Roles of Bcl-3 in the pathogenesis of murine type 1 diabetes.
Roles of Bcl-3 in the pathogenesis of murine type 1 diabetes.
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作者：
Ruan Q;Zheng SJ;Palmer S;Carmody RJ;Chen YH
长期以来，人们认识到自身免疫常常与免疫缺陷有关。这一悖论背后的机制尚不清楚。Bcl-3（B细胞淋巴瘤3）是IκB（核因子-κB的抑制剂）家族的非典型成员，其是淋巴器官发生和生殖中心反应所需的。由于淋巴器官的微结构缺陷，缺乏Bcl-3的小鼠具有免疫缺陷。本研究的目的是确定Bcl-3在1型糖尿病中的潜在作用。通过将Bcl-3缺陷型C57 BL/6小鼠与NOD小鼠回交产生Bcl-3缺陷型NOD小鼠。通过病理学和免疫学方法研究了这些小鼠自发和诱导的1型糖尿病。Bcl-3对炎症基因转录的影响在启动子报告基因测定中进行评估。我们发现Bcl-3缺陷型NOD和C57 BL/6小鼠比野生型小鼠更容易患自身免疫性糖尿病。糖尿病易感性的增加是由造血细胞而非非造血细胞中的Bcl-3缺陷引起的。Bcl-3缺陷并没有显着影响抗胰岛Th 1或Th 2自身免疫反应，但显着增加炎性趋化因子和辅助性T细胞17（Th 17）型细胞因子的表达。转染后，Bcl-3显着抑制炎症趋化因子和细胞因子基因的启动子活性。这些结果表明，除了介导淋巴器官发生，Bcl-3通过抑制炎性趋化因子和细胞因子基因转录来预防自身免疫性糖尿病。因此，单个Bcl 3基因突变导致自身免疫和免疫缺陷。
It has long been recognized that autoimmunity is often associated with immunodeficiency. The mechanism underlying this paradox is not well understood. Bcl-3 (B-cell lymphoma 3) is an atypical member of the IκB (inhibitor of the nuclear factor-κB) family that is required for lymphoid organogenesis and germinal center responses. Mice deficient in Bcl-3 are immunodeficient because of the microarchitectural defects of their lymphoid organs. The goal of this study is to define the potential roles of Bcl-3 in type 1 diabetes. Bcl-3–deficient NOD mice were generated by backcrossing Bcl-3–deficient C57BL/6 mice to NOD mice. Spontaneous and induced type 1 diabetes were studied in these mice by both pathologic and immunologic means. The effect of Bcl-3 on inflammatory gene transcription was evaluated in a promoter reporter assay. We found that Bcl-3–deficient NOD and C57BL/6 mice were, paradoxically, more susceptible to autoimmune diabetes than wild-type mice. The increase in diabetes susceptibility was caused by Bcl-3 deficiency in hematopoietic cells but not nonhematopoietic cells. Bcl-3 deficiency did not significantly affect anti-islet Th1 or Th2 autoimmune responses, but markedly increased inflammatory chemokine and T helper 17 (Th17)-type cytokine expression. Upon transfection, Bcl-3 significantly inhibited the promoter activities of inflammatory chemokine and cytokine genes. These results indicate that in addition to mediating lymphoid organogenesis, Bcl-3 prevents autoimmune diabetes by inhibiting inflammatory chemokine and cytokine gene transcription. Thus, a single Bcl3 gene mutation leads to both autoimmunity and immunodeficiency.
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影响因子：
4.8
作者：
Muehlbauer, Marcus;Chilton, Paula M.;Jobin, Christian
通讯作者：
Jobin, Christian
DOI：
10.1073/pnas.89.6.2489
发表时间：
1992-03-15
影响因子：
11.1
作者：
HATADA, EN;NIETERS, A;SCHEIDEREIT, C
通讯作者：
SCHEIDEREIT, C
影响因子：
5.3
作者：
NOLAN, GP;FUJITA, T;BALTIMORE, D
通讯作者：
BALTIMORE, D
影响因子：
7.7
作者：
Ma, LL;Qian, SG;Lu, L
通讯作者：
Lu, L
影响因子：
10.5
作者：
KERR, LD;DUCKETT, CS;VERMA, IM
通讯作者：
VERMA, IM