Gain-of-function polymorphism in mouse and human Ltk:: implications for the pathogenesis of systemic lupus erythematosus
Gain-of-function polymorphism in mouse and human Ltk:: implications for the pathogenesis of systemic lupus erythematosus
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DOI：
10.1093/hmg/ddh020
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发表时间：
2004-01-15
影响因子：
3.5
通讯作者：
Hirose, S
中科院分区：
文献类型：
--
作者：
Li, N;Nakamura, K;Hirose, S
系统性红斑狼疮（systemic lupus erythematosus，SLE）是一种复杂的多基因疾病，是典型的抗体介导的自身免疫性疾病，其特征在于产生针对多种自身抗原的自身抗体和免疫复合物型组织炎症，最突出的是肾脏。有证据表明，诱发自身反应性B细胞异常增殖/成熟的遗传因素引发并传播疾病。在SLE易感的新西兰黑（NZB）小鼠及其与新西兰白色（NZW）小鼠杂交的F-1中，B细胞异常主要归因于自身反应性CD 5（+）B1细胞。我们的全基因组扫描，以寻找这些小鼠中B1细胞异常激活的易感基因，结果表明，编码白细胞酪氨酸激酶（LTK）的基因Ltk是一个可能的候选基因。LTK是一种受体型蛋白酪氨酸激酶，属于胰岛素受体超家族，主要在B淋巴细胞前体和神经元组织中表达。该基因的序列和功能分析表明，NZB在磷脂酰肌醇3-激酶（PI 3 K）的p85亚基的结合基序YXXM附近的LTK激酶结构域中具有功能获得性多态性。SLE患者也存在这种Ltk多态性，其频率显著高于健康对照。我们的研究结果表明，这些多态性LTKs引起的PI 3 K通路的上调，并可能形成一个遗传易感性的自我反应性B细胞异常增殖的SLE。
Systemic lupus erythematosus (SLE), a complex multigenic disease, is a typical antibody-mediated autoimmune disease characterized by production of autoantibodies against a variety of autoantigens and immune complex-type tissue inflammation, most prominently in the kidney. Evidence suggests that genetic factors predisposing to aberrant proliferation/maturation of self-reactive B cells initiate and propagate the disease. In SLE-prone New Zealand Black (NZB) mice and their F-1 cross with New Zealand White (NZW) mice, B cell abnormalities can be ascribed mainly to self-reactive CD5(+) B1 cells. Our genome-wide scans to search for susceptibility genes for aberrant activation of B1 cells in these mice showed evidence that the gene, Ltk, encoding leukocyte tyrosine kinase (LTK), is a possible candidate. LTK is a receptor-type protein tyrosine kinase, belonging to the insulin receptor superfamily, and is mainly expressed in B lymphocyte precursors and neuronal tissues. Sequence and functional analyses of the gene revealed that NZB has a gain-of-function polymorphism in the LTK kinase domain near YXXM, a binding motif of the p85 subunit of phosphatidylinositol 3-kinase (PI3K). SLE patients also had this type of Ltk polymorphism with a significantly higher frequency compared with the healthy controls. Our findings suggest that these polymorphic LTKs cause up-regulation of the PI3K pathway and possibly form one genetic component of susceptibility to abnormal proliferation of self-reactive B cells in SLE.