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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

1
Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101.
2
Center for Immunity and Immunotherapies, Seattle Children's Research Institute, 1900 Ninth Avenue, Seattle, WA 98101.
3
Department of Pediatrics and Pharmacology, University of Washington School of Medicine.
#
Contributed equally

Abstract

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.

PMID:
27816669
PMCID:
PMC5148640
DOI:
10.1016/j.clim.2016.10.018
[Indexed for MEDLINE]
Free PMC Article

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