Regulation of rheumatoid factor synthesis.
Rheumatoid arthritis is associated with high titers of IgM and IgG autoantibodies against IgG (rheumatoid factors, RF) and is prevalent in individuals with the HLA haplotypes Dw4, Dw14 and DR1. Our investigations have aimed to determine the molecular genetic basis for RF autoantibody synthesis in people, in an effort to understand eventually how RF production may become improperly regulated in rheumatoid patients. The results have defined several cross-reactive idiotypes on the heavy and light chains of RFs that are serologic markers for specific immunoglobulin variable region genes. These autoantibody associated genes are highly conserved in human populations and are preferentially rearranged and expressed during early B cell development, and in certain lymphoproliferative diseases. They may be associated with a B cell subpopulation that is important for the processing and presentation to T cells of protein antigens trapped in immune complexes. These RF-associated idiotypes are eventually lost during the T cell dependent antibody diversification that accompanies rheumatoid arthritis. The stimuli for the diversification have not been clearly established. However, the rheumatoid arthritis disease susceptibility determinant on the beta-1 chain of individuals with the HLA Dw4, Dw14 or DR1 haplotypes is reproduced by the gp110 protein of the Epstein-Barr virus, and is a potent stimulus for T cell proliferation. Moreover, anti-gp110 antibodies are abundant in rheumatoid arthritis patients. Thus, it is possible that their continual binding and processing of gp110-IgG immune complexes by RF precursor B cells in the joints and other extravascular sites may lead to the emergence of self-reactive T cells that can trigger anti-IgG autoantibody synthesis in the absence of an external antigen.
Carson
D A
DA
Research Institute of the Scripps Clinic, La Jolla, California 92037.
Chen
P P
PP
Kipps
T J
TJ
Roudier
J
J
Silverman
G J
GJ
Tighe
H
H
D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology; D003429:Cross Reactions; D005803:Genes, Immunoglobulin; D006801:Humans; D007130:Immunoglobulin Idiotypes; D012217:Rheumatoid Factor / Q000096:biosynthesis* / Q000235:genetics
D007130:Immunoglobulin Idiotypes; D012217:Rheumatoid Factor