High affinity rheumatoid factor transgenic B cells are eliminated in normal mice.
Although systemic autoimmune diseases can be accompanied by multiple autoantibodies, certain specificities are dominant. Presumably, these specificities and their cognate Ags have properties that make them particularly amenable to autoimmune induction. Rheumatoid factors (RFs) are a dominant class of autoantibodies in rheumatoid arthritis and certain other autoimmune syndromes. To study the regulation of RFs in normal and autoimmune animals, we previously created a RF Ig transgenic model based on an RF isolated from an autoimmune MRL/lpr mouse. Using this model, called AM14, we were surprised to find that normal mice do not regulate disease-related RF B cells. This raised the question of whether RFs in general are not susceptible to tolerance induction, perhaps due to the unique properties of serum IgG and its FcRs. Alternatively, RFs can be tolerized, and the disease-related RFs are below the affinity threshold for such tolerance. To distinguish these possibilities, we generated a second RF transgenic model with the same specificity but much higher affinity than AM14. We found that, in contrast to AM14, high affinity RF B cells are subject to central tolerance, showing that there is not an absolute defect in RF B cell tolerance, but, rather, that RF B cell tolerance is affinity dependent even in normal animals. This is also the first model in which a disease-related specificity has been shown clearly to delete in a system in which Ag-positive and negative mice can be produced and compared.
Wang
H
H
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Shlomchik
M J
MJ
D000818:Animals; D000915:Antibody Affinity; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001853:Bone Marrow / Q000276:immunology; D001947:Breeding; D017637:Clonal Deletion; D006825:Hybridomas / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic / Q000254:growth & development; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism; D012217:Rheumatoid Factor / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D013154:Spleen / Q000276:immunology; D019076:Transgenes / Q000276:immunology*
D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D011947:Receptors, Antigen, B-Cell; D012217:Rheumatoid Factor