Genetic dissection of the effects of stimulatory and inhibitory IgG fc receptors on murine lupus
Genetic dissection of the effects of stimulatory and inhibitory IgG fc receptors on murine lupus
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DOI：
10.4049/jimmunol.177.3.1646
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发表时间：
2006-08-01
影响因子：
4.4
通讯作者：
Hirose, Sachiko
中科院分区：
文献类型：
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作者：
Lin, Qingshun;Xiu, Yan;Hirose, Sachiko
免疫复合体(IC)介导的组织炎症由刺激和抑制免疫球蛋白Fc受体(Fc-Gamma Rs)控制。系统性红斑狼疮是IC介导的自身免疫性疾病的一个原型，因此，这两种Fc-γ受体的失衡可能参与了其发病机制。然而，每个Fc-Gamma R如何以及在多大程度上导致这种疾病仍不清楚。在易患狼疮的BXSB小鼠中，虽然刺激的Fc-Gamma受体是完整的，但由于启动子区域的多态性，抑制的Fc-Gamma RIIB的表达受到了损害。为了分析刺激和抑制FcγRs的作用，我们建立了两个基因操纵的BXSB菌株：一个缺乏刺激Fc Gamma Rs(BXSB，Gamma(-/-))，另一个携带野生型Fcgr2b(BXSB.IIBB6/(B6))。在两个突变株中，疾病特征都明显受到抑制。然而，尽管肾功能完整，但与显示完整肾脏病理和抗DNA水平的BXSB.IIB相反，BXSB(-/-)在肾小球中有IC沉积，与高血清Ig G抗DNA抗体水平有关。与野生型BXS%一样，BXSB、GAMY(-/-)中的淋巴细胞被激活，但BXSB、IIBB6/B6中的淋巴细胞不被激活。我们的结果有力地表明，BXSB小鼠中两种类型的Fc-Gamma Rs在疾病进展过程中参与了不同的过程，其中，刺激性Fc-Gamma R在IC介导的组织炎症的效应阶段发挥作用，而BXSB-型受损的Fc-Gamma RIIB促进了自身反应性淋巴细胞的自发激活和相关的大量自身抗体和IC的产生。
Immune complex (IC)-mediated tissue inflammation is controlled by stimulatory and inhibitory IgG Fc receptors (Fc gamma Rs). Systemic lupus erythematosus is a prototype of IC-mediated autoimmune disease; thus, imbalance of these two types of Fc gamma Rs is probably involved in pathogenesis. However, how and to what extent each Fc gamma R contributes to the disease remains unclear. In lupus-prone BXSB mice, while stimulatory Fc gamma Rs are intact, inhibitory Fc gamma RIIB expression is impaired because of promoter region polymorphism. To dissect roles of stimulatory and inhibitory Fc gamma Rs, we established two gene-manipulated BXSB strains: one deficient in stimulatory Fc gamma Rs (BXSB.,gamma(-/-)) and the other carrying wild-type Fcgr2b (BXSB.IIBB6/(B6)). The disease features were markedly suppressed in both mutant strains. Despite intact renal function, however, BXSB.,gamma(-/-) had IC deposition in glomeruli associated with high-serum IgG anti-DNA Ab levels, in contrast to BXSB.IIB, which showed intact renal pathology and anti-DNA levels. Lymphocytes in BXSB.,gamma(-/-) were activated, as in wild-type BXS% but not in BXSB.IIBB6/B6. Our results strongly suggest that both types of Fc gamma Rs in BXSB mice are differently involved in the process of disease progression, in which, while stimulatory Fc gamma Rs play roles in effecter phase of IC-mediated tissue inflammation, the BXSB-type impaired Fc gamma RIIB promotes spontaneous activation of self-reactive lymphocytes and associated production of large amounts of autoantibodies and ICs.