Project 2: Microbiome pathobionts and Lupus pathogenesis

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ABSTRACT Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease affecting many organ systems, with hallmarks of B-cell abnormalities and clonal expansions in the blood, specific types of circulating autoantibodies and immune-complex mediated tissue injury. While the cause is unknown, in-depth genome- wide association studies have identified genetic intervals and alleles that are associated with disease predisposition. Environmental factors appear to have a large, although still poorly understood, influence. There have been accelerating advances in understanding how the bacterial communities that live in us and on us contribute to inflammatory and autoimmune disorders. Bacterial species, that in most hosts are normal components of our microbial communities, have been implicated in pathogenesis and therefore termed pathogenic symbionts or pathobionts. Yet in the great majority of adults these same commensal species are completely innocuous or even beneficial. We have found that SLE patients with active disease have imbalances (termed dysbiosis) in the distribution/diversity of bacterial taxa in their intestinal microbiomes. Our overarching goal is to test the hypothesis that specific pathobiont commensal intestinal bacterial species contribute to lupus flares. In these studies we seek to understand how specific candidate pathobiont bacterial isolates contribute to Lupus pathogenesis and the expansion of disease-associated blood B-cell clones. In addition, we will study the effect of transferred gut microbiomes in murine models. The relationships between clones in the gut-associated B-cell compartment and in the systemic compartment in SLE patients will also be investigated.