Organ-specific autoimmune disease: a deficiency of tolerogenic stimulation.
Organ-specific autoimmune disease: a deficiency of tolerogenic stimulation.
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器官特异性自身免疫性疾病：耐受性刺激的缺乏。
DOI：
10.1084/jem.194.5.f31
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发表时间：
2001-09-03
影响因子：
15.3
通讯作者：
Goodnow, C C
中科院分区：
文献类型：
--
作者：
Lesage, S;Goodnow, C C
众所周知，器官特异性自身免疫性疾病在家族中发生，但在一个家族中，一个成员可能患有1型糖尿病，另一种自身免疫性甲状腺疾病和另一种多发性硬化症（1）。是什么原因导致不同的自身免疫性疾病沿着遗传线聚集，什么逻辑导致免疫系统瞄准不同的器官靶点？在这个问题上，Salomon等人做出了一个矛盾的发现，即干扰单个共刺激分子B7-2，将NOD小鼠品系中自身免疫的目标从胰岛细胞转移到外周神经上（2）。这一发现为器官特异性自身免疫性疾病的发病机制提供了重要的分子线索，并说明了在临床应用新的免疫干预措施时需要谨慎。器官特异性自身免疫性易感性的遗传非常复杂。主要组织相容性复合体的特定单倍型，如HLA-DR 3-DQB 1 * 0201，与人类对多种器官特异性自身免疫性疾病的易感性密切相关（3）。然而，HLA型只占遗传易感性的一小部分，不同HLA等位基因的杂合性可以提高或降低风险。非MHC基因AIRE的突变可引起孟德尔综合征APECED，其特征为自身免疫表现，范围从阿狄森氏病、甲状腺和甲状旁腺疾病到1型糖尿病，与HLA类型无关（4，5）。AIRE基因产物似乎是存在于一些胸腺上皮细胞和树突细胞中的核酸结合蛋白。其与器官特异性自身免疫的联系只能推测，可能与胸腺中用于耐受诱导的器官特异性抗原的呈递有关。通过NOD小鼠器官特异性自身免疫的遗传分析，已经最清楚地阐明了MHC和非MHC遗传基因座之间不可预测的相互作用，在NOD小鼠中，已经有可能产生在20个基因座中的一个或多个上不同的许多同源亚系。
It is well appreciated that organ-specific autoimmune diseases run in families, but that within a family one member may have type 1 diabetes, another autoimmune thyroid disease, and another multiple sclerosis (1). What causes clustering of different autoimmune diseases along genetic lines, and what logic causes the immune system to take aim at different organ targets? In this issue, Salomon et al. make the paradoxical finding that interference with a single costimulatory molecule, B7-2, shifts the aim of autoimmunity in the NOD mouse strain away from the pancreatic islet cell and onto the peripheral nerves (2). The finding adds an important molecular clue to the pathogenesis of organ-specific autoimmune disease, and illustrates the caution that will be needed as new immunological interventions are applied in the clinic.The inheritance of susceptibility to organ-specific autoimmunity is extraordinarily complex. Particular haplotypes of the major histocompatibility complex, such as HLA-DR3-DQB1* 0201, are strongly associated with human susceptibility to multiple organ-specific autoimmune disorders (3). HLA-type nevertheless accounts for only a fraction of inherited susceptibility, and heterozygosity for different HLA alleles can either raise or lower the risk. Independent of HLA-type, mutations in a non-MHC gene, AIRE, cause a Mendelian syndrome, APECED, characterized by autoimmune manifestations ranging from Addison’s, thyroid, and parathyroid disease to type 1 diabetes (4, 5). The AIRE gene product appears to be a nucleic acid binding protein present in some thymic epithelial and dendritic cells. Its connection to organ-specific autoimmunity can only be speculated, perhaps related to presentation of organ specific antigens for tolerance induction in the thymus. The unpredictable interactions between MHC and non-MHC genetic loci have been most clearly illuminated by the genetic analysis of organ-specific autoimmunity in the NOD mouse, where it has been possible to create numerous congenic substrains differing at one or more of the 20