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、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。 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。 在一项全国性的登记研究中，我们招募了436名JIIM患者，其中354人被归类为JDM，33人被归类为JPM，49人被归类为JCTM。这项研究的目的是比较人口统计学、临床特征、实验室测量，包括肌炎自身抗体；以及这些临床亚组之间的结果，以及与另一项自然病史研究中登记的特发性炎症性肌病(IIM)成人患者的公开数据进行比较。我们使用随机森林分类和Logistic回归模型来比较临床亚组，遵循单因素分析。JDM以典型的皮疹为特征，包括Gottrons丘疹、向日葵皮疹、颧部皮疹、甲周毛细血管改变及其他光敏性和血管病理性皮疹。JPM的特点是更严重的虚弱，更高的肌酸激酶水平，发作减少，以及更频繁的心脏病。JCTM以间质性肺疾病、雷诺现象、关节痛、颧部皮疹多见。自身抗体频率的差异也很明显，抗p155/140、抗MJ和抗Mi-2在JDM患者中更常见，抗信号识别颗粒和抗Jo-1在JPM中更常见，抗U1-RNP、PM-SCL和其他肌炎相关自身抗体在JCTM中更常见。JCTM患者的死亡率最高，而JPM患者的住院率和轮椅使用率最高。青少年IIM亚组和成年IIM亚组的一些人口统计学和临床特征是相同的。然而，JDM和JPM患者间质性肺疾病、雷诺现象、“机械手”和腕管综合征的发生率较低，死亡率也较低。我们得出结论，幼年型肌炎是一组不同的疾病，具有不同的临床亚型，由不同的临床和人口学特征、实验室特征和结果定义。 为了确定青少年和成人皮肌炎(DM)的新的遗传关联，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，我们对欧洲血统的成年和青少年DM患者(n=1,178)和对照组(n=4,724)进行了全基因组关联研究(GWAS)。为了评估与其他自身免疫性疾病的遗传重叠，我们检查了主要组织相容性复合体(MHC)基因外的141个单核苷酸多态(SNPs)是否易患DM，这些SNPs以前与自身免疫性疾病相关。与对照组相比，糖尿病患者在80个SNPs的MHC区域有较强的信号，该区域由GWAS水平意义(P&lt；5，10(-8))组成。对141个以前与自身免疫性疾病相关的非MHC SNP的分析表明，与3个基因连锁的3个SNP与DM相关，错误发现率(FDR)为0.05。这些基因分别是磷脂酶C样蛋白1(PLCL1；rs6738825，fdr=0.00089)、B淋巴样酪氨酸激酶(blk；rs2736340，fdr=0.0031)和趋化因子(C-C基序)配体21(ccl21；rs951005，fdr=0.0076)。这些基因之前都没有与糖尿病相关的报道。我们的发现证实了MHC是与DM相关的主要遗传区，并表明DM与其他自身免疫性疾病具有非MHC的遗传特征，这表明存在其他新的危险基因。首次鉴定出与糖尿病共有的自身免疫性疾病的遗传易感性，可能会增强对发病机制的理解，并带来新的诊断和治疗方法。

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. We enrolled 436 patients with JIIM, including 354 classified as JDM, 33 as JPM, and 49 as JCTM, in a nationwide registry study. The aim of the study was to compare demographics; clinical features; laboratory measures, including myositis autoantibodies; and outcomes among these clinical subgroups, as well as with published data on adult patients with idiopathic inflammatory myopathies (IIM) enrolled in a separate natural history study. We used random forest classification and logistic regression modeling to compare clinical subgroups, following univariate analysis. JDM was characterized by typical rashes, including Gottrons papules, heliotrope rash, malar rash, periungual capillary changes, and other photosensitive and vasculopathic skin rashes. JPM was characterized by more severe weakness, higher creatine kinase levels, falling episodes, and more frequent cardiac disease. JCTM had more frequent interstitial lung disease, Raynaud phenomenon, arthralgia, and malar rash. Differences in autoantibody frequency were also evident, with anti-p155/140, anti-MJ, and anti-Mi-2 seen more frequently in patients with JDM, anti-signal recognition particle and anti-Jo-1 in JPM, and anti-U1-RNP, PM-Scl, and other myositis-associated autoantibodies more commonly present in JCTM. Mortality was highest in patients with JCTM, whereas hospitalizations and wheelchair use were highest in JPM patients. Several demographic and clinical features were shared between juvenile and adult IIM subgroups. However, JDM and JPM patients had a lower frequency of interstitial lung disease, Raynaud phenomenon, "mechanic's hands" and carpal tunnel syndrome, and lower mortality than their adult counterparts. We conclude that juvenile myositis is a heterogeneous group of illnesses with distinct clinical subgroups, defined by varying clinical and demographic characteristics, laboratory features, and outcomes. To identify new genetic associations with juvenile and adult dermatomyositis (DM), 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 DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.