Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
J Immunol. 2018 Sep 1;201(5):1353-1358. doi: 10.4049/jimmunol.1800168. Epub 2018 Jul 18.
Genetic deletion of the Src family tyrosine kinase Lyn in mice recapitulates human systemic lupus erythematosus, characterized by hyperactive BCR signaling, splenomegaly, autoantibody generation, and glomerulonephritis. However, the molecular regulators of autoimmunity in Lyn-deficient mice and in human lupus remain poorly characterized. In this study, we report that conditional deletion of the membrane-cytoskeleton linker protein ezrin in B cells of Lyn-deficient mice (double knockout [DKO] mice) ameliorates B cell activation and lupus pathogenesis. B cells from DKO mice respond poorly to BCR stimulation, with severe downregulation of major signaling pathways. DKO mice exhibit reduced splenomegaly as well as significantly lower levels of autoantibodies against a variety of autoantigens, including dsDNA, histone, and chromatin. Leukocyte infiltration and deposition of IgG and complement component C3 in the kidney glomeruli of DKO mice are markedly reduced. Our data demonstrate that ezrin is a novel molecular regulator of B cell-associated lupus pathology.
在 Lyn 基因敲除小鼠中，Src 家族酪氨酸激酶 Lyn 的缺失可重现人类系统性红斑狼疮的特征，表现为 BCR 信号过度活跃、脾肿大、自身抗体产生和肾小球肾炎。然而，Lyn 基因敲除小鼠和人类狼疮中的自身免疫分子调节因子仍未得到充分描述。在这项研究中，我们报告称，B 细胞中膜-细胞骨架连接蛋白 ezrin 的条件性缺失可改善 Lyn 基因敲除小鼠（双重敲除 [DKO] 小鼠）中的 B 细胞激活和狼疮发病机制。DKO 小鼠的 B 细胞对 BCR 刺激的反应较差，主要信号通路严重下调。DKO 小鼠脾肿大减轻，针对多种自身抗原的自身抗体水平显著降低，包括 dsDNA、组蛋白和染色质。DKO 小鼠肾脏肾小球中的白细胞浸润和 IgG 及补体成分 C3 的沉积明显减少。我们的数据表明，ezrin 是与 B 细胞相关的狼疮病理的一种新型分子调节因子。
