title: Reduced B lymphoid kinase (Blk) expression enhances proinflammatory cytokine production and induces nephrosis in C57BL/6-lpr/lpr mice.
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.
authors.affiliation: Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, New York, United States of America.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Samuelson
authors.affiliation: Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, New York, United States of America.
authors.forename: Renee M
authors.initials: RM
authors.lastname: Laird
authors.affiliation: Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, New York, United States of America.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Papillion
authors.affiliation: Department of Pathology, State University of New York Upstate Medical University, Syracuse, New York, United States of America.
authors.forename: Arthur H
authors.initials: AH
authors.lastname: Tatum
authors.affiliation: Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, New York, United States of America.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Princiotta
authors.affiliation: Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, New York, United States of America.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Hayes
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000150:complications / Q000201:enzymology / Q000473:pathology; D001402:B-Lymphocytes / Q000201:enzymology; D002452:Cell Count; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D003713:Dendritic Cells / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D009401:Nephrosis / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D010641:Phenotype; D011485:Protein Binding; D011507:Proteinuria / Q000150:complications / Q000201:enzymology / Q000473:pathology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D018836:Inflammation Mediators; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; C000592904:B lymphoid kinase, mouse; D019061:src-Family Kinases