title: Evidence that human immunoglobulin M rheumatoid factors can Be derived from the natural autoantibody pool and undergo an antigen driven immune response in which somatically mutated rheumatoid factors have lower affinities for immunoglobulin G Fc than their germline counterparts.
abstract: The question of whether immunoglobulin (Ig)M rheumatoid factors (RF) arise as the result of an abnormal expansion of already existing clones producing natural autoantibodies or emerge as new clones that are somatically mutated owing to an antigen driven immune response has never been conclusively answered. In this study, an inhibition ELISA was utilized to measure the affinities of recombinant antibodies using VH segments reverted back to their closest germline counterparts (germline revertants). In all cases, the somatically mutated parental RFs had a decreased affinity for immunoglobulin (Ig)G Fc compared to the germline revertant, indicating that the antibodies in the germline configuration had the higher affinities. This demonstrates that somatic mutation is not a prerequisite to generate disease associated antibodies. The presence of mutations in the parental IgM RFS suggests that these cells had been involved in a germinal centre reaction. As the germinal centre is the conventional site of the acquisition of mutations during an antigen driven response, these data suggest a role for germinal centres in the generation of the antibody diversity in addition to the selection of higher affinity antibodies. Assuming that only antigen selected cells survive deletion, these data support the hypothesis that IgM RFS can be derived from the natural autoantibody repertoire and result from an antigen driven response. Mechanisms controlling the survival of B cells based on the affinity/avidity of the immunoglobulin receptor are shown to be functional in patients with rheumatoid arthritis.
authors.affiliation: Department of Microbiology, University of Texas South-Western Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235, USA.
authors.forename: M O
authors.initials: MO
authors.lastname: Carayannopoulos
authors.forename: K N
authors.initials: KN
authors.lastname: Potter
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: J B
authors.initials: JB
authors.lastname: Natvig
authors.forename: J D
authors.initials: JD
authors.lastname: Capra
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000915:Antibody Affinity / Q000276:immunology*; D000917:Antibody Formation; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005803:Genes, Immunoglobulin; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D011994:Recombinant Proteins; D012217:Rheumatoid Factor / Q000235:genetics / Q000276:immunology*
chemical_list: D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011994:Recombinant Proteins; D012217:Rheumatoid Factor