Activation-Induced Cytidine Deaminase Deficiency Causes Organ-Specific Autoimmune Disease
Activation-Induced Cytidine Deaminase Deficiency Causes Organ-Specific Autoimmune Disease
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DOI：
10.1371/journal.pone.0003033
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发表时间：
2008-08-21
期刊：
影响因子：
3.7
通讯作者：
Ohno, Hiroshi
中科院分区：
文献类型：
--
作者：
Hase, Koji;Takahashi, Daisuke;Ohno, Hiroshi
生发中心B细胞表达的激活诱导胞苷脱氨酶（AID）是体细胞超突变（SHM）和类开关重组（CSR）的中心调控因子。携带AID突变的人不仅会出现与B细胞增生相关的常染色体隐性高igm综合征（HIGM2），还会出现机制未知的自身免疫性疾病。我们在此报道AID（-/-）小鼠在大约6月龄时自发地在包括胃在内的非淋巴组织中发育出三级淋巴器官（TLOs）。在后期，AID（-/-）小鼠发展为严重的胃炎，其特征是胃腺丧失和上皮增生。即使在无菌（GF）条件下，疾病的发展也没有减弱。AID（-/-）小鼠胃自身抗原特异性血清IgM升高，血清IgM水平与胃炎病理评分相关。过继性转移实验提示自身免疫CD4(+) T细胞作为末端效应细胞介导胃炎的发生。这些结果表明，由于AID缺乏导致的异常b细胞扩增可以驱动b细胞自身免疫，进而促进TLO的形成，最终导致器官特异性自身免疫效应CD4(+) T细胞的繁殖。因此，AID通过对自身反应性B细胞的负调控，在自身免疫性疾病的遏制中起着重要作用。
Activation-induced cytidine deaminase (AID) expressed by germinal center B cells is a central regulator of somatic hypermutation (SHM) and class switch recombination (CSR). Humans with AID mutations develop not only the autosomal recessive form of hyper-IgM syndrome (HIGM2) associated with B cell hyperplasia, but also autoimmune disorders by unknown mechanisms. We report here that AID(-/-) mice spontaneously develop tertiary lymphoid organs (TLOs) in non-lymphoid tissues including the stomach at around 6 months of age. At a later stage, AID(-/-) mice develop a severe gastritis characterized by loss of gastric glands and epithelial hyperplasia. The disease development was not attenuated even under germ-free (GF) conditions. Gastric autoantigen -specific serum IgM was elevated in AID(-/-) mice, and the serum levels correlated with the gastritis pathological score. Adoptive transfer experiments suggest that autoimmune CD4(+) T cells mediate gastritis development as terminal effector cells. These results suggest that abnormal B-cell expansion due to AID deficiency can drive B-cell autoimmunity, and in turn promote TLO formation, which ultimately leads to the propagation of organ-specific autoimmune effector CD4(+) T cells. Thus, AID plays an important role in the containment of autoimmune diseases by negative regulation of autoreactive B cells.