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The Role of Fc Gamma Receptors in Experimental Arthritis
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Induction of collagen-induced arthritis (CIA), an animal model for human rheumatoid arthritis, is dependent on anti-collagen type II (CII) antibodies. The effector mechanism by which autoantibodies contribute to inflammatory reactions in autoimmune diseases is not well understood. In this thesis I have studied the effector pathways used by IgG anti-CII antibodies to initiate arthritis, namely the IgG Fc receptors (FcγRs) and the complement system. We have found that FcγRIII is crucial for development of CIA, as CII-immunized mice lacking this receptor do not develop arthritis and IgG1 and IgG2b anti-CII antibodies require FcγRIII to trigger arthritis when transferred to naïve mice. The antibody-mediated arthritis was further enhanced in mice deficient in the inhibitory FcγRIIB, indicating that FcγRIIB regulates the activation of FcγRIII. Furthermore, we demonstrate that FcγRIII exist as three distinct haplotypes in mice, FcγRIII:H, FcγRIII:V and FcγRIII:T. Mice expressing the FcγRIII:H haplotype are more susceptible to CIA than mice expressing the FcγRIII:V haplotype, indicating that certain FcγRIII haplotype predisposes for CIA. We also show that the most likely FcγRIII-expressing effector cell in CIA is the macrophage, since FcγRIII-expressing macrophages exclusively can induce arthritis in FcγRIII-deficient mice challenged for CIA.

The complement system was also investigated in development of CIA. We found that this effector pathway is also necessary for onset of arthritis, as CIA was inhibited by treatment with anti-complement factor 5 (C5) antibodies. C5-deficient mice could neither develop CIA unless provided with C5-containing sera.

Taken together, the work presented in this thesis indicates that FcγRs and the complement system are crucial for the induction of experimental arthritis. These findings are important for understanding the mechanisms behind rheumatoid arthritis and blocking of these effector pathways may in the future be used as treatment of rheumatoid arthritis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 56
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1397
Keywords [en]
Immunology, Rheumatoid arthritis, Antibodies, Fc receptors, Complement, Transgenic/Knockout mice
Keywords [sv]
Immunologi
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-4724ISBN: 91-554-6123-9 (print)OAI: oai:DiVA.org:uu-4724DiVA, id: diva2:165585
Public defence
2005-02-04, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-01-14 Created: 2005-01-14 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Expression of FcγRIII is required for development of collagen-induced arthritis
Open this publication in new window or tab >>Expression of FcγRIII is required for development of collagen-induced arthritis
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2002 In: European Journal of Immunology, Vol. 32, p. 2915-2922Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92480 (URN)
Available from: 2005-01-14 Created: 2005-01-14Bibliographically approved
2. FcγRIII-expressing macrophages are essential for the development of collagen-induced arthritis
Open this publication in new window or tab >>FcγRIII-expressing macrophages are essential for the development of collagen-induced arthritis
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-92481 (URN)
Available from: 2005-01-14 Created: 2005-01-14 Last updated: 2010-01-13Bibliographically approved
3. Induction of arthritis by single monoclonal IgG anti-collagen type II antibodies and enhancement of arthritis in mice lacking inhibitory FcγRIIB
Open this publication in new window or tab >>Induction of arthritis by single monoclonal IgG anti-collagen type II antibodies and enhancement of arthritis in mice lacking inhibitory FcγRIIB
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2003 In: European Journal of Immunology, Vol. 33, p. 2269-2277Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92482 (URN)
Available from: 2005-01-14 Created: 2005-01-14Bibliographically approved
4. IgG Fc receptor polymorphisms and C5 influence susceptibility to collagen-induced arthritis
Open this publication in new window or tab >>IgG Fc receptor polymorphisms and C5 influence susceptibility to collagen-induced arthritis
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-92483 (URN)
Available from: 2005-01-14 Created: 2005-01-14Bibliographically approved

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