Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF.
Peripheral autoantigen binding B cells are poorly competitive with naive B cells for survival and undergo rapid cell death. However, in monoclonal Ig-transgenic mice lacking competitor B cells, autoantigen binding B cells can survive for extended periods. The basis for competitive elimination of autoantigen binding B cells has been unknown. Here we demonstrate that autoantigen binding B cells have increased dependence on BAFF for survival. In monoclonal Ig-transgenic mice, each autoantigen binding B cell receives elevated amounts of BAFF, exhibiting increased levels of NFkappaB p52 and of the prosurvival kinase Pim2. When placed in a diverse B cell compartment, BAFF receptor engagement and signaling are reduced and the autoantigen binding cells are unable to protect themselves from Bim and possibly other death-promoting factors induced by chronic BCR signaling. These findings indicate that under conditions where BAFF levels are elevated, autoantigen-engaged cells will be rescued from rapid competitive elimination, predisposing to the development of autoimmune disease.
Lesley
Robin
R
Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 USA.
Xu
Ying
Y
Kalled
Susan L
SL
Hess
Donna M
DM
Schwab
Susan R
SR
Shu
Hong-Bing
HB
Cyster
Jason G
JG
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000502:physiology*; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007108:Immune Tolerance; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
D001324:Autoantigens; D053264:B-Cell Activating Factor; D008565:Membrane Proteins; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha