Interferons and cytotoxic lymphocytes in dermatomyositis and cutaneous lupus

描述(申请人提供)：干扰素(IFN)和细胞毒性淋巴细胞(CTL)诱导的死亡是导致皮肤狼疮(CLE)和皮肌炎(DM)损伤的主要致病因素，但这些途径相互作用的程度和方式尚不清楚。这一双重PI计划将定义CLE和DM的致病机制，以期提高诊断、疾病监测和治疗的准确性。在这些疾病的诊断和治疗方面存在许多空白，包括对参与放大免疫介导的组织损伤的成分的了解不完全，以及缺乏用于诊断、分类和预测/监测治疗反应的准确探针和生物标志物。该提案基于重要的初步数据、广泛的科学和临床专业知识以及广泛定义的临床材料的成熟和不断增长的资源。我们最近的研究已经确定了一种与MDA5自身抗体相关的独特的皮肤表型(在血清阴性的DM患者中)，MDA5是一种受I型IFN调节的自身抗原，在淋巴细胞介导的细胞毒作用中被切割。我们的初步研究表明，在DM和SLE中存在新的I型和/或II型干扰素诱导的自身抗原(这种特异性在常规抗体筛查中未被检测到)，并为II型干扰素特异性标记物在部分CLE患者中优先表达提供了证据，表明这一途径在某些CLE患者中可能是可治疗的。此外，我们最近定义了新的角质形成细胞特异性自身抗原，可被DM/CLE患者的抗体识别，并迄今已鉴定出1种：角蛋白-5，一种在基底角质形成细胞中表达的未成熟的II型角蛋白。在UVB或CTL诱导的细胞死亡过程中，几种干扰素诱导的和角质形成细胞特异性的自身抗原被修饰，将这些抗原置于界面性皮炎损伤和修复途径的中心。该建议的具体目标是：(I)开发和验证创新工具(识别干扰素诱导或增殖性角质形成细胞自身抗原的新型自身抗体，以及细胞毒性T淋巴细胞介导的细胞死亡的标记物)，以确定和量化DM和CLE中活跃的致病途径；(Ii)通过定义新的自身抗原表达位点(S)，询问受影响患者皮肤的疾病机制，并定义CTL活性是否集中在这些细胞上；以及(Iii)使用DM/CLE中三条不同机制的通路的新型精确标记物，以确定哪些通路会因新的治疗干预而改变，并与最显著的临床疗效相关。这些研究将为精确确定个体患者体内特定靶组织中致病通路的活性提供有力的新工具，从而促进自身免疫性皮肤病的诊断、预测和临床病程的监测。这些研究将解决使用这些标记物定义的疾病亚组对新引入的治疗是否有不同的反应，提供目标组织中特定途径标记物可用于患者分类和治疗选择的概念证据。

DESCRIPTION (provided by applicant): Interferons (IFNs) and cytotoxic lymphocyte (CTL)-induced death are major pathogenic factors underlying injury in cutaneous lupus (CLE) and dermatomyositis (DM), but the extent of, and manner in which these pathways interact remains unclear. This dual PI program will define pathogenic mechanisms in CLE and DM, with a view to improved precision in diagnosis, disease monitoring and therapy. Numerous gaps exist in the diagnosis and management of these diseases, including incomplete understanding of the components participating in amplification of immune-mediated tissue damage, and lack of precise probes and biomarkers for diagnosis, subclassification and prediction/monitoring response to therapy. The proposal is based on significant preliminary data, broad scientific and clinical expertise, and a well-established and growing resource of extensively defined clinical materials. Our recent studies have identified a distinct cutaneous phenotype (in seronegative DM patients) associated with autoantibodies to MDA5, an autoantigen regulated by type I IFNs and cleaved during lymphocyte-mediated cytotoxicity. Our preliminary studies show that there are novel type I and/or type II IFN-inducible autoantigens targeted in DM and SLE (such specificities are undetected in conventional antibody screens) and provide evidence for expression of type II-IFN-specific markers preferentially in a subset of CLE patients, suggesting that this pathway might be therapeutically tractable in some CLE patients. Additionally, we have recently defined novel keratinocyte-specific autoantigens recognized by antibodies from patients with DM/CLE, and have identified 1 to date: keratin-5, an immature type II keratin expressed in basal keratinocytes. Several IFN-induced and keratinocyte-specific autoantigens are modified during UVB- or CTL-induced cell death, placing these antigens at the hub of damage and repair pathways in interface dermatitis. The specific goals of this proposal are: (i) generate and validate innovative tools (novel autoantibodies recognizing IFN-induced or proliferative keratinocyte autoantigens, and markers of CTL- mediated cell death in the skin) to define and quantify pathogenic pathways active in DM and CLE, (ii) interrogate disease mechanisms in affected patient skin by defining the site(s) of novel autoantigen expression, and define whether CTL activity is focused on these cells and (iii) use novel precision markers of 3 distinct mechanistic pathways in DM/CLE to define which pathways change in response to new therapeutic intervention, and are associated with the most striking clinical effects. The proposed studies will provide powerful new tools to precisely define the activity of pathogenic pathways in specific target tissues in individual patients in vivo, thereby facilitating diagnosis, prediction nd monitoring of clinical course in autoimmune skin diseases. The studies will address whether disease subsets defined using these markers respond differently to newly introduced therapy, providing proof of concept that specific pathway markers in target tissue can be used for patient classification and selection of therapy.