Concordance of Increased B1 Cell Subset and Lupus Phenotypes in Mice and Humans Is Dependent on BLK Expression Levels

Abstract

Polymorphisms in the BLK gene have been associated with autoimmune diseases, including systemic lupus erythematosus (SLE), with risk correlating with reduced expression of BLK. How reduced expression of BLK causes autoimmunity is unknown. Using Blk+/+, Blk+/−, and Blk−/− mice, we show that aged female Blk+/− and Blk−/− mice produced higher anti-dsDNA IgG antibodies and developed immune complex-mediated glomerulonephritis, compared to Blk+/+ mice. Starting at young age, Blk+/− and Blk−/− mice accumulated increased numbers of splenic B1a cells, which differentiated into class-switched CD138+IgG-secreting B1a cells. Increased infiltration of B1a-like cells into the kidneys was also observed in aged Blk+/− and Blk−/− mice. In human, we found that healthy individuals had BLK genotype-dependent levels of anti-dsDNA IgG antibodies as well as increased numbers of a B1-like cell population, CD19+CD3−CD20+CD43+CD27+, in peripheral blood. Furthermore, we describe the presence of B1-like cells in the tubulointerstitial space of human lupus kidney biopsies. Taken together, our study reveals a previously unappreciated role of reduced BLK expression on extraperitoneal accumulation of B1a cells in mice, and the presence of IgG autoantibodies and B1-like cells in human.

Review: Abnormal B Cell Development in Systemic Lupus Erythematosus: What the Genetics Tell Us

“…Blk –/– mice develop autoimmune disease, with anti‐dsDNA autoantibodies and immune complex–mediated glomerulonephritis, together with an increase in the proportion of B‐1 cells (a low‐affinity IgM‐producing subtype of B cells in mice) . Expansion of this subtype of B cells in other murine models of lupus is well documented and is thought to be important, particularly in driving nephritis . In a mechanism similar to that of the Lyp variant, this may contribute to autoimmunity by impairing central tolerance mechanisms.…”

B1a cells play a pathogenic role in the development of autoimmune arthritis

“…Remarkably, depletion of B1a cells by osmotic pressure ameliorates the development of type I diabetes [ 5 ], and reduces renal injury after kidney ischemia or reperfusion [ 9 ], indicating the involvement of B1a cells in disease progression. Early reports have found increased CD5 + B cells in patients with rheumatoid arthritis (RA) [ 10 , 11 ], Sjögren's syndrome [ 12 ] and systemic lupus erythematosus (SLE) [ 7 , 13 , 14 ]. Recent studies have characterized the human counterpart of murine B1 cells with the phenotype of CD20 + CD43 + CD27 + CD70 − present in the umbilical cord and adult peripheral blood [ 15 ].…”

Associations of secreted phosphoprotein 1 and B lymphocyte kinase gene polymorphisms with autoimmune thyroid disease

“…Observations suggested that BLK was implicated in antibody production and possible formation of the TSHRAb in GD if BLK is dysregulated. Evidence showed that healthy subjects with the rs2736340 risk TT genotype have higher B1a‐like cells and higher circulating anti–double‐stranded (ds)DNA than those without the risk TT genotype . Moreover, Gourth et al demonstrated that rs13277113 and rs2736340 were associated with various autoantibodies and clinical subtypes in SS .…”

“…Evidence showed that healthy subjects with the rs2736340 risk TT genotype have higher B1a-like cells and higher circulating anti-double-stranded (ds)DNA than those without the risk TT genotype. 44 Moreover, Gourth et al demonstrated that rs13277113 and rs2736340 were associated with various autoantibodies and clinical subtypes in SS. 38 In this study, there were no correlations of the BLK SNPs, rs1377113 and rs2736340, with TSHRAb levels; thus, genetic variants only exerted a predominant role in F I G U R E 2 Anti-microsomal antibody (AmiA) titres at the baseline for different genotypes of rs13277113 (Panel A) and rs2736340 (Panel B), and the combined genotypes of rs3277113 and rs2736340 (Panel C) in autoimmune thyroid disease.…”