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Clin Immunol. 2016 Dec;173:171-180. doi: 10.1016/j.clim.2016.10.018. Epub 2016 Nov 2.

The BANK1 SLE-risk variants are associated with alterations in peripheral B cell signaling and development in humans.

Author information

Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101.
Center for Immunity and Immunotherapies, Seattle Children's Research Institute, 1900 Ninth Avenue, Seattle, WA 98101.
Department of Pediatrics and Pharmacology, University of Washington School of Medicine.
Contributed equally


Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the development of autoantibodies that drive disease pathogenesis. Genetic studies have associated nonsynonymous variants in the BANK1 B cell scaffolding gene with susceptibility to SLE and autoantibodies in lupus. To determine how the BANK1 SLE-risk variants contribute to the dysregulated B cell program in lupus, we performed genotype/phenotype studies in human B cells. Targeted phospho-proteomics were used to evaluate BCR/CD40 signaling in human B cell lines engineered to express the BANK1 risk or non-risk variant proteins. We found that phosphorylation of proximal BCR signaling molecules was reduced in B cells expressing the BANK1 risk protein compared to the non-risk protein. Similar to these findings, we observed decreased B cell signaling in primary B cells from genotyped healthy control subjects carrying the BANK1 risk haplotype, including blunted BCR- and CD40-dependent AKT activation. Consistent with decreased AKT activation, we found that BANK1 risk B cells expressed increased basal levels of FOXO1 protein and increased expression of FOXO1 target genes upon stimulation compared to non-risk B cells. Healthy subjects carrying the BANK1 risk haplotype were also characterized by an expansion of memory B cells. Taken together, our results suggest that the SLE susceptibility variants in the BANK1 gene may contribute to lupus by altering B cell signaling, increasing FOXO1 levels, and enhancing memory B cell development.

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