Impaired B Cell Apoptosis Results in Autoimmunity That Is Alleviated by Ablation of Btk

Jacqueline A. Wright, Cassandra Bazile, Emily S. Clark, Gianluca Carlesso, Justin Boucher, Eden Kleiman, Tamer Mahmoud, Lily I. Cheng, Darlah M. López-Rodríguez, Anne B. Satterthwaite, Norman H. Altman, Eric L. Greidinger, Wasif N. Khan

Research output: Contribution to journalArticlepeer-review

Abstract

While apoptosis plays a role in B-cell self-tolerance, its significance in preventing autoimmunity remains unclear. Here, we report that dysregulated B cell apoptosis leads to delayed onset autoimmune phenotype in mice. Our longitudinal studies revealed that mice with B cell-specific deletion of pro-apoptotic Bim (BBimfl/fl) have an expanded B cell compartment with a notable increase in transitional, antibody secreting and recently described double negative (DN) B cells. They develop greater hypergammaglobulinemia than mice lacking Bim in all cells and accumulate several autoantibodies characteristic of Systemic Lupus Erythematosus (SLE) and related Sjögren’s Syndrome (SS) including anti-nuclear, anti-Ro/SSA and anti-La/SSB at a level comparable to NODH2h4 autoimmune mouse model. Furthermore, lymphocytes infiltrated the tissues including submandibular glands and formed follicle-like structures populated with B cells, plasma cells and T follicular helper cells indicative of ongoing immune reaction. This autoimmunity was ameliorated upon deletion of Bruton’s tyrosine kinase (Btk) gene, which encodes a key B cell signaling protein. These studies suggest that Bim-mediated apoptosis suppresses and B cell tyrosine kinase signaling promotes B cell-mediated autoimmunity.

Original languageEnglish (US)
Article number705307
JournalFrontiers in immunology
Volume12
DOIs
StatePublished - Aug 26 2021

Keywords

  • apoptosis
  • autoantibodies
  • autoimmunity
  • B cell tolerance
  • Bcl-2-like 11 (Bim)
  • Bruton’s tyrosine kinase (Bkt)
  • Sjogren’s syndrome
  • systemic lupus - erythematosus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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