Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease

多学科研究-包括临床、免疫学、病理学、流行病学和分子遗传学调查-正在被用来补充每个领域的发现，并克服每种方法固有的局限性。目前的研究主要集中在：探索可能的环境风险和保护因素;通过候选基因和全基因组SNP分析确定遗传风险和保护因素;确定自身免疫性疾病的临床，实验室和免疫学特征之间的关联，用于诊断，预后和致病目的;以及了解单卵双胞胎之间表观遗传学，基因表达和蛋白质组模式的差异。通过对双胞胎和与系统性自身免疫性疾病不一致的近亲兄弟姐妹的研究，正在评估暴露于二氧化硅、有机溶剂、紫外线、疫苗接种、选定的药物和膳食补充剂、激素和妊娠、烟草烟雾、压力性生活事件和感染因子在系统性自身免疫性疾病发展中的作用。 一组被称为肌炎综合征或特发性炎性肌病（IIM）的、知之甚少的、危及生命的自身免疫性肌肉疾病被定义为慢性肌肉炎症和无力，并且与特异性自身抗体相关。肌炎的主要形式是多发性肌炎，其中多个肌肉受到炎症的影响，以及皮肌炎，其中患者也发生皮肤炎症。然而，似乎有其他类型的肌炎的基础上的临床表现，病理和自身抗体。我们正在研究这些疾病的成人（IIM）和青少年（JIM）形式，以了解发病机制和风险因素的可能差异。 我们最近取得进展的一个研究领域涉及确定与青少年和成人IIM的新遗传关联。为了实现这一目标，我们与世界各地的许多研究人员合作，称为肌炎遗传联盟（MYOGEN）。使用来自MYOGEN的样本，我们对欧洲血统的成人和青少年肌炎患者和对照组进行了全基因组关联研究（GWAS）。为了确定遗传危险因素，我们对1710例主要肌炎表型进行了GWAS，其中包括705例成人皮肌炎，473例青少年皮肌炎，532例多发性肌炎，以及206例成人皮肌炎，青少年皮肌炎或多发性肌炎患者的抗组氨酰-tRNA合成酶（抗Jo-1）自身抗体，并将其与4724名对照进行比较。在主要组织相容性复合体（MHC）区域，所有肌炎表型一起，以及单独研究的四种临床和自身抗体表型，在GWAS中显示出强相关性（P < 5 X 10-8）的单核苷酸多态性被鉴定。插补和回归分析发现，等位基因包括人类白细胞抗原（HLA）8.1祖先单倍型（AH8.1）定义基本上所有的遗传风险的表型研究。尽管HLA DRB 1 *03：01等位基因与成人和青少年皮肌炎的相关性略强，HLA B*08：01与多发性肌炎和抗Jo-1自身抗体阳性肌炎的相关性略强，但AH8.1的多个等位基因需要完全的风险效应。我们的研究结果表明，AH8.1的等位基因构成了地理上不同的高加索人群中与主要肌炎表型相关的主要遗传危险因素。 我们正在使用免疫芯片方法继续这些研究，并评估其他表型。

Multidisciplinary studies - including clinical, immunologic, pathologic, epidemiologic and molecular genetic investigations - are being used to complement findings in each area and overcome limitations inherent in each approach. Current studies are focusing on: exploring possible environmental risk and protective factors; identifying genetic risk and protective factors by candidate gene and whole genome SNP analyses; defining the associations among clinical, laboratory and immunologic features of autoimmune diseases for diagnostic, prognostic and pathogenic purposes; and understanding differences in epigenetics, gene expression and proteomic patterns between monozygotic twins discordant for disease. Evaluation of exposures to silica, organic solvents, ultraviolet light, vaccinations, selected drugs and dietary supplements, hormones and pregnancy, tobacco smoke, stressful life events and infectious agents in the development of systemic autoimmune diseases are being conducted via a study of twins and close siblings discordant for systemic autoimmune disease. A group of poorly-understood, life-threatening autoimmune muscle diseases called the myositis syndromes or idiopathic inflammatory myopathies (IIM) are defined by chronic muscle inflammation and weakness and are associated with specific autoantibodies. The major forms of myositis are polymyositis, in which multiple muscles are affected by inflammation, and dermatomyositis, in which patients also develop skin inflammation. Yet there appear to be other types of myositis based on the clinical presentations, pathology and autoantibodies. We are studying both the adult (IIM) and juvenile (JIIM) forms of these diseases to understand possible differences in pathogenesis and risk factors. One area of investigation in which we have made recent advances involves identifying new genetic associations with juvenile and adult IIM. To accomplish this goal, we formed collaborations with many investigators around the world called the Myositis Genetic Consortium (MYOGEN). Using samples from MYOGEN, we performed a genome-wide association study (GWAS) of adult and juvenile myositis patients of European ancestry and controls. To identify genetic risk factors , we conducted GWAS of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis; 532 polymyositis, and 206 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P < 5 X 10-8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. We are continuing these investigations using Immunochip approaches and assessing additional phenotypes.