The long-term goals of this research program are to define mechanisms of Sjogren's syndrome (SS) as a way to impact disease therapy, prediction and prevention. SS is a systemic autoimmune disease, which predominantly affects salivary and lacrimal glands, leading to significant morbidity. Occurring alone (primary) or in the context of other systemic rheumatic diseases (e.g. Rheumatoid arthritis, SLE - 'secondary'), the causes and mechanisms of SS remain obscure, and therapy remains empirical and symptom-focused. The autoimmune rheumatic diseases share significant mechanistic similarity in terms of amplification and tissue damage, making discoveries about initiation and propagation of SS broadly relevant. The striking association of unique autoimmune responses with specific/phenotypes is of significant diagnostic and prognostic value, and provides a major clue to disease mechanism. Human disease tissue and immune markers provide important tools to interrogate disease mechanism. In previous studies, we have observed striking and specific alterations in the structure of autoantigens during various forms of cell death. We have also recently described markedly enhanced autoantigen expression in the target tissues in myositis, particularly in regenerating muscle cells. Similar findings have recently been made in SS salivary glands. Our data has also identified an important but previously unrecognized similarity between molecular pathways of differentiation and the type I interferon signature noted to be present in SLE, myositis and SS. In this R37 continuation, (i) we will investigate the cell types and differentiation states that express increased autoantigen levels directly in SS biopsies. We will investigate SS autoantigen expression in various differentiating cell models relevant to systemic rheumatic diseases, including hematopoietic and muscle stem cells, and salivary and other epithelial cells. We will use microarray-based transcriptional profiling to define the pathways upstream of antigen expression, and any forces that restrain full differentiation. These studies will identify the source and mechanisms of antigen drive in SS and other rheumatic diseases;(ii) We will extend our studies to define the effects of various cytotoxic lymphocyte granule components on epithelial cell structure and function, with a particular focus on defining mechanisms underlying the effects of human granzymes, and demonstrating these events in SS tissue;(iii) We will address whether regenerating cells provide a source of endogenous ligands for innate immune receptors (e.g. Toll-like receptors) both in vitro and in vivo , and thereby play a dual role in driving systemic autoimmunity. Together, these studies will define novel pathways critical to SS and other rheumatic diseases, with significant therapeutic potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DE012354-14
Application #
8018473
Study Section
Special Emphasis Panel (NSS)
Program Officer
Burgoon, Penny W
Project Start
1998-05-01
Project End
2013-03-31
Budget Start
2011-02-01
Budget End
2013-03-31
Support Year
14
Fiscal Year
2011
Total Cost
$541,610
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Xu, George J; Shah, Ami A; Li, Mamie Z et al. (2016) Systematic autoantigen analysis identifies a distinct subtype of scleroderma with coincident cancer. Proc Natl Acad Sci U S A 113:E7526-E7534
Shah, Ami A; Casciola-Rosen, Livia; Rosen, Antony (2015) Review: cancer-induced autoimmunity in the rheumatic diseases. Arthritis Rheumatol 67:317-26
Duan-Porter, Wei D; Woods Jr, Virgil L; Maurer, Kimberly D et al. (2014) Dynamic conformations of nucleophosmin (NPM1) at a key monomer-monomer interface affect oligomer stability and interactions with granzyme B. PLoS One 9:e115062
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 1γ. 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
Romero, Violeta; Fert-Bober, Justyna; Nigrovic, Peter A et al. (2013) Immune-mediated pore-forming pathways induce cellular hypercitrullination and generate citrullinated autoantigens in rheumatoid arthritis. Sci Transl Med 5:209ra150
Cottrell, Tricia R; Hall, John C; Rosen, Antony et al. (2012) Identification of novel autoantigens by a triangulation approach. J Immunol Methods 385:35-44
Darrah, Erika; Rosen, Antony; Giles, Jon T et al. (2012) Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: novel insights into autoantigen selection in rheumatoid arthritis. Ann Rheum Dis 71:92-8
Hall, John C; Casciola-Rosen, Livia; Berger, Alan E et al. (2012) Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases. Proc Natl Acad Sci U S A 109:17609-14
Casciola-Rosen, Livia; Hall, John C; Mammen, Andrew L et al. (2012) Isolated elevation of aldolase in the serum of myositis patients: a potential biomarker of damaged early regenerating muscle cells. Clin Exp Rheumatol 30:548-53

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