The Role of IL-17 Axis in Inflammatory Myositis

IL-17 轴在炎症性肌炎中的作用

• 批准号: 8609001
• 负责人: Timothy B Niewold
• 金额: $ 31.97万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-20 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8609001
• 关键词: Acute-Phase Reaction; Anatomy; Animal Model; Antibodies; Antigens; Arthritis; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Biochemical; Biological Markers; Biopsy; Blood; Cells; Clinic; Clinical; Data; Dendritic Cells; Dermatomyositis; Detection; Development; Diagnosis; Diagnostic; Disease; Employee Strikes; Exanthema; Flare; Gene Expression; Genomics; Human; Immune; Immune System Diseases; Immune response; Impairment; Indium; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injectable; Injury; Interferon Type I; Interferons; Interleukin-17; Interruption; Lead; Life; Light; Location; Longitudinal Studies; Measures; Mediator of activation protein; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Muscle; Muscle Weakness; Myositis; Nature; Organ; Pathogenesis; Pathway interactions; Patients; Play; Production; Proteins; Proteomics; Reaction; Research Personnel; Rodent; Role; Sedimentation process; Serum; Severities; Signal Transduction; Stimulus; Syndrome; Systemic Lupus Erythematosus; T cell differentiation; T-Lymphocyte; TNF gene; Testing; Therapeutic; Tissues; Viral; biological adaptation to stress; chemokine; cytokine; driving force; immunopathology; improved; indexing; mortality; mouse model; novel; pathogen; peripheral blood; prevent; protein misfolding; public health relevance; research study; respiratory; skin disorder; therapeutic protein; therapeutic target

DESCRIPTION (provided by applicant): Dermatomyositis (DM) exemplifies a group of uncommon but life- and organ-threatening autoimmune syndromes collectively known as idiopathic inflammatory myositis (IIM). Patients with DM suffer debilitating muscle weakness, respiratory impairment, and disfiguring skin rashes. Organ damage in DM is associated with intense inflammatory and immune reactions, both systemic and local; however, the key cellular and molecular investigators of immune dysfunction are unknown. Our recent genomic and proteomic studies reveal striking association between DM disease activity and serum levels of the pro-inflammatory cytokine interleukin-17 (IL-17) and type-I interferon (IFN) regulated chemokines. Further, high levels of IL-17 and IFN-related chemokines are detected in muscle biopsies from both DM patients and from rodents with experimental myositis. These observations lead us to hypothesize that a) increased IL-17 and related molecules will serve as sensitive biomarkers of disease activity and severity in DM and b) dysregulation of the IL-17 axis and the type-I IFN-related chemokines are a key driving force in the immunopathology of DM. We propose to test these hypotheses using genomic, immunohistochemical, and biochemical approaches. First, we will determine the precise anatomic and cellular location of IL-17 in diseased human DM muscle and determine the requirement for and sufficiency of IL-17 in a myositis animal model. Second, we will assess the predictive and diagnostic value of measuring peripheral blood components of the IL-17 axis and IFN-related chemokines in a longitudinal study of Mayo clinic DM patients. Finally, we will explore the therapeutic value of antagonizing the IL-17 axis in myositis. Using injectable anti-IL-17 antibodies, we will determine whether blocking IL-17 function can ameliorate or prevent muscle damage in a mouse model of myositis. Data arising from the proposed experiments will shed new light on the immunopathogenesis of DM, will establish the value of novel biomarkers for DM disease activity assessment, and will quantitate therapeutic potential of IL-17 manipulation in inflammatory myositis.

描述(申请人提供)：皮肌炎(DM)是一组不常见但威胁生命和器官的自身免疫综合征的例子，统称为特发性炎症性肌炎(IIM)。糖尿病患者会出现衰弱的肌肉无力、呼吸障碍和毁容的皮疹。糖尿病的器官损害与强烈的炎症和免疫反应有关，包括全身和局部；然而，免疫功能障碍的关键细胞和分子研究人员尚不清楚。我们最近的基因组和蛋白质组学研究显示，糖尿病疾病的活动性与血清促炎细胞因子白介素17(IL-17)和I型干扰素(干扰素)调节的趋化因子水平显著相关。此外，在糖尿病患者和患有实验性肌炎的啮齿动物的肌肉活检中都检测到高水平的IL-17和干扰素相关趋化因子。这些观察结果使我们推测：a)IL-17及其相关分子的增加将成为糖尿病疾病活动性和严重性的敏感生物标志物，以及b)IL-17轴和I型干扰素相关趋化因子的失调是糖尿病免疫病理中的关键驱动力。我们建议使用基因组、免疫组织化学和生化方法来检验这些假说。首先，我们将确定IL-17在患病的人类DM肌肉中的精确解剖和细胞定位，并在肌炎动物模型中确定IL-17的需求和充分性。其次，我们将评估在一项对梅奥诊所糖尿病患者的纵向研究中，检测外周血中IL-17轴成分和干扰素相关趋化因子的预测和诊断价值。最后，我们将探讨拮抗IL-17轴在肌炎中的治疗价值。使用可注射的抗IL-17抗体，我们将确定阻断IL-17功能是否可以改善或防止肌炎小鼠模型的肌肉损伤。来自拟议实验的数据将为DM的免疫发病机制提供新的线索，将建立新的生物标志物在DM疾病活动评估中的价值，并将量化IL-17操作在炎症性肌炎中的治疗潜力。

项目成果

Changes in novel biomarkers of disease activity in juvenile and adult dermatomyositis are sensitive biomarkers of disease course.

• DOI: 10.1002/art.34659
• 发表时间: 2012-12
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Reed, Ann M.;Peterson, Erik;Bilgic, Hatice;Ytterberg, Steven R.;Amin, Shreyasee;Hein, Molly S.;Crowson, Cynthia S.;Ernste, Floranne;Gillespie, Emily Baechler
• 通讯作者: Gillespie, Emily Baechler

Single-cell gene expression patterns in lupus monocytes independently indicate disease activity, interferon and therapy.

狼疮单核细胞中的单细胞基因表达模式独立指示疾病活动、干扰素和治疗

• DOI: 10.1136/lupus-2016-000202
• 发表时间: 2017
• 期刊: Lupus science & medicine
• 影响因子: 3.9
• 作者: Jin Z;Fan W;Jensen MA;Dorschner JM;Bonadurer GF 3rd;Vsetecka DM;Amin S;Makol A;Ernste F;Osborn T;Moder K;Chowdhary V;Niewold TB
• 通讯作者: Niewold TB

Drugs in early clinical development for Systemic Lupus Erythematosus.

• DOI: 10.1517/13543784.2016.1162291
• 发表时间: 2016
• 期刊: Expert opinion on investigational drugs
• 影响因子: 6.1
• 作者: Postal M;Sinicato NA;Appenzeller S;Niewold TB
• 通讯作者: Niewold TB

Associations between type I interferon and antiphospholipid antibody status differ between ancestral backgrounds.

I型干扰素和抗磷脂抗体状态之间的关联在祖先背景之间有所不同。

• DOI: 10.1136/lupus-2017-000246
• 发表时间: 2018
• 期刊: Lupus science & medicine
• 影响因子: 3.9
• 作者: Iwamoto T;Dorschner J;Jolly M;Huang X;Niewold TB
• 通讯作者: Niewold TB

Defining biological subsets in systemic lupus erythematosus: progress toward personalized therapy.

• DOI: 10.1007/s40290-017-0178-6
• 发表时间: 2017-04
• 期刊: Pharmaceutical medicine
• 影响因子: 2.5
• 作者: Sinicato NA;Postal M;Appenzeller S;Niewold TB
• 通讯作者: Niewold TB