STRUCTURAL RESTRICTION IN THE HEAVY-CHAIN CDR3 OF HUMAN RHEUMATOID FACTORS

We have compared the variable regions of 14 new IgM rheumatoid factors (RFs), produced in healthy human immunized donors (HIDs) with RFs ori ginating from patients with rheumatoid arthritis (RA) and monoclonal I g RFs (paraproteins or M-components, MG). Two groups with very restric ted variable region structures were found. Twelve RFs (3 HID, 3 MC, an d 6 RA) encoded by variable heavy (V-H) chain germ-line genes with clo sest homology to DP-10 co-express the Kv325 variable light (V-L) chain germ-line gene. These RFs have a remarkable restriction in the length (12-14 amino acids) and structure of the CDR(H)3. One HID RF has a CD R(H)3 only two amino acids different from the CDR(H)3 of a MC RF. Two sets of clonally related RFs, one from an RA patient and one from an H ID, have CDR(H)3s that differ by only three amino acids. Five RFs (3 H ID, 1 MC, and 1 RA) encoded by V-H germ-line gene segments with closes t homology to DP-54 all use the Kv328 V-L germ-line gene combined to J kappa 1. Four are rearranged to the D21/9 D segment in the same readi ng frame, with CDR(H)3s of 16 to 17 amino acids. Three RFs (1 HID, 1 R A, and 1 MC) have CDR(H)3s differing by only three amino acids. The hi ghly homologous V-regions in RFs from these two groups imply an initia l selection to very similar, if not identical, epitopes. However, it r emains to he seen whether somatic hypermutation alters the fine specif icity of these autoantibodies.