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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044684-14
Application #
8213575
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mancini, Marie
Project Start
1997-09-30
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
14
Fiscal Year
2012
Total Cost
$342,904
Indirect Cost
$133,816
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Mohassel, Payam; Rosen, Paul; Casciola-Rosen, Livia et al. (2015) Expression of the dermatomyositis autoantigen transcription intermediary factor 1? in regenerating muscle. Arthritis Rheumatol 67:266-72
Shah, Ami A; Casciola-Rosen, Livia; Rosen, Antony (2015) Review: cancer-induced autoimmunity in the rheumatic diseases. Arthritis Rheumatol 67:317-26
Fiorentino, David F; Chung, Lorinda S; Christopher-Stine, Lisa et al. (2013) Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1ýý. Arthritis Rheum 65:2954-62
Hall, John C; Casciola-Rosen, Livia; Samedy, Lesly-Ann et al. (2013) Anti-melanoma differentiation-associated protein 5-associated dermatomyositis: expanding the clinical spectrum. Arthritis Care Res (Hoboken) 65:1307-15
Fiorentino, David; Casciola-Rosen, Livia (2012) Autoantibodies to transcription intermediary factor 1 in dermatomyositis shed insight into the cancer-myositis connection. Arthritis Rheum 64:346-9
Casciola-Rosen, Livia (2011) Histidyl-transfer RNA synthetase: a key participant in idiopathic inflammatory myopathies. Arthritis Rheum 63:331-3
Fiorentino, David; Chung, Lorinda; Zwerner, Jeff et al. (2011) The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study. J Am Acad Dermatol 65:25-34
Mammen, Andrew L; Chung, Tae; Christopher-Stine, Lisa et al. (2011) Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 63:713-21
Danoff, Sonye K; Casciola-Rosen, Livia (2011) The lung as a possible target for the immune reaction in myositis. Arthritis Res Ther 13:230
Mammen, Andrew L; Mahoney, James A; St Germain, Amanda et al. (2011) A novel conserved isoform of the ubiquitin ligase UFD2a/UBE4B is expressed exclusively in mature striated muscle cells. PLoS One 6:e28861

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