Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disorder whose etiology remains unknown. There is strong evidence for a genetic basis to this disease, and many genetic alleles that predispose an individual to SLE have been identified from studies in patients with SLE and in mouse models of lupus. With recent advances, however, such as the completion of the Human Genome Project and the International HapMap Project, it is possible to perform GWAS to identify additional susceptibility genes in humans. Indeed, several groups using this experimental approach have identified over twenty-five new susceptibility loci in SLE patients of different ethnicity and race. BLK is one of the newly identified susceptibility genes, and risk alleles that map to the BLK locus result in reduced expression. BLK encodes B lymphoid kinase, a Src family kinase whose expression was initially reported to be restricted to the B cell lineage, but we show that it is also expressed in plasmacytoid dendritic cells and IL-17-producing γδ and CD4-CD8- αβ T cells. To investigate the contribution of BLK risk alleles to disease development, we reduced Blk expression in autoimmune-prone B6.lpr mice. We report that Blk+/-.lpr mice exhibit enhanced proinflammatory cytokine production and accelerated onset of lymphoproliferation and kidney disease compared to B6.lpr mice. These data suggest that BLK risk alleles promote disease through the dysregulation of a proinflammatory cytokine network.
- Copyright © 2013 by The American Association of Immunologists, Inc.