The genetics of rheumatoid arthritis suggest that a combination of inherited alleles and environmental factors contribute to the development of arthritis. T cell reactivity is implicated in RA based on the linkage of RA to particular MHC alleles. Our animal model, proteoglycan-induced arthritis (PGIA) has many similarities to RA and so has the potential to provide important information on the mechanism of human disease. Similar to RA, PGIA is critically dependent on auto reactive T cell activation. In PGIA, activation of Th1 cells and the production of IFN3 are critical for development of severe arthritis. In this, the """"""""conventional"""""""" model of PGIA, the route of antigen exposure is intraperitoneal. We demonstrate that altering the route of antigen exposure from intraperitoneal to intradermal induces a Th17 instead of a Th1 T cell response. These findings suggest that antigen presentation changes the early events in T cell polarization and that the innate microenvironment at these different tissue sites may provide unique signals that foster T cell differentiation. Very little is known about how autoimmune responses initiated at different tissue sites might affect disease. The overall goal is to understand the rules governing T cell differentiation at distinct tissue sites. Our strategy in aim 1 is to determine the cytokine environment which contributes to Th cell polarization and to determine if the immunopathology of the resulting arthritis is similar (or different) in Th1- versus Th17-mediated PGIA.
In aim 2 and aim 3 we will begin to dissect the mechanism by which the route of antigen exposure contributes to T cell polarization.
In aim 2 we will locate the lymphoid tissue sites where T cells are initially primed and produce cytokines and attempt to redirect the differentiating T cell population by altering the cytokine environment.
In aim 3 we will identify the antigen presenting cells which drive Th1/Th17 mediated PGIA and determine the cytokines and co-stimulatory molecules involved in T cell polarization. If we can begin to understand how these T cell subsets are initiated we may be able to identify different subtypes of RA which could lead to the development of more effective therapeutic strategies for selective blockade of disease. This is an important and exciting area of investigation, which is expected to shed new light on the mechanisms of CD4+T cell mediated disease in RA, and more generally in autoimmune disease.
Public Health Relevance Statement Rheumatoid Arthritis (RA) is a chronic inflammatory autoimmune disease characterized by synovial proliferation and infiltrating of leukocytes which leads to destruction of cartilage and bone. Pro-inflammatory effector T helper cells have been divided into three subsets designated as T helper (Th) 1, Th2 and Th17. Th subsets are distinct subsets based on their cytokine secretion pattern, chemokine receptor expression, and clearance of infectious organisms. Models of autoimmune disease can be divided into either Th1-dependent or Th17-dependent. It is presently unclear what causes this heterogeneity in effector T cell differentiation. Based on preliminary results we hypothesize that the context in which the antigen is first encountered in the immune system determines the T cell effector choice. We hypothesize that contact with environmental antigens or infectious agents at different tissue sites predispose T helper cells to differentiation into Th1 or Th17 cells. Different tissue sites have unique cytokine and co-stimulatory microenvironments that are predisposed to the generation of specific Th cytokine phenotypes. The activation of different CD4+ T cell subsets in RA may contribute to disease heterogeneity. This proposal will elucidate the mechanism (s) by which the route of antigen exposure affect/modify fundamental T cell polarization. These studies aim to develop novel insights into the autoimmune disease process that will facilitate the diagnosis and treatment of RA.
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