Links between innate immunity and autoimmunity are currently being explored in a variety of contexts. The program proposed here focuses on whether elements of the innate immune system might protect from autoimmunity and, if so, by what mechanism(s). Project 1 addresses this issue in a recently developed murine model of inflammatory arthritis, the K/BxN T cell receptor transgenic line. Disease in these animals, critically dependent on both T and B cells, is mediated by antibodies against a ubiquitously expressed protein, glucose-6-phosphate isomerase, or GPI. Specifically, we will: 1) Establish the physiological and genetic basis of various in GPI levels at different ages and in different strains, to set the groundwork for subsequent analyses. 2) Test the influence of components of the complement network on initiation of arthritis in KRN T cell receptor transgenic mice specifically C1q, CD21/35, MBL, natural Abs in order to directly test their influence on this model of autoimmunity. 3) Assess the influence of components of the complement network on T cell tolerance in KRN T cells receptor transgenic animals the same elements as above in order to evaluate this link, so far unexplored. The results will be extended to other T cell receptor transgenic systems, as well. Results from these studies will serve will serve to generalize (or not) recent findings on systemic lupus erythematosus and related disorders, and will provide novel mechanistic information.
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