Polymorphisms in IgG Fc receptor IIB regulatory regions associated with autoimmune susceptibility
Polymorphisms in IgG Fc receptor IIB regulatory regions associated with autoimmune susceptibility
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DOI：
10.1007/s002510050641
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发表时间：
2000-05-01
期刊：
影响因子：
3.2
通讯作者：
Shirai, T
中科院分区：
文献类型：
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作者：
Jiang, Y;Hirose, S;Shirai, T
自身免疫性疾病涉及多个基因。虽然这些基因的功能在很大程度上是未知的，但有些可能与B细胞的内在高反应性有关。B细胞应答由通过B细胞抗原受体（BCR）复合物的信号传导阈值控制。II型IgG Pc受体的B1同种型（Fc γ RIIB 1）仅在B细胞上表达，并作为抑制BCR引发的活化的负调节因子。因此，它的等位基因变异与功能缺陷，可以检查可能与自身免疫性疾病的易感性。我们发现，在小鼠品系中报道的Fc γ RIIB转录调控区中存在三种类型的多态性。与正常健康小鼠品系（第III组）相比，自身免疫性疾病易感品系（第I组）共有三个缺失位点：两个在启动子区，一个在第三内含子。菌株（组II）本身不容易发生自身免疫，但有可能加速自身免疫性疾病，在第三内含子中共有两个缺失位点：一个与组I中的相同，另一个是组II特有的。这些多态性与抗原刺激后生发中心B细胞中Fc γ RIIB 1表达的下调程度和IgG抗体应答的上调密切相关。我们的数据表明，这些Fc γ RIIB多态性是进化选择的自然防御病原体，这样的多态性，反过来，可能形成的基础上的一个方面的自身免疫易感性。
Autoimmune diseases involve multiple genes. While functions of these genes are largely unknown, some may be related to an intrinsic hyperresponsiveness of B cells. B-cell responses are controlled by signaling thresholds through the B-cell antigen receptor (BCR) complex. The B1 isoform of type II IgG Pc receptors (Fc gamma RIIB1) is exclusively expressed on B cells and serves as a negative regulator for inhibiting BCR-elicited activation. Thus, its allelic variants associated with functional deficits could be examined for possible associations with susceptibility to autoimmune diseases. We found that there are three types of polymorphisms in the reported Fc gamma RIIB transcription regulatory regions in mouse strains. Compared to normal healthy mouse strains (group III), autoimmune disease-prone strains (group I) share three deletion sites: two in the promoter region and one in the third intron. Strains (group II) that per se are not autoimmune-prone, but have potentials to accelerate autoimmune diseases share two deletion sites in the third intron: one identical to that in group I and the other unique to group II. These polymorphisms correlated well with extents of down-regulation of Fc gamma RIIB1 expression in germinal-center B cells upon stimulation with antigens and upregulation of IgG antibody responses. Our data imply that these Fc gamma RIIB polymorphisms are selected evolutionarily for natural defense against pathogens, and that such polymorphisms may, in turn, form the basis of one aspect of autoimmune susceptibility.