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--正被用来补充每个领域的研究结果，并克服每种方法固有的局限性。目前的研究集中在：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和测序分析确定遗传风险和保护因素；为诊断、预后和致病目的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系；以及了解与疾病不一致的同卵双胞胎在表观遗传学、基因表达和蛋白质组模式方面的差异。正在通过对与系统性自身免疫性疾病不一致的双胞胎和近亲兄弟姐妹进行研究，评估暴露于二氧化硅、有机溶剂和其他异物、紫外线、疫苗、选定的药物和膳食补充剂、激素和怀孕、烟草烟雾、应激性生活事件和感染剂在系统性自身免疫性疾病发展中的作用。我们还在评估与疾病爆发有关的环境因素。 一组知之甚少、危及生命的自身免疫性肌肉疾病称为肌炎综合征或特发性炎症性肌病(IIM)，由慢性肌肉炎症和无力定义，并与特定的自身抗体有关。肌炎的主要形式是多发性肌炎和皮肌炎，在多发性肌炎中，多个肌肉受到炎症的影响，在皮肌炎中，患者也会发生皮肤炎症。然而，根据临床表现、病理和自身抗体，似乎还有其他类型的肌炎。我们正在研究这些疾病的成人(IIM)和青少年(JIIM)形式，以了解发病机制和危险因素可能存在的差异。 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的新的遗传关联。为了实现这一目标，我们与世界各地的许多研究人员组成了名为肌炎遗传联盟(Myogen)的合作。使用来自Myogen的样本，我们对欧洲血统和对照的成年和青少年肌炎患者进行了全基因组关联研究(GWAS)。为了确定遗传危险因素，我们对成人皮肌炎、青少年皮肌炎、多发性肌炎以及抗组氨酰-tRNA合成酶(抗Jo-1)自身抗体阳性的成人皮肌炎、青少年皮肌炎或多发性肌炎患者的主要肌炎表型进行了GWA，并与对照组进行了比较。在所有肌炎表型的主要组织相容性复合体(MHC)区域，以及分别研究的四种临床和自身抗体表型中，都发现了与GWAS有很强相关性的单核苷酸多态(P&lt；5×10-8)。归因和回归分析发现，包含人类白细胞抗原(HLA8.1)祖先单倍型(AH8.1)的等位基因基本上定义了所研究表型中的所有遗传风险。虽然HLADRB1*03：01等位基因与成人和青少年皮肌炎的相关性稍强，而HLAB*08：01等位基因与多发性肌炎和抗Jo-1自身抗体阳性肌炎的相关性较强，但AH8.1的多个等位基因仍需要多个等位基因才能发挥全部危险作用。我们的发现表明，AH8.1等位基因包括与地理上不同的高加索人群中的主要肌炎表型相关的主要遗传风险因素。其他研究发现，与其他自身免疫性疾病相关的基因也出现在肌炎表型中。我们正在继续使用免疫芯片和其他方法进行这些研究，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 and sequencing 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 and other xenobiotics, 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. We are also assessing environmental agents associated with disease flares. 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 adult dermatomyositis, juvenile dermatomyositis; polymyositis, and adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 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. Other studies have found that genes associated with other autoimmune diseases are also seen in myositis phenotypes. We are continuing these investigations using Immunochip and other approaches and assessing additional phenotypes.