1. Reduced B lymphoid kinase (Blk) expression enhances proinflammatory cytokine production and induces nephrosis in C57BL/6-lpr/lpr mice.
- Author
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Samuelson EM, Laird RM, Papillion AM, Tatum AH, Princiotta MF, and Hayes SM
- Subjects
- 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 enzymology, Cytokines biosynthesis, Inflammation Mediators metabolism, Nephrosis enzymology, Nephrosis pathology, src-Family Kinases metabolism
- 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 αβ 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.
- Published
- 2014
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