B cell tolerance checkpoints that restrict pathways of antigen-driven differentiation.
Autoreactive B cells can be regulated by deletion, receptor editing, or anergy. Rheumatoid factor (RF)-expressing B lymphocytes in normal mice are not controlled by these mechanisms, but they do not secrete autoantibody and were presumed to ignore self-Ag. Surprisingly, we now find that these B cells are not quiescent, but instead are constitutively and specifically activated by self-Ag. In BALB/c mice, RF B cells form germinal centers (GCs) but few Ab-forming cells (AFCs). In contrast, autoimmune mice that express the autoantigen readily generate RF AFCs. Most interestingly, autoantigen-specific RF GCs in BALB/c mice appear defective. B cells in such GCs neither expand nor are selected as efficiently as equivalent cells in autoimmune mice. Thus, our data establish two novel checkpoints of autoreactive B cell regulation that are engaged only after initial autoreactive B cell activation: one that allows GCs but prevents AFC formation and one that impairs selection in the GC. Both of these checkpoints fail in autoimmunity.
William
Jacqueline
J
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Euler
Chad
C
Primarolo
Nicole
N
Shlomchik
Mark J
MJ
D000818:Animals; D000917:Antibody Formation; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012217:Rheumatoid Factor / Q000276:immunology; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology
D001324:Autoantigens; C497868:Cd22 protein, mouse; D007074:Immunoglobulin G; D051918:Sialic Acid Binding Ig-like Lectin 2; D012217:Rheumatoid Factor