The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B cell activation and systemic autoimmunity
The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B cell activation and systemic autoimmunity
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DOI：
10.4049/jimmunol.177.4.2285
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发表时间：
2006-08-15
影响因子：
4.4
通讯作者：
Acha-Orbea, Hans
中科院分区：
文献类型：
--
作者：
Genton, Celine;Wang, Ying;Acha-Orbea, Hans
Lat(Y136F) 敲入小鼠在 T 细胞激活连接子 Tyr(136) 上存在点突变，并显示 Th2 效应细胞积聚以及 IgG1 和 IgE 高丙种球蛋白血症。 B 细胞激活并不是突变对 B 细胞的直接影响，因为在没有 T 细胞的情况下，突变 B 细胞不会表现出激活的表型。将用于激活 T 细胞突变型 T 细胞的接头过继转移到野生型、T 细胞缺陷的受体中后，受体 B 细胞被激活。我们在体内和体外证明，Lat(Y136F) 突变促进 T 细胞依赖性 B 细胞激活，导致生发中心、记忆和浆细胞形成，甚至以不依赖 MHC II 类的方式。生理性 T 细胞依赖性 B 细胞反应中发现的所有血浆和记忆 B 细胞群均已被发现。对 Lat(Y136F) 小鼠次级淋巴器官中发现的丰富浆母细胞的表征揭示了先前未表征的 CD93 表达亚群的存在，该亚群的存在在免疫后的野生型小鼠中得到了证实。在 Lat(Y136F) 小鼠中，B 细胞激活是多克隆的，而不是 Ag 驱动的，因为血清 IgG1 和 IgE 浓度的增加同样涉及具有不同特异性的 Ab 和自身抗体。尽管非补体固定 IgG1 和 IgE 是 Lat(Y136F) 血清中唯一显着增加的同种型，但我们观察到早发的全身性自身免疫性肾炎，显示 IgE 自身抗体沉积和严重的蛋白尿。这些结果表明，Lat(Y136F) 小鼠中发育的 Th2 细胞可以触发多克隆 B 细胞激活，从而导致系统性自身免疫性疾病。
Lat(Y136F) knock-in mice harbor a point mutation in Tyr(136) of the linker for activation of T cells and show accumulation of Th2 effector cells and IgG1 and IgE hypergammaglobulinemia. B cell activation is not a direct effect of the mutation on B cells since in the absence of T cells, mutant B cells do not show an activated phenotype. After adoptive transfer of linker for activation of T cell mutant T cells into wild-type, T cell-deficient recipients, recipient B cells become activated. We show in vivo and in vitro that the Lat(Y136F) mutation promotes T cell-dependent B cell activation leading to germinal center, memory, and plasma cell formation even in an MHC class II-independent manner. All the plasma and memory B cell populations found in physiological T cell-dependent B cell responses are found. Characterization of the abundant plasmablasts found in secondary lymphoid organs of Lat(Y136F) mice revealed the presence of a previously uncharacterized CD93-expressing subpopulation, whose presence was confirmed in wild-type mice after immunization. In Lat(Y136F) mice, B cell activation was polyclonal and not Ag-driven because the increase in serum IgG1 and IgE concentrations involved Abs and autoantibodies with different specificities equally. Although the noncomplement-fixing IgG1 and IgE are the only isotypes significantly increased in Lat(Y136F) serum, we observed early-onset systemic autoimmunity with nephritis showing IgE autoantibody deposits and severe proteinuria. These results show that Th2 cells developing in Lat(Y136F) mice can trigger polyclonal B cell activation and thereby lead to systemic autoimmune disease.