Abstract

): The U1-70kDa ribonucleoprotein, a prevalent autoantigen in rheumatic disease patients, undergoes proteolytic cleavage in apoptosis. A model of autoimmune diseases proposes that modified forms of self antigens can lead to recognition of previously cryptic epitopes, allowing an auto-reactive immune response to evolve. Thus, apoptotically modified Ul-70kDa is a candidate antigen that may be involved in the evolution of autoimmune rheumatic diseases. The long-term objective of this application is to develop an independent program of research that leads to improved diagnosis, treatment, and prevention of rheumatic diseases, based on an improved understanding of the contribution of apoptotically modified self antigens to the generation of autoimmune responses. The following specific aims will examine the role of apoptotic Ul-70kDa in autoimmune disease. First, it will be determined whether apoptotic Ul-70kDa is antigenically distinct from intact Ul-70kDa. Sera from patients with intact Ul-70kDa antibodies will be tested for antibodies specific for the apoptotic form of U170kDa by ELISA and immunoblot. Immunoglobulins generated from Fab phage expression libraries selected against apoptotic Ul-70kDa will also be screened for apoptosis-specific Ul-70kDa reactivity. Epitope mapping will be performed with all apoptotic Ul-70kDa specific antisera and Fab to identify the immunologically distinct areas on the apoptotic form of the antigen. Second, in a large cohort of rheumatic disease patients from whom multiple serial blood samples have been drawn, it will be determined whether anti-apoptotic U170kDa responses precede anti-intact Ul-70kDa immune responses. As a result of this research, the contribution of apoptotic U1 -70kDa epitopes to the immunopathogenesis of rheumatic diseases will be elucidated. Assays for antibodies to apoptotically modified Ul-70kDa with potential clinical relevance to the diagnosis and management of rheumatic diseases, will be developed. In the future, this work may lead to the development of specific immunotherapy strategies for the treatment of Ul-70kDa-associated rheumatic disorders.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI001842-03
Application #
6532643
Study Section
Special Emphasis Panel (ZAI1-GLM-I (M2))
Program Officer
Prograis, Lawrence J
Project Start
2000-09-30
Project End
2003-12-31
Budget Start
2002-08-01
Budget End
2003-12-31
Support Year
3
Fiscal Year
2002
Total Cost
$122,850
Indirect Cost

  Institution

Name
University of Missouri-Columbia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
112205955
City
Columbia
State
MO
Country
United States
Zip Code
65211

  Publications

Greidinger, Eric L; Zang, Yunjuan; Fernandez, Irina et al. (2009) Tissue targeting of anti-RNP autoimmunity: effects of T cells and myeloid dendritic cells in a murine model. Arthritis Rheum 60:534-42
Trivedi, Sapna; Greidinger, Eric L (2009) Endosomal Toll-like receptors in autoimmunity: mechanisms for clinical diversity. Therapy 6:433-442
Greidinger, Eric L; Zang, YunJuan; Martinez, Laisel et al. (2007) Differential tissue targeting of autoimmunity manifestations by autoantigen-associated Y RNAs. Arthritis Rheum 56:1589-97
Greidinger, Eric L; Zang, YunJuan; Jaimes, Kimberly et al. (2006) A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum 54:661-9
De Silva-Udawatta, Mihiri; Kumar, Senthil R; Greidinger, Eric L et al. (2004) Cloned human TCR from patients with autoimmune disease can respond to two structurally distinct autoantigens. J Immunol 172:3940-7
Warner, Natalya Z; Greidinger, Eric L (2004) Patients with antibodies to both PmScl and dsDNA. J Rheumatol 31:2169-74
Hoffman, Robert W; Gazitt, Tal; Foecking, Mark F et al. (2004) U1 RNA induces innate immunity signaling. Arthritis Rheum 50:2891-6
Greidinger, Eric L; Gazitt, Tal; Jaimes, Kimberly F et al. (2004) Human T cell clones specific for heterogeneous nuclear ribonucleoprotein A2 autoantigen from connective tissue disease patients assist in autoantibody production. Arthritis Rheum 50:2216-22
Greidinger, Eric L; Foecking, Mark F; Magee, Joseph et al. (2004) A major B cell epitope present on the apoptotic but not the intact form of the U1-70-kDa ribonucleoprotein autoantigen. J Immunol 172:709-16
Setty, Yatish N; Pittman, Cory B; Mahale, Adit S et al. (2002) Sicca symptoms and anti-SSA/Ro antibodies are common in mixed connective tissue disease. J Rheumatol 29:487-9

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