The BANK1 SLE-risk variants are associated with alterations in peripheral B cell signaling and development in humans.
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.
Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101.
Elizabeth M
EM
Dam
Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101.
Tania
T
Habib
Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101.
Janice
J
Chen
Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101.
Andrew
A
Funk
Center for Immunity and Immunotherapies, Seattle Children's Research Institute, 1900 Ninth Avenue, Seattle, WA 98101.
Veronika
V
Glukhova
Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101.
Mel
M
Davis-Pickett
Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101.
Shan
S
Wei
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.
Richard
R
James
Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101.
Jane H
JH
Buckner
Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101.
Karen
K
Cerosaletti
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D000071161:Forkhead Box Protein O1 / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C447641:BANK1 protein, human; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D008565:Membrane Proteins