Journal
FRONTIERS IN IMMUNOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.705307
Keywords
autoimmunity; apoptosis; Bcl-2-like 11 (Bim); B cell tolerance; systemic lupus; erythematosus; autoantibodies; Sjogren's syndrome; Bruton's tyrosine kinase (Bkt)
Categories
Funding
- National Institutes of Health [R21AI088511-01]
- Intramural Funding Program, Sylvester Comprehensive Cancer Center, University of Miami
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The dysregulation of B cell apoptosis leads to delayed onset of autoimmune phenotype in mice, characterized by expanded B cell compartment and increased autoantibody levels. The studies suggest that Bim-mediated apoptosis suppresses B cell-mediated autoimmunity, while B cell tyrosine kinase signaling promotes autoimmune reactions.
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 (BBim(fl/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 Sjogren'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.
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