Regulation of autoreactive anti-IgG (rheumatoid factor) B cells in normal and autoimmune mice.
In systemic autoimmune disease, autoantibodies target specific self-components in patterns that depend on the particular underlying disease. Therefore, in order to understand how tolerance to these self-components breaks down, it is important to study B cells with those specificities, rather than artificial autoantigens. We have been investigating the regulation of autoreactive B cells with specificity for self IgG2a (the rheumatoid factor or RF specificity) in order to understand how normal mice regulate RF autoantibodies and how this fails in autoimmune mice. A transgenic (Tgic) mouse based on an RF isolated from a diseased MRL/lpr/lpr mouse was constructed and studied in both normal and autoimmune-prone genetic backgrounds. Normal mice do not appear to regulate the RF clone negatively, nor do they appear to activate it substantially. Thus, a disease-related RF is "clonally indifferent." However, in a, Fas-deficient autoimmune-prone animal, these RF B cells are activated to divide and secrete in an antigen-specific manner. A high-affinity RF Tgic mouse was also constructed to determine whether RFs could be tolerized in normal mice. These B cells were deleted or edited in the presence of the autoantigen, which originated from maternal IgG in young mice. Interestingly, shortly after weaning, many mice began to produce autoreactive RF. Escape from tolerance could last for months and was most likely perpetuated by a positive feedback mechanism. Such a mechanism could exist in autoimmune animals and could have important implications for chronic autoimmune disease, as discussed.
Wang
H
H
Yale University School of Medicine, Department of Laboratory Medicine, New Haven, CT 06520-8035, USA.
Schlomchik
M J
MJ
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D012217:Rheumatoid Factor / Q000276:immunology*
D001323:Autoantibodies; D007074:Immunoglobulin G; D012217:Rheumatoid Factor