The inhibitory Fcγ receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells
The inhibitory Fcγ receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells
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DOI：
10.1038/ni1151
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发表时间：
2005-01-01
影响因子：
30.5
通讯作者：
Ravetch, JV
中科院分区：
文献类型：
--
作者：
Fukuyama, H;Nimmerjahn, F;Ravetch, JV
编码Fc免疫球蛋白G受体IIB（Fc γ RIIB）的基因缺失导致C57 BL/6小鼠而非BALB/c小鼠发生暴发性狼疮样疾病。在这里，我们研究了这种株特异性，上位性的耐受性丧失使用基因靶向免疫球蛋白可变重链（V-H）等位基因3 H9或56 R，编码DNA特异性重链，C57 BL/6或BALB/c的背景上表达。C57 BL/6和V-H 56 R（B6.56R）的组合导致耐受性丧失;杂交瘤和单细胞分析表明免疫球蛋白轻链使用的Fc γ RIIB非依赖性差异，与受体编辑的改变一致。Fc γ RIIB缺陷导致血清中针对DNA的免疫球蛋白G（IgG）抗体增加，具有浆细胞表型的抗DNA反应性IgG（+）B细胞频率增加，以及B6.56 R小鼠肾小球和肾脏疾病中的免疫复合物沉积。因此，Fc γ RIIB提供远端外周检查点以限制自身反应性浆细胞的积累，从而维持耐受性。
Deletion of the gene encoding the Fc immunoglobulin G receptor IIB (FcgammaRIIB) results in a fulminant, lupus-like disease in C57BL/6 but not BALB/c mice. Here we have investigated this strain-specific, epistatic loss of tolerance using gene-targeted immunoglobulin variable heavy-chain (V-H) alleles 3H9 or 56R, which encode DNA-specific heavy chains, expressed on the C57BL/6 or BALB/c background. The combination of C57BL/6 and V-H 56R (B6.56R) resulted in a loss of tolerance; hybridoma and single-cell analysis indicated an FcgammaRIIB-independent difference in immunoglobulin light-chain usage, consistent with an alteration in receptor editing. FcgammaRIIB deficiency resulted in an increase in immunoglobulin G (IgG) antibodies to DNA in the serum, an increased frequency of anti-DNA-reactive IgG(+) B cells with a plasma cell phenotype and immune complex deposition in the glomeruli and renal disease in B6.56R mice. Thus, FcgammaRIIB provides a distal peripheral checkpoint to limit the accumulation of autoreactive plasma cells, thereby maintaining tolerance.