Specifity and genetic control of B cell reactivity in experimental arthritis

Detta är en avhandling från Patrik Wernhoff, Department of Cell and Molecular Biology, Section for Medical Inflammation Research, I 11/BMC, 221 84 Lund

Sammanfattning: Collagen-induced arthritis (CIA) and pristane-induced arthritis (PIA) are animal models for human rheumatoid arthritis (RA), and can be induced in susceptible mouse and rat strains. CIA is induced by immunization of type II collagen (CII), a cartilage specific protein together with Freund’s adjuvant. PIA is induced by intradermal injection of pristane (2,6,10,14-tetrametylpentadecane). In rats, induction of CIA is both T and B-cell dependent, whereas PIA induces a chronic T-cell dependent arthritis. In this study we focused on the role of B-cells in both the CIA and the PIA model. In rats, immunization of CII induces a strong B-cell response against CII, characterized by rapid IgG production. The B-cell recognition of rat CII was analyzed for epitope specificity and V gene selection. We were able to characterize several epitopes on the CII molecule. The recognition tended to be directed against the CB-11 fragment of CII. Interestingly, some of the selected epitopes were shared between species. The major epitope, as recognized by several different antibodies, was shared with the mouse, as previously defined. One epitope, defined from the rat response, was also predominantly recognized in RA patients. Analyze of the V genes showed a biased usage for specific epitopes, The VHQ52 and Vk12/13 families was predominantly used. Individual V genes displayed germline characteristics, The genetic control of B-cell responses was analyzed in a cross between E3 and DA. In the F2 progeny, we investigated the levels of rheumatoid factor, total immunoglobulin and isotype production. A total genome scan revealed linkages to previously defined disease loci. Rheumatoid factor production was controlled by a major locus (Rf1) on chromosome 11

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