A signal adaptor SLAM-associated protein regulates spontaneous autoimmunity and Fas-dependent lymphoproliferation in MRL-Faslpr lupus mice
A signal adaptor SLAM-associated protein regulates spontaneous autoimmunity and Fas-dependent lymphoproliferation in MRL-Faslpr lupus mice
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DOI：
10.4049/jimmunol.176.1.395
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发表时间：
2006-01-01
影响因子：
4.4
通讯作者：
Ono, M
中科院分区：
文献类型：
--
作者：
Komori, H;Furukawa, H;Ono, M
自身抗体的产生和淋巴结病是系统性自身免疫性疾病的共同特征。小鼠生殖系中的定向或自发突变已经产生了许多具有这些特征的自身免疫模型。重要的是，这些模型为该基因在预防自身免疫中的功能提供了证据，表明该基因在正常免疫反应和动态平衡中发挥着不可或缺的作用。我们在这里描述了一种新的小鼠突变株的病理学和遗传学特征，该突变株自发地发生在Fas缺陷株MRL/Mp.Fas(LPR)(MRL/LPR)中。众所周知，MRL/LPR可以稳定地显示系统性红斑狼疮样疾病。然而，突变的小鼠几乎没有表现出自身免疫表型，尽管最初的Fas表达缺陷没有改变。对(突变体MRL/LPR X C3H/LPR)F-2小鼠的连锁分析表明，核苷酸插入导致了小接头蛋白、信号淋巴细胞激活分子(SLAM)相关蛋白(SAP)的表达缺失。SAP是SLAM家族受体的下游分子，介导酪氨酸激酶Fyn的激活信号。最近的研究表明，SAP在T、B和NK细胞激活和NKT细胞发育中具有多效性作用。本研究将为SAP在MRL/LPR狼疮小鼠的自身免疫性疾病、自身抗体和淋巴结病的发生中发挥重要作用提供证据。
Autoantibody production and lymphadenopathy are common features of systemic autoimmune disease. Targeted or spontaneous mutations in the mouse germline have generated many autoimmune models with these features. Importantly, the models have provided evidence for the gene function in prevention of autoimmunity, suggesting an indispensable role for the gene in normal immune response and homeostasis. We describe here pathological and genetic characterizations of a new mutant strain of mice, the mutation of which spontaneously occurred in the Fas-deficient strain, MRL/Mp.Fas(lpr) (MRL/lpr). MRL/lpr is known to stably exhibit systemic lupus erythematosus-like diseases. However, the mutant mice barely displayed autoimmune phenotypes, though the original defect in Fas expression was unchanged. Linkage analysis using (mutant MRL/lpr X C3H/lpr)F-2 mice demonstrated a nucleotide insertion that caused loss of expression of small adaptor protein, signaling lymphocyte activation molecule (SLAM)associated protein (SAP). SAP is known to be a downstream molecule of SLAM family receptors and to mediate the activation signal for tyrosine kinase Fyn. Recent studies have shown pleiotropic roles of SAP in T, B, and NK cell activations and NKT cell development. The present study will provide evidence for an essential role for SAP in the development of autoimmune diseases, autoantibodies, and lymphadenopathy in MRL/lpr lupus mice.