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 1 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 of a B cell lymphoma cell line, we found deletion of BANK1 resulted in increased autophagy. Expression of the BANK1 non-risk gene in these cells restored autophagy to parental levels, while expression of the BANK1 risk gene resulted in increased autophagy relative to the non-risk gene. Finally, we tested the prediction that increasing autophagy in B cells would promote plasmablast development. To do so, we deleted BANK1 in primary human B cells and quantified the capacity of the edited cells to form plasmablasts/plasma cells in vitro. We detected increased plasmablast and plasma cell numbers in BANK1 deficient primary B cells compared to BANK1 sufficient cells, as well as increased immunoglobulin levels. Our results support the hypothesis that the SLE risk variants or deficiency in BANK1 promotes autophagy and plasmablast development.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2019
- Accession Number
- AD1086579
Entities
People
- Karen Cerosaletti
- Richard G James
Organizations
- Benaroya Research Institute