HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry
HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry
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DOI：
10.1073/pnas.1906593116
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发表时间：
2020-01-07
影响因子：
11.1
通讯作者：
Remmers, Elaine F.
中科院分区：
文献类型：
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作者：
Gourh, Pravitt;Safran, Sarah A.;Remmers, Elaine F.
系统性硬化症（SSc）是一种临床异质性自身免疫性疾病，其特征是针对不同核抗原的相互排斥的自身抗体。我们在一个新招募的大型非裔美国人 (AA) 队列和欧洲裔美国人 (EA) 人群中检查了 SSc 及其自身抗体子集的 HLA 关联。在 AA 人群中，非洲血统为主的 HLA-DRB1* 08:04 和 HLA-DRB1* 11:02 等位基因与总体 SSc 风险相关，HLA-DRB1* 08:04 等位基因与 SSc 的严重抗纤维蛋白 (AFA) 抗体子集密切相关（比值比 = 7.4）。这些非洲血统为主的等位基因可能有助于解释 AA 人群中 SSc 的频率和严重程度增加。在 EA 人群中，HLA-DPB1* 13:01 和 HLA-DRB1* 07:01 等位基因分别与 SSc 的抗拓扑异构酶 (ATA) 和抗着丝粒抗体阳性子集的相关性比与总体 SSc 风险的相关性更强，这强调了 HLA 在定义自身抗体亚型中的重要性。在 AA 和 EA 患者中，HLA-DPB1* 13:01 等位基因与 SSc 的 ATA+ 子集的关联显示出跨血统效应。在多个人群中观察到 SSc 患病率与 HLA-DPB1* 13:01 等位基因频率之间存在直接相关性 (r = 0.98，P = 3 x 10(-6))。 SSc 自身抗体子集的条件分析揭示了几个相关的氨基酸残基，大部分位于 II 类 HLA 分子的肽结合沟中。利用 HLA α/β 等位基因异二聚体，我们通过生物信息学方法预测了拓扑异构酶 1、原纤维蛋白和着丝粒蛋白 A 的免疫显性肽，并发现它们与拟病毒科和藻藻DNA病毒科的病毒蛋白序列同源。总而言之，这些数据表明 HLA 等位基因、自身抗体和环境触发因素在 SSc 发病机制中可能存在联系。
Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1* 08:04 and HLA-DRB1* 11:02 alleles were associated with overall SSc risk, and the HLA-DRB1* 08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1* 13:01 and HLA-DRB1* 07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1* 13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1* 13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 x 10(-6)). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA alpha/beta allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.