Studies over the last decade have dramatically changed our understanding of the early natural history of rheumatoid arthritis (RA) by demonstrating convincingly that RA-related autoantibodies are elevated in asymptomatic individuals for at least several years prior to the development of clinically apparent signs and symptoms of RA. This autoantibody positive but asymptomatic phase is then followed shortly before the onset of clinically apparent signs and symptoms of arthritis by the development of increased systemic inflammation that is manifest by elevated serum/plasma levels of cytokines and chemokines. Because of these findings, we now have a general conceptual framework of how the disease develops in its earliest phases. However, despite these gains in knowledge, the initial citrullinated epitopes to which pathogenic B and T cells respond are unknown. This knowledge is critical to our understanding of the immunologic mechanisms that underlie disease development as well as the future design of tolerance-based therapies. We have established a unique cohort of individuals under the umbrella of the Studies of the Etiology of Rheumatoid Arthritis (SERA) who are at the highest definable risk for the future development of RA. Two Co-Investigators in this project application, Drs. Robinson and Buckner, have developed novel approaches to identify and characterize antigen-specific B and T cell responses to citrullinated and other RA-related autoantigens. To advance our understanding of the autoimmune response at the earliest time points in the development of RA, we propose to utilize these techniques in high-risk SERA participants and pursue the following Specific Aims:
Specific Aim #1. Identify the innate and adaptive immune response modifications that are causally associated with the break in tolerance to citrullinated autoantigens and progression to active disease;
Specific Aim #2. Use novel single-B-cell expression techniques to identify the RA-related autoantigens that are targeted in the initial preclinical phases of disease development;
and Specific Aim #3. Determine what peptide autoantigens are recognized by T cells in the initial phases of the loss of self tolerance in the preclinical period of disease development.

Public Health Relevance

The proposed research is relevant to public health because it utilizes a unique cohort of subjects and biomaterials and is focused on a strategy that will improve our understanding of the mechanisms whereby individuals develop preclinical autoimmunity and then subsequently transition to clinically apparent rheumatoid arthritis (RA). Unique antigens and epitopes recognized by subjects who are progressing to the development of RA will be defined. The proposed research will address questions directly bearing on the programmatic goals of NIAID that are focused on supporting research into the causes, treatment and prevention of autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Study Section
Special Emphasis Panel (ZAI1-ALW-I (M2))
Program Officer
Esch, Thomas R
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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Kinslow, Jennifer D; Blum, Lisa K; Deane, Kevin D et al. (2016) Elevated IgA Plasmablast Levels in Subjects at Risk of Developing Rheumatoid Arthritis. Arthritis Rheumatol 68:2372-83
Chang, Hui-Hsin; Liu, Guang-Yaw; Dwivedi, Nishant et al. (2016) A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22. JCI Insight 1:e90045
Sokolove, Jeremy; Wagner, Catriona A; Lahey, Lauren J et al. (2016) Increased inflammation and disease activity among current cigarette smokers with rheumatoid arthritis: a cross-sectional analysis of US veterans. Rheumatology (Oxford) 55:1969-1977
Robinson, William H; Mao, Rong (2016) Biomarkers to guide clinical therapeutics in rheumatology? Curr Opin Rheumatol 28:168-75
Raza, Karim; Klareskog, Lars; Holers, V Michael (2016) Predicting and preventing the development of rheumatoid arthritis. Rheumatology (Oxford) 55:1-3
Gan, Ryan W; Young, Kendra A; Zerbe, Gary O et al. (2016) Lower omega-3 fatty acids are associated with the presence of anti-cyclic citrullinated peptide autoantibodies in a population at risk for future rheumatoid arthritis: a nested case-control study. Rheumatology (Oxford) 55:367-76
Sparks, Jeffrey A; Chang, Shun-Chiao; Deane, Kevin D et al. (2016) Associations of Smoking and Age With Inflammatory Joint Signs Among Unaffected First-Degree Relatives of Rheumatoid Arthritis Patients: Results From Studies of the Etiology of Rheumatoid Arthritis. Arthritis Rheumatol 68:1828-38
Wagner, Catriona A; Sokolove, Jeremy; Lahey, Lauren J et al. (2015) Identification of anticitrullinated protein antibody reactivities in a subset of anti-CCP-negative rheumatoid arthritis: association with cigarette smoking and HLA-DRB1 'shared epitope' alleles. Ann Rheum Dis 74:579-86
Robinson, William H; Mao, Rong (2015) Decade in review-technology: Technological advances transforming rheumatology. Nat Rev Rheumatol 11:626-8
Robinson, William H (2015) Sequencing the functional antibody repertoire--diagnostic and therapeutic discovery. Nat Rev Rheumatol 11:171-82

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