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Neetu Gupta, Debasis Pore, Neetha Parameswaran, Emily Huang, Dina Dejanovic, Loss of B cell Ezrin in lupus-prone Lyn-deficient mice downregulates B cell activation and autoimmune pathology, The Journal of Immunology, Volume 200, Issue Supplement_1, May 2018, Page 40.7, https://doi.org/10.4049/jimmunol.200.Supp.40.7
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Abstract
Systemic lupus erythematosus (SLE) is an aggressive autoimmune disorder that afflicts 1.5 million Americans. Human GWAS studies have reported a strong association between the Src family tyrosine kinase Lyn and incidence of SLE, and B cells from SLE patients exhibit decreased Lyn expression. Genetic deletion of Lyn in mice results in loss of peripheral B cell tolerance and development of human SLE-like autoimmunity, characterized by hyperactive B cell antigen receptor (BCR) signaling, autoantibody production and glomerulonephritis. However, the molecular regulators of B cell pathogenesis in Lyn-deficient mice have not been fully characterized. We have previously shown that the membrane-cytoskeleton linker protein ezrin regulates multiple aspects of B cell function through its dynamic switching between phosphorylated and dephosphorylated states. We observed that ezrin is hyperphosphorylated in Lyn-deficient B cells, suggesting that it may impact B cell activation in this context. To test this hypothesis, we generated conditional deletion of ezrin in the B cells of Lyn-deficient mice (hereafter referred to as DKO mice). Compared to Lyn-deficient mice, the DKO mice exhibited a significant decrease in splenomegaly and reduction in autoantibodies against a variety of autoantigens. Glomerulonephritis and deposition of IgG and complement factor C3 in the kidneys of DKO mice were also markedly reduced. The DKO B cells were hyporesponsive to BCR stimulation and displayed a calcium mobilization pattern reminiscent of that observed in anergic B cells. Our data demonstrate that ezrin regulates B cell hyperactivation and associated pathology in the absence of Lyn, and suggest that ezrin may be a novel molecular target in SLE.
