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.

Public Health Relevance

Dermatomyositis (DM) is a poorly understood autoimmune, inflammatory disorder of skin and muscle that entails significant morbidity and mortality. Our preliminary data reveal associations between DM disease activity and abnormalities of pro-inflammatory molecules IL-17 and Type I Interferons. Our proposal will investigate whether blood levels of these and related molecules can help clinicians assess and/or predict DM disease activity. Our studies will also test the requirement for IL-17 in mouse models of inflammatory muscle disease, and will explore the potential for manipulating activity of IL-17 and related proteins for therapeutic purposes in DM. Data arising from the proposed experiments will shed new light on the pathogenesis of DM, will establish the value of novel biomarkers for DM disease activity assessment, and will quantitate therapeutic potential of modulating IL-17 in inflammatory muscle disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR057781-05
Application #
8609001
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Nuckolls, Glen H
Project Start
2010-04-20
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$293,641
Indirect Cost
$49,669
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Smith, P Brian; Benjamin Jr, Daniel K; Reed, Ann M (2017) The Role of a Division of Quantitative Sciences Division in Enhancing Academic Productivity of a Department of Pediatrics. J Pediatr 180:4-5
Sinicato, Nailú Angélica; Postal, Mariana; Appenzeller, Simone et al. (2017) Defining biological subsets in systemic lupus erythematosus: progress toward personalized therapy. Pharmaceut Med 31:81-88
Ungprasert, P; Sagar, V; Crowson, C S et al. (2017) Incidence of systemic lupus erythematosus in a population-based cohort using revised 1997 American College of Rheumatology and the 2012 Systemic Lupus International Collaborating Clinics classification criteria. Lupus 26:240-247
Ghodke-Puranik, Yogita; Dorschner, Jessica M; Vsetecka, Danielle M et al. (2017) Lupus-Associated Functional Polymorphism in PNP Causes Cell Cycle Abnormalities and Interferon Pathway Activation in Human Immune Cells. Arthritis Rheumatol 69:2328-2337
Thanarajasingam, Uma; Jensen, Mark A; Dorschner, Jessica M et al. (2017) Brief Report: A Novel ELANE Mutation Associated With Inflammatory Arthritis, Defective NETosis, and Recurrent Parvovirus Infection. Arthritis Rheumatol 69:2396-2401
López De Padilla, Consuelo M; Crowson, Cynthia S; Hein, Molly S et al. (2017) Gene Expression Profiling in Blood and Affected Muscle Tissues Reveals Differential Activation Pathways in Patients with New-onset Juvenile and Adult Dermatomyositis. J Rheumatol 44:117-124
Loke, P'ng; Niewold, Timothy B (2017) By CyTOF: Heterogeneity of Human Monocytes. Arterioscler Thromb Vasc Biol 37:1423-1424
Niewold, Timothy B (2016) Connective tissue diseases: Targeting type I interferon in systemic lupus erythematosus. Nat Rev Rheumatol 12:377-8
Wampler Muskardin, Theresa; Vashisht, Priyanka; Dorschner, Jessica M et al. (2016) Increased pretreatment serum IFN-?/? ratio predicts non-response to tumour necrosis factor ? inhibition in rheumatoid arthritis. Ann Rheum Dis 75:1757-62
López de Padilla, Consuelo M; Niewold, Timothy B (2016) The type I interferons: Basic concepts and clinical relevance in immune-mediated inflammatory diseases. Gene 576:14-21

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