The nature of the extracellular matrix (ECM), in any given tissue, contributes to the susceptibility of that tissue to immunologic injury. For autoimmunity and rheumatoid arthritis (RA), it becomes critical to fully understand the nature of the interaction of the different subsets of T lymphocytes within the ECM of the tissue that they infiltrate. Little is known about key components within the ECM that are required for this interaction and what factors are responsible for stimulating resident tissue cells to produce such an ECM. This supplemental project will take advantage of the availability of specific subsets of T cells being studied in the parent grant 5R01AR037296-18 to address the role of the ECM in the control of T lymphocyte adhesion and activation. Synovial fibroblasts from normal and RA patients will be stimulated to produce an ECM enriched in hyaluronan and versican by 1) over-expressing the HAS-1 gene, 2) treating with the viral mimetic poly IC, or 3) stimulating the fibroblasts with TNF1. Previous studies by the Wight group have shown that hyaluronan and versican in the ECM participate in monocyte adhesion to the ECM but no studies have been done with T lymphocytes. Four major subpopulations of HLA-DR4 restricted autoreactive human CD4+ T cells will be evaluated: TH1 (antigen-specific; gamma-IFN+); TH2 (antigen-specific; IL13+); TH17 (antigen-specific, IL-17+); and Treg (CD25+CD127low FOXP3+).
The aims of this application will be to identify conditions in which synovial fibroblasts produce an ECM that binds T cells; to determine if different subsets of T cells differ in their ability to interact with and be activated by an ECM enriched in versican and hyaluronan; and to determine if T cell adhesion and activation can be blocked by targeting the versican and/or hyaluronan component of the ECM. This collaboration will join investigators who have expertise in the immunology of T cells with cell biologists who have expertise in ECM biology to explore mechanisms related to T cell infiltration in RA. ? ? ?
Rheumatoid arthritis involves the interaction of lymphocytes with components of the joint tissue. However, little is known about how this interaction takes place. This project will define the nature of this interaction and set the stage for future therapeutic developments to block this interaction and alleviate the inflammation associated with RA. This supplemental project brings the expertise of a senior investigator in matrix biology into a significant interdisciplinary collaboration in the area of immunology and tissue engineering. This project will expand the scope of the ongoing NIAMS research supported by AR037296 by adding a highly innovative and potentially high impact approach from the area of matrix biology, to address important aspects of T cell immunobiology relating to the persistence and progression of matrix-lymphocyte interactions relating to rheumatoid arthritis.
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