Background and aims Systemic lupus erythematosus (SLE) is characterised by hyperactive B cell antigen receptor (BCR) signalling, autoantibody production and glomerulonephritis. Human GWAS studies have shown a strong association between alterations in the Src family kinase Lyn and incidence of SLE. Mice with genetic deletion of Lyn lose peripheral B cell tolerance and display all the hallmark symptoms associated with human SLE. Therefore, Lyn-/- mice represent a clinically relevant model to investigate the molecular regulation of B cell autoimmunity in SLE. We have previously reported that the membrane-cytoskeleton linker protein Ezrin regulates various facets of B cell function through its dynamic phosphorylation and dephosphorylation. Interestingly, we observed that Ezrin is hyperphosphorylated in Lyn-/- B cells, leading to the hypothesis that Ezrin facilitates B cell autoimmunity in Lyn-/- mice.
Methods To test our hypothesis we generated double knockout mice (DKO) bearing systemic deletion of Lyn and conditional deletion of Ezrin in the B cell lineage. B cell activation, lupus-associated autoantibodies and kidney pathology were investigated.
Results Compared to Lyn-deficient mice, the DKO mice displayed reduced germinal centre B cell and plasma cell differentiation, and decrease in autoantibody levels and glomerulonephritis. Further, an increase in BCR repertoire diversity and inhibition of BCR signalling pathways was observed in DKO B cells.
Conclusions Investigation of proteins that drive B cell hyperactivation in SLE is important for the development of effective and novel therapies. Our data demonstrate that ezrin is an important regulator of B cell activation in the absence of Lyn, and thus a potential molecular target in SLE.
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