Rheumatoid arthritis (RA) is one of the most common debilitating systemic inflammatory conditions. Dr. Su's research investigates how T cells recognizing self-antigens contribute to the initiation and propagation of autoimmune diseases. To date, little is known about which autoantigens are involved in RA and how T cells recognizing these self-proteins may become pathogenic in disease. One major limitation that has hindered progress in this field is the difficulty in identifying the specific T cell populations and self-antigens that are involved. Dr. Su has generated preliminary data that demonstrate for the first time that T cells specific for a putative RA autoantigen, the human glycoprotein 39 (Hcgp39), can be identified directly ex vivo from RA patients. Interestingly, Hcgp39-specific T cells can also be found in some healthy individuals. This data lead her to propose the hypothesis that autoantigen-specific T cells are functionally inactive in a healthy person, but cells recognizing the same self-antigen are functionally prone to inflammation in RA patients. In this K08, she proposes to study how the autoantigen-specific T cell repertoire changes in healthy and diseased states over time. She will then determine the functional differences between these self-recognizing T cells and investigate whether T cells from RA patients and healthy people have T cell receptors that recognize the same antigen with different avidity and flexibility. She will carry out these experiments using peptide-MHC tetramers and magnetic column enrichment to identify self-antigen specific CD4 T cells. Functional characterization and T cell receptor analysis of tetramer tagged cells will be performed on the single cell level. The main objective of this proposed research is to understand how T cells that recognize self-proteins contribute to the pathogenesis of rheumatoid arthritis. Dr. Su's immediate career goal is to obtain excellent training to become an independent investigator. Her long-term career goal is to make significant contribution to the field of Immunology and develop new diagnostic and treatment strategies for autoimmune diseases. This application details a carefully thought out career development plan that includes extensive collaborative interaction with other laboratories, attendance at seminars and scientific meetings, and classes in biostatistics. Dr. Su has strong institutional support that will allow her to focus on the proposed research. This K08 Mentored Clinical Scientist Career Development Award will facilitate Dr. Su's development as a physician scientist to ultimately become a fully independent investigator.

Public Health Relevance

Rheumatoid arthritis (RA) is an inflammatory disease that can cause erosive deforming arthritis. It affects over a million Americans, and is associated with high levels of discomfort, disability, and health care cost. The proposed research will examine how T cells recognizing self-proteins are involved in disease pathogenesis and may lead to new insights that can facilitate the development of novel diagnostic and therapeutic options for RA. )

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Mao, Su-Yau
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Su, Laura F; Del Alcazar, Daniel; Stelekati, Erietta et al. (2016) Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood. Proc Natl Acad Sci U S A 113:E6192-E6198
Su, Laura F; Davis, Mark M (2013) Antiviral memory phenotype T cells in unexposed adults. Immunol Rev 255:95-109
Su, Laura F; Kidd, Brian A; Han, Arnold et al. (2013) Virus-specific CD4(+) memory-phenotype T cells are abundant in unexposed adults. Immunity 38:373-83
Wang, Chunlin; Krishnakumar, Sujatha; Wilhelmy, Julie et al. (2012) High-throughput, high-fidelity HLA genotyping with deep sequencing. Proc Natl Acad Sci U S A 109:8676-81