Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene.
Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene.
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DOI：
10.4049/jimmunol.0900367
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发表时间：
2009-11-15
期刊：
影响因子：
--
通讯作者：
Thomas JW
中科院分区：
文献类型：
--
作者：
Kendall PL;Moore DJ;Hulbert C;Hoek KL;Khan WN;Thomas JW
1型糖尿病是由T细胞介导的对产生胰岛素的β细胞的破坏引起的。虽然消除B淋巴细胞已被证明在预防疾病方面是成功的，但调节B细胞功能作为预防1型糖尿病的手段尚未被研究。B淋巴细胞的发育、命运和功能依赖于BCR信号传导，其部分由布鲁顿酪氨酸激酶（BTK）介导。当引入NOD小鼠时，btk缺陷仅适度减少B细胞数量，但显着防止糖尿病。在NOD中，btk缺陷反映了在其他菌株中观察到的B细胞亚群的变化，但也改善了B细胞相关的耐受性，如不能产生胰岛素自身抗体所示。抗胰岛素BCR H链转基因的引入恢复了btk缺陷型NOD小鼠的糖尿病，表明如果btk缺陷型B细胞具有关键的自身免疫特异性，则它们在功能上能够促进自身免疫糖尿病。这表明btk缺陷的疾病保护作用可能反映了B细胞库中自身反应特异性的缺乏。因此，可以调节经由BTK的信号传导以改善B细胞耐受性，并预防T细胞介导的自身免疫性糖尿病。
Type 1 diabetes results from T cell-mediated destruction of insulin-producing β cells. Although elimination of B lymphocytes has proven successful at preventing disease, modulation of B cell function as a means to prevent type 1 diabetes has not been investigated. The development, fate, and function of B lymphocytes depend upon BCR signaling, which is mediated in part by Bruton’s tyrosine kinase (BTK). When introduced into NOD mice, btk deficiency only modestly reduces B cell numbers, but dramatically protects against diabetes. In NOD, btk deficiency mirrors changes in B cell subsets seen in other strains, but also improves B cell-related tolerance, as indicated by failure to generate insulin autoantibodies. Introduction of an anti-insulin BCR H chain transgene restores diabetes in btk-deficient NOD mice, indicating that btk-deficient B cells are functionally capable of promoting autoimmune diabetes if they have a critical autoimmune specificity. This suggests that the disease-protective effect of btk deficiency may reflect a lack of autoreactive specificities in the B cell repertoire. Thus, signaling via BTK can be modulated to improve B cell tolerance, and prevent T cell-mediated autoimmune diabetes.
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