ABSTRACT
BLK, 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 BLK locus result in reduced gene expression. To determine whether BLK is indeed a bona fide susceptibility gene, we developed an experimental mouse model, namely the Blk+/-.lpr/lpr (Blk+/-.lpr) mouse, in which Blk 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 αß T cells and in plasmacytoid dendritic cells (pDCs). Moreover, we found that solely reducing Blk expression in C57BL/6-lpr/lpr mice enhanced proinflammatory cytokine production and accelerated the onset of lymphoproliferation, proteinuria, and kidney disease. Together, these findings suggest that BLK risk alleles confer susceptibility to SLE through the dysregulation of a proinflammatory cytokine network.
Subject(s)
Cytokines/biosynthesis , Inflammation Mediators/metabolism , Nephrosis/enzymology , Nephrosis/pathology , src-Family Kinases/metabolism , Animals , Autoimmune Diseases/complications , Autoimmune Diseases/enzymology , Autoimmune Diseases/pathology , B-Lymphocytes/enzymology , Cell Count , Cytokines/blood , Dendritic Cells/metabolism , Immune Tolerance/immunology , Inducible T-Cell Co-Stimulator Ligand/metabolism , Inducible T-Cell Co-Stimulator Protein/metabolism , Inflammation Mediators/blood , Kidney/pathology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Inbred MRL lpr , Mice, Transgenic , Nephrosis/blood , Nephrosis/complications , Phenotype , Protein Binding , Proteinuria/complications , Proteinuria/enzymology , Proteinuria/pathology , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , T-Lymphocytes/enzymologyABSTRACT
Blk was identified two decades ago as a B-cell-specific member of the Src family of tyrosine kinases. Recent studies, however, have discovered that Blk is expressed in many cell types outside of the B lineage, including early thymic precursors, interleukin-17-producing γδ T cells and pancreatic ß-cells. In light of these recent discoveries, we performed a more comprehensive analysis of Blk expression patterns in hematopoietic cells and found that Blk is differentially expressed in mature B-cell subsets, with marginal zone (MZ) B cells expressing high levels, B1 B cells expressing intermediate-to-high levels and follicular (FO) B cells expressing low levels of Blk. To determine whether these differences in Blk expression levels reflected differential requirements for Blk in MZ, B1 and FO B-cell development, we analyzed the effects of reducing and eliminating Blk expression on B-cell development. We report that both Blk haploinsufficiency and Blk deficiency impaired the generation of MZ B cells. Moreover, although there were fewer MZ B cells in Blk(+/-) and Blk(-/-) mice as compared with Blk(+/+) mice, Blk-mutant MZ B cells were hyper-responsive to B-cell receptor stimulation, both in vitro and in vivo. Thus, this study has revealed a previously unappreciated role for Blk in the development and activation of MZ B cells.
