Gram Negative Enteric Pathogens and Autoimmunity

Infection with Enteric Gram-Negative pathogens has been associated with the subsequent development of autoimmune disease. Utilizing a murine model, we have found that a significant fraction of the CD8+ CTLs evoked following Salmonella infection utilize a novel class I-like antigen presentation structure with limited polymorphism. These CD8+ CTLs recognize a conserved Salmonella-GroEL derived peptide presented by the murine class I- like molecule Qa-1, the murine orthologue of the human class I molecule HLA-E. In addition, these CTLs cross recognize an analogous peptide derived from the mammalian GroEL molecule as well as stressed macrophages. Thus CD8+ CTLs evoked following infection with Salmonella are autoreactive. We have proposed that these CTLs may play a role in the subsequent development of autoimmune disease. We propose a series of studies investigating the potential role for bacterial-reactive T cells in human arthritis disease.
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In aim number 1 we will use human subjects exposed to Salmonella to investigate the normal host T cell immune response to Salmonella infection. The T cell responses evoked will be characterized with regard to functional status, epitopes recognized and antigen presentation structures utilized.
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Using this information we will generate, in Aim number 2, epitope-specific T cell tracking reagents and utilize them in the characterization of this response in individuals exposed to gram-negative pathogens and address whether bacterial-reactive T cells are present in individuals that have diagnosed arthritis-related disease. This patient population is derived from the large patient cohort seen by the Division of Rheumatology at our institution and includes individuals with Reactive Arthritis, Reiter's Disease and Ankylosing Spondylitis. In these studies an attempt will be made to co-related the presence of bacterial-specific and/or autoreactive T cells and disease state. We believe these studies will yield insights into the etiological link between gram-negative infection and autoimmune diseases and provide the conceptual basis for expanded studies in development of autoreactive T cells and their role in disease.