcγRIIb, CR1 and CR2 on B cells in autoimmune arthritis. By using a model for rheumatoid arthritis, I discovered that the initial self-reactive B cell response in arthritis was associated with the splenic marginal zone B cell population. Marginal zone B cells express high levels of CR1/CR2 and FcγRIIb, suggesting that they normally require high regulation. Further, female mice deficient in CR1/CR2 displayed increased susceptibility to arthritis compared to CR1/CR2-sufficient female mice. When investigating whether sex hormones affected arthritis susceptibility, we found that ovariectomy, of the otherwise fairly resistant CR1/CR2-sufficient mice, reduced the expression of CR1 on B cells and rendered the mice more susceptible to arthritis.

In humans, a significantly reduced CR1 and FcγRIIb expression was found on B cells in aging women, but not in men. This may contribute to the increased risk for women to develop autoimmune disease as reduced receptor expression may lead to the activation of self-reactive B cells. In agreement, lower CR1, CR2 and FcγRIIb expression was seen in patients with rheumatoid arthritis.

 

Finally, a soluble form of FcγRIIb was used to investigate FcγRIIb’s ability to bind self-reactive IgG in an attempt to treat autoimmune arthritis. Treatment of mice with established arthritis was associated with less self-reactive IgG antibodies and consequently less disease, suggesting that soluble FcγRIIb may be used as a novel treatment in arthritis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 680
Keyword
B cells, complement receptors, fc gamma receptor IIb, autoimmune arthritis, rheumatoid arthritis
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-109428 (URN)978-91-554-7629-8 (ISBN)
Public defence
2009-11-27, C8:301, Uppsala Biomedical Center, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-11-06 Created: 2009-10-15 Last updated: 2009-11-06Bibliographically approved

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