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

Publication date: Available online 2 November 2016
Source:Clinical Immunology
Author(s): Elizabeth M. Dam, Tania Habib, Janice Chen, Andrew Funk, Veronika Glukhova, Mel Davis-Pickett, Shan Wei, Richard James, Jane H Buckner, Karen Cerosaletti
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.

Graphical abstract

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