Interferons and cytotoxic lymphocytes in dermatomyositis and cutaneous lupus

皮肌炎和皮肤狼疮中的干扰素和细胞毒性淋巴细胞

• 批准号: 8725793
• 负责人: LIVIA A CASCIOLA-ROSEN
• 金额: $ 20万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725793
• 关键词: Address; Affect; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune Process; Biological Markers; Biopsy; Cell Death; Cell-Mediated Cytolysis; Cells; Cessation of life; Classification; Cleaved cell; Clinical; Cutaneous; Cutaneous Lupus Erythematosus; Cytoplasmic Granules; Data; Dermatitis; Dermatomyositis; Diagnosis; Disease; Disease Management; Disease Marker; Employee Strikes; Event; Generations; Goals; Growth Factor; Heterogeneity; Immune; Immune response; Immunoblotting; In Situ; Individual; Injury; Interferon Type I; Interferon Type II; Interferons; Intravenous Immunoglobulins; Keratin; Lymphocyte; Mediating; Modification; Molecular; Molecular Diagnosis; Monitor; Outcome; Pathologic; Pathway interactions; Patients; Pattern; Phenotype; Play; Prevalence; Reporting; Resources; Rheumatism; Role; Serum; Site; Skin; Specificity; Systemic Lupus Erythematosus; Therapeutic Intervention; Tissues; Ultraviolet B Radiation; Validation; base; clinical effect; clinical material; clinical phenotype; cytokine; cytotoxic; cytotoxicity; disease diagnosis; human tissue; improved; in vivo; inhibitor/antagonist; innovation; keratin 5; keratinocyte; longitudinal analysis; lupus cutaneous; novel; novel therapeutic intervention; programs; repaired; response; skin disorder; tool

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.

描述（由申请人提供）：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仍不清楚。这一双重PI计划将确定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管理中存在许多差距，包括对参与免疫介导的组织损伤放大的组分的不完全理解，以及缺乏用于诊断、亚分类和预测/监测对治疗的反应的精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完善和不断增长的资源。我们最近的研究已经确定了一个独特的皮肤表型（血清阴性DM患者）与自身抗体MDA 5，一种自身抗原调节I型干扰素和裂解淋巴细胞介导的细胞毒性。我们的初步研究表明，有新的I型和/或II型IFN-诱导的自身抗原靶向DM和SLE（这种特异性是未检测到的常规抗体筛选），并提供证据表明，II型IFN-特异性标志物的表达优先在一个子集的CLE患者，这表明，这种途径可能是治疗上听话的一些CLE患者。此外，我们最近已经定义了新的角质形成细胞特异性自身抗原识别的抗体从DM/CLE患者，并已确定1到目前为止：角蛋白-5，不成熟的II型角蛋白表达在基底角质形成细胞。在UVB或CTL诱导的细胞死亡过程中，几种IFN诱导的和角质形成细胞特异性自身抗原被修饰，将这些抗原置于界面皮炎的损伤和修复途径的中心。该提案的具体目标是：（i）产生和验证创新工具（识别IFN诱导的或增殖的角质形成细胞自身抗原的新型自身抗体，以及皮肤中CTL介导的细胞死亡的标志物）来定义和定量DM和CLE中活性的致病途径，（ii）通过定义新型自身抗原表达的位点来探究受影响的患者皮肤中的疾病机制，并确定CTL活性是否集中在这些细胞上，以及（iii）使用DM/CLE中3种不同机制途径的新精确标记物来确定哪些途径响应于新的治疗干预而改变，并且与最显著的临床效果相关。这些研究将为精确确定个体患者体内特定靶组织中致病途径的活性提供强有力的新工具，从而促进自身免疫性皮肤病临床过程的诊断、预测和监测。这些研究将解决使用这些标志物定义的疾病子集是否对新引入的治疗有不同的反应，提供概念证明，即靶组织中的特定途径标志物可用于患者分类和治疗选择。

项目成果

Identification of clinical features and autoantibodies associated with calcinosis in dermatomyositis.

• DOI: 10.1001/jamadermatol.2013.10416
• 发表时间: 2014-07
• 期刊: JAMA DERMATOLOGY
• 影响因子: 10.9
• 作者: Valenzuela, Antonia;Chung, Lorinda;Casciola-Rosen, Livia;Fiorentino, David
• 通讯作者: Fiorentino, David

Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease.

• DOI: 10.1002/acr.22498
• 发表时间: 2015-05
• 期刊: ARTHRITIS CARE & RESEARCH
• 影响因子: 4.7
• 作者: Narang, Neera S.;Casciola-Rosen, Livia;Li, Shufeng;Chung, Lorinda;Fiorentino, David F.
• 通讯作者: Fiorentino, David F.