摘要：

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, FcγRIIB, a potent negative regulator of the BCR. To test this possibility, we determined the development of RF in C57BL/6 (B6) mice lacking FcγRIIB, in relation to the H2 haplotype, complement C3, and the Y-linked autoimmune acceleration ( Yaa ) mutation. FcγRIIB-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 H2 b haplotype, but were suppressed almost completely by the H2 d haplotype. Strikingly, the absence of C3 failed to modulate RF production, but strongly inhibited anti-DNA production. Furthermore, we observed that partial FcγRIIB deficiency (i.e., heterozygous level of FcγRIIB expression) was sufficient to induce the production of RF and anti-DNA autoantibodies in the presence of the Yaa mutation. In contrast to FcγRIIB, 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 FcγRIIB, together with the H2 b and Yaa gene, while C3 regulates positively and specifically anti-DNA, but not RF autoimmune responses. Rheumatoid factors (RF) 3 are defined as autoantibodies with specificity for the Fc portion of IgG. The presence of RF is a characteristic feature of patients with rheumatoid arthritis, and RF-containing immune complexes (IC) could contribute to several pathological manifestations, such as necrotizing arteritis and arthritis, in these patients. The development of similar lesions in lupus-prone MRL- lpr/lpr mice deficient in the Fas apoptosis receptor ( 1 , 2 , 3 ) is likely related to the fact that these mice spontaneously produce high titers of RF ( 4 , 5 , 6 ). The activation of RF-specific B cells results from BCR-dependent uptake of IC, presentation of antigenic peptides derived from IC, and interaction with Ag-specific T cells. However, this process is likely to be tightly controlled, because RF activities are hardly detectable in sera from nonautoimmune mice, and the spontaneous production of RF is not a common feature of systemic lupus erythematosus. It has been shown that the only murine strains that spontaneously produce high titers of RF are deficient in Fas-mediated apoptosis ( 5 , 6 ). The absence of substantial RF production in mice is likely to be related to the unique feature of the autoantigens involved in RF autoimmune responses; high-affinity RF-producing B cells, generated during the germinal center response from low-affinity RF-specific B cells activated by IC, should be eliminated efficiently by apoptosis through interaction with excess amounts of monomeric IgG. Notably, activated B cells in the germinal center are particularly sensitive to apoptosis because of their down-regulated Bcl-2 and up-regulated Fas expression ( 7 ). This is consistent with our recent finding that autoimmune-prone mice overexpressing a Bcl-2 transgene in B cells are able to produce substantial titers of RF ( 8 ). In addition, the activation of RF-producing B cells can be inhibited through the interaction of RF autoantigens (i.e., IgG present in IC) with the low-affinity IgG FcR, FcγRIIB. FcγRIIB is an inhibitory receptor containing an ITIM motif and, upon its coligation to the BCR, recruits the inositol polyphosphate phosphatase. This leads to the hydrolysis of phosphatidylinositol 3,4,5-triphosphate and prevents further activation of BCR signaling ( 9 ). Thus, FcγRIIB sets thresholds for the IC-mediated activation of B cells. Consequently, FcγRIIB could efficiently down-regulate the development of RF autoimmune responses more selectively than other autoimmune responses, such as anti-DNA. Since mice deficient in FcγRIIB can

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