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RIIB in the Induction of Rheumatoid Factors1
* Department of Pathology and Immunology, Centre Médical Universitaire, Geneva, Switzerland;
Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany;
Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, MA 02115; and
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021
Rheumatoid factors (RF) are autoantibodies with specificity for the Fc portion of IgG, and IgG-containing immune complexes are likely to be the major source of RF autoantigens. Therefore, the activation of RF-producing B cells could be controlled specifically through recognition of IgG immune complexes by the low-affinity IgG FcR, Fc
RIIB, a potent negative regulator of the BCR. To test this possibility, we determined the development of RF in C57BL/6 (B6) mice lacking FcRIIB, in relation to the H2 haplotype, complement C3, and the Y-linked autoimmune acceleration (Yaa) mutation. FcRIIB-null B6 mice displayed substantial anti-IgG2a RF activities in their sera, in addition to anti-DNA autoantibodies. Their RF and anti-DNA responses were linked to the H2b haplotype, but were suppressed almost completely by the H2d haplotype. Strikingly, the absence of C3 failed to modulate RF production, but strongly inhibited anti-DNA production. Furthermore, we observed that partial FcRIIB deficiency (i.e., heterozygous level of FcRIIB expression) was sufficient to induce the production of RF and anti-DNA autoantibodies in the presence of the Yaa mutation. In contrast to FcRIIB, the deficiency in another BCR negative regulator, CD22, was unable to promote RF and anti-DNA autoimmune responses in B6 mice. Our results indicate that RF autoimmune responses are critically controlled by FcRIIB, together with the H2b and Yaa gene, while C3 regulates positively and specifically anti-DNA, but not RF autoimmune responses.
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