Impact of the SLE Gene BANK1 on Autophagy and Plasmablast Differentiation in Lupus
Abstract
The objective of this study is to elucidate the mechanisms underlying dysregulated plasmablast and plasma cell homeostasis in SLE, resulting in production of autoantibodies that drive disease pathogenesis. Our preliminary data support a mechanistic link between SLE genetic risk variants in the BANK1 gene with autophagy and plasmablast development. During year 2 of the grant we performed experiments to test the hypothesis that the SLE-associated risk variants in BANK1 promote autophagy, leading to increased plasmablast differentiation and immunoglobulin secretion. Using gene editing, we found, expression of the BANK1 risk or non-risk cDNA elicited a selective disadvantage relative to cells deficient in BANK1. We also found that BANK1 protein levels decreased as plasmablast differentiation progressed, which is consistent with the idea that more autophagy is required as plasmablast differentiation progresses and that a reduction in BANK1 levels, as a repressor of autophagy, will enable increased levels of autophagy and plasmablast differentiation. In parallel, we are testing autophagy and plasmablast differentiation using primary human B cells from controls and lupus patients genotyped for the BANK1 variants. We observed that plasmablast differentiation from nave B cells was detectable by day 7 of in vitro culture and was followed by differentiation of plasma cells at day 9 expressing IgG. The addition of the TLR9 agonist CpG increased plasmablast and plasma cell differentiation. At the same time points, we saw that autophagy preceded plasmablast differentiation, consistent with autophagy being required for plasmablast differentiation. Conclusions regarding the effect of BANK1 genotype will be determined upon unblinding at the completion of these experiments. Our results support the hypothesis that BANK1 promotes autophagy and plasmablast development
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2022
- Accession Number
- AD1165688
Entities
People
- Karen Cerosaletti
- Richard G James
Organizations
- Benaroya Research Institute