Reduced B Lymphoid Kinase (Blk) Expression Enhances Proinflammatory Cytokine Production and Induces Nephrosis in C57BL/6-<i>lpr/lpr</i> Mice

<div><p><i>BLK</i>, which encodes B lymphoid kinase, was recently identified in genome wide association studies as a susceptibility gene for systemic lupus erythematosus (SLE), and risk alleles mapping to the <i>BLK</i> locus result in reduced gene expression. To determine whether <i>BLK</i> is indeed a <i>bona fide</i> susceptibility gene, we developed an experimental mouse model, namely the Blk^+/−.<i>lpr/lpr</i> (Blk^+/−.<i>lpr</i>) mouse, in which <i>Blk</i> expression levels are reduced to levels comparable to those in individuals carrying a risk allele. Here, we report that Blk is expressed not only in B cells, but also in IL-17-producing γδ and DN αβ T cells and in plasmacytoid dendritic cells (pDCs). Moreover, we found that solely reducing Blk expression in C57BL/6-<i>lpr</i>/<i>lpr</i> mice enhanced proinflammatory cytokine production and accelerated the onset of lymphoproliferation, proteinuria, and kidney disease. Together, these findings suggest that <i>BLK</i> risk alleles confer susceptibility to SLE through the dysregulation of a proinflammatory cytokine network.</p>