Rheumatoid factors isolated from patients with autoimmune disorders are derived from germline genes distinct from those encoding the Wa, Po, and Bla cross-reactive idiotypes.

Abstract

To better understand the structural basis for rheumatoid factor activity, the nucleotide sequence of the light chain variable regions of nine human monospecific IgM rheumatoid factors were analyzed. Rheumatoid factors were isolated from three patients with rheumatoid arthritis, a patient with systemic lupus erythematosus, and a normal individual. The VL gene segments used by these rheumatoid factors are not as restricted as previous work on mixed cryoglobulin rheumatoid factors had suggested. Each of the different VK families is represented and there are two examples where a V, gene segment is used. Molecules with structures similar to those of the Wa and Po CRI, characteristic of mixed cryoglobulin rheumatoid factors, are not common among these rheumatoid factors isolated from patients with rheumatoid arthritis. While there are clear examples of rheumatoid factors that are direct copies of germline genes, most of the sequence data suggest that the processes of antigenic selection and somatic mutation contribute significantly to the generation of monospecific rheumatoid factors in patients with autoimmune disease. (J. Clin. Invest. 1991.

A somatically mutated VκIV gene encoding a human rheumatoid factor light chain

“…Recent publications concerning the sequences of V genes encoding RF from patients with RA also present strong evidence that some RF from patients with RA differ from those from patients with lymphoproliferative disorders and that somatic mutation is involved in the diversification [12,[25][26][27]. These investigations extend and support earlier serologic studies of fine specificities and cross-reacting idiotypes of hybridomas and serum immunoglobulins of patients with RA and healthy controls [6][7][8][9]28,29].…”

“…For the VKIV gene this could be accomplished using PCR, since there is only one human germline gene ofthe VKIV family [14,15]. Although there are some RF light and heavy chains reported which differ from known germline genes, there is so far no direct comparison of a gene encoding a RF with the germline gene of the same individual [12,[25][26][27]. While we present the sequence of a single chain of one RF, our findings are of importance to the recent discussion on the biological significance of RF, for the following reasons.…”

Molecular analysis of rheumatoid factors derived from rheumatoid synovium suggests an antigen‐driven response in inflamed joints

“…Significantly, 7 nucleotides in the CDR3 of kalc6 cannot be accounted for by either the VK1 or the J K~ genes; this demonstrates the existence of an N region (13,23).…”

“…The data indicate a strong selection pressure from an antigen (34). Humka3d5 used a J K~ gene segment which was 39 bp in length and contained an N region of 4-6 nucleotides (Table 1 and Figure 3) (13,22).…”

Crystal Structure of a Human Autoimmune Complex between IgM Rheumatoid Factor RF61 and IgG1 Fc Reveals a Novel Epitope and Evidence for Affinity Maturation

“…Interaction with the Fc epitope is in both cases a combined result of germline residues, VDJ rearrangements, and somatic mutations in CDRs, rather than solely a property of unmutated germline genes. 25,26 For both of these RFs, somatically mutated residues play an important role in the interaction, so that while they may have different origins, affinity maturation and selection by Fc appear to be a common feature.…”