The Blimp-1 SLE risk variant regulates inflammatory function in dendritic cells

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DESCRIPTION (provided by applicant): Genome wide association studies (GWAS) have identified many genetic loci which are associated with SLE; however, we still need to understand the contribution of each to disease initiation or pathogenesis. Specifically, GWAS identified that B lymphocyte induced maturation protein-1 (Blimp-1) has a susceptibility polymorphism for systemic lupus erythematosus (SLE) rs548234 but neither the significance of the polymorphism for Blimp-1 expression and function, nor its significance for SLE pathogenesis has been identified. We have generated a novel mouse model of SLE in which Blimp-1 is deleted in a dendritic cell (DC) specific manner (DCBlimp-1ko mice). Compared to the other established models, DCBlimp-1ko mice show a more pronounced gender dependent disease development, similar to the human disease. Moreover, the lupus-like phenotype in DCBlimp-1ko mice depends on the presence of estrogen. Blimp-1 deficient DCs show an activated phenotype and increased expression of proinflammatory cytokines following toll-like receptor (TLR) stimulation. We determined that Blimp-1 directly regulates expression of microRNA Let-7c in DCs, thus Blimp-1 induction leads to an aberrant increase of Let-7c and a decrease in the Let-7c target molecule, suppressor of cytokine signaling-1 (SOCS-1). We investigated the function of DCs from healthy individuals with the SLE risk allele of Blimp-1. Our preliminary studies demonstrate that there is a decrease in the level of Blimp-1 and increase in Let-7c in DCs of risk allele carriers. The differential expression of Blimp-1 and Let-7c is DC specific since there is no significant difference in Blimp-1 expression between B cells of risk allele and non-risk allele carriers. DCs of risk allele carriers also secrete an increased level of IL-6 following TLR stimulation. Finally, these phenotypic and functional changes depend on gender, since male risk allele carriers exhibit a much milder phenotype. We hypothesize that Blimp-1 has a critical immune tolerogenic function in DCs. In this proposal, we will identify how the risk allele affects the expression of Blimp-1 in DCs. We will identify target molecules of Blimp-1 which regulate the proinflammatory phenotype in DCs. We will also investigate the role of estrogen in Blimp-1 expression or function. Finally, we will compare risk allele or non-risk allele SLE patients to determine whether a similar pattern of DC function occurs in all SLE patients. Where limitations to human studies are great, we will employ the DCBlimp-1ko mouse model. There are strong similarities between human Blimp-1 risk allele carriers and DCBlimp-1ko mice and these similarities give us a unique opportunity to understand its contribution to human disease pathogenesis.