Rheumatic Disease Sera: Probes of Disease Mechanisms

描述（由申请人提供）：许多自身免疫性风湿性疾病的原因和机制仍然不清楚，治疗在很大程度上仍然是经验性和非特异性的。该研究计划的长期目标是确定这些疾病的机制，以影响疾病的诊断，治疗，预测和预防。最近的研究表明，肌炎中的自身抗原在发炎的肌肉中高水平表达，特别是在再生的肌肉细胞中。这些研究表明，（i）再生细胞可能提供自身抗原的关键来源，（ii）免疫介导的细胞损伤可能集中在这些再生细胞上，诱导驱动免疫应答的抗原释放，并通过刺激更多的再生来增强抗原表达。初步研究表明，肌炎患者的自身抗体特异性识别以前未定义的自身抗原，仅在成肌细胞或分化的肌肉细胞中表达，并且细胞毒性淋巴细胞聚集在肌炎肌肉中的这些细胞周围。本申请将鉴定这些新的自身抗原，确定它们在多发性肌炎和皮肌炎中的表达模式，以及在个体患者中抗原表达和免疫应答是否相关（表明抗原表达可能影响免疫靶点的选择）。本申请还将寻求提供体内证据，证明表达这种肌肉特异性和分化特异性抗原的细胞是肌炎中免疫效应途径的优先焦点。此外，由于大多数这些自身抗原是颗粒酶B的底物，这些研究将确定这些片段是否存在于细胞毒性位点的原位。这些数据将提供重要的信息，在风湿性疾病的颗粒酶途径的活动和作用。这些目标将通过追求以下具体目标来实现：（1）使用分化的成肌细胞作为自身抗原的来源来鉴定肌炎患者中的新型表型特异性自身抗体，并确定其诊断灵敏度和特异性;（2）确定体内自身抗体应答与抗原表达之间的关系;和（3）确定肌炎活检中免疫效应途径靶向的细胞类型和分化状态。这些研究将确定不同的肌肉细胞类型和分化状态的内容作为免疫应答的靶点，以及表达这些抗原的细胞作为自身免疫性肌炎中免疫效应途径的焦点。证明抗原源和特异性免疫效应子途径在体内疾病传播部位相互作用将突出可能在治疗上易于处理的前馈环的组分（例如抗原表达、颗粒酶B抑制）。除了致病的见解，这些研究也将导致新的诊断检测肌炎和潜在的其他自身免疫性风湿性diseases .Narrative的发展：这些研究将调查自身免疫性风湿性疾病的机制，试图设计新的诊断标志物，和途径，可能是新的治疗方法的目标。特别是，我们将重点关注在自身免疫中完成受损组织修复的细胞，这些细胞本身似乎是免疫损伤的靶点。我们将定义在修复细胞中识别的分子，以及这些分子如何参与持续的损伤。

DESCRIPTION (provided by applicant): The causes and mechanisms of many autoimmune rheumatic diseases remain obscure, and therapy largely remains empirical and non-specific. The long-term goal of this research program is to define mechanisms in these diseases as a way to impact disease diagnosis, therapy, prediction and prevention. Recent studies have demonstrated that autoantigens in myositis are expressed at high levels in inflamed muscle, particularly in regenerating muscle cells. These studies have suggested that (i) regenerating cells may provide a critical source of autoantigen, and (ii) immune-mediated cell damage may be focused on such regenerating cells, inducing antigen release that drives the immune response, and augmenting antigen expression through stimulating more regeneration. Preliminary studies demonstrate that autoantibodies from myositis patients specifically recognize previously undefined autoantigens expressed exclusively in myoblasts or differentiating muscle cells, and that cytotoxic lymphocytes cluster around such cells in myositis muscle. This application will identify these novel autoantigens, define their expression patterns in polymyositis and dermatomyositis and whether antigen expression and immune response are related in individual patients (indicating that antigen expression may shape selection of immune targets). This application will also seek to provide evidence in vivo that cells expressing such muscle- and differentiation-specific antigens are the preferential focus of immune effector pathways in myositis. Furthermore, since most of these autoantigens are substrates for granzyme B, these studies will define whether such fragments are present in situ at sites of cytotoxicity. Such data would provide important information regarding the activity and role of the granzyme pathway in rheumatic diseases. These goals will be achieved by pursuing the following specific aims: (1) Use differentiating myoblasts as a source of autoantigens to identify novel phenotype-specific autoantibodies in myositis patients, and define their diagnostic sensitivity and specificity; (2) Define the relationship between autoantibody response and antigen expression in vivo; and, (3) Define the cell type and differentiation state targeted by immune effector pathways in myositis biopsies. These studies will define the contents of distinct muscle cell types and differentiation states as targets of the immune response, and the cells expressing such antigens as the focus of immune effector pathways in autoimmune myositis. Proving that antigen source and specific immune effector pathways are interacting at the site of disease propagation in vivo will highlight components of a feedforward loop that may be therapeutically tractable (e.g. antigen expression, granzyme B inhibition). In addition to pathogenic insights, the studies will also result in the development of new diagnostic assays for myositis and potentially other autoimmune rheumatic diseases .Narrative: These studies will investigate mechanisms in autoimmune rheumatic diseases to try to design new markers for diagnosis, and pathways that might be targets of new therapies. In particular, we will focus on the cells accomplishing repair of damaged tissues in autoimmunity, which appear, themselves to be targets of immune damage. We will define the molecules recognized in repairing cells, and how these may participate in ongoing damage.