Overexpression of activation-induced cytidine deaminase in B cells is associated with production of highly pathogenic autoantibodies
Overexpression of activation-induced cytidine deaminase in B cells is associated with production of highly pathogenic autoantibodies
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DOI：
10.4049/jimmunol.178.8.5357
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发表时间：
2007-04-15
影响因子：
4.4
通讯作者：
Mountz, John D.
中科院分区：
文献类型：
--
作者：
Hsu, Hui-Chen;Wu, Yalei;Mountz, John D.
受体编辑缺陷或B细胞检查点缺陷与自身免疫性疾病中多反应性自身抗体频率增加有关。然而，IG体细胞超突变和/或类别转换重组可能是致病性多反应性自身抗体发展的机制。在这项研究中，我们报告说，在BXD 2小鼠模型的自身免疫性疾病，激活诱导的胞苷脱氨酶（AID）的表达升高的循环滤泡CD 86（+）的B细胞亚群和增加的生发中心B细胞活性与致病性多反应性自身抗体的生产。该过程需要来自BXD 2小鼠的CD 4 T细胞，其表达增加的CD 28水平以及对抗CD 3和抗CD 28刺激的增加的增殖应答。用AdCTLA 4-IG抑制BXD 2小鼠中的CD 28-CD 86相互作用导致B细胞中AID的正常化和IgG自身抗体的抑制。这种治疗也阻止了生发中心自身抗体产生B细胞的发展，表明使AID功能的最佳微环境对于致病性自身抗体的形成是重要的。综上所述，我们的数据表明，AID在B细胞中的表达是治疗自身免疫性疾病的有希望的治疗靶点，并且该基因的抑制可能是CTLA 4-IG治疗的分子靶点。
Defective receptor editing or defective B cell checkpoints have been associated with increased frequency of multireactive auto-antibodies in autoimmune disease. However, Ig somatic hypermutation and/or class switch recombination may be mechanisms enabling the development of pathogenic multireactive autoantibodies. In this study, we report that, in the BXD2 mouse model of autoimmune disease, elevated expression of activation-induced cytidine deaminase (AID) in recirculating follicular CD86(+) subsets of B cells and increased germinal center B cell activity are associated with the production of pathogenic multireactive autoantibodies. CD4 T cells from BXD2 mice that expressed increased levels of CD28 and an increased proliferative response to anti-CD3 and anti-CD28 stimulation are required for this process. Inhibition of the CD28-CD86 interaction in BXD2 mice with AdCTLA4-Ig resulted in normalization of AID in the B cells and suppression of IgG autoantibodies. This treatment also prevented the development of germinal center autoantibody-producing B cells, suggesting that an optimal microenvironment enabling AID function is important for the formation of pathogenic autoantibodies. Taken together, our data indicate that AID expression in B cells is a promising therapeutic target for the treatment of autoimmune diseases and that suppression of this gene may be a molecular target of CTLA4-Ig therapy.