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Molecular analysis of the VxIII‐Jx junctional diversity of polyclonal rheumatoid factors during rheumatoid arthritis frequently reveals N addition

Much interest was stirred in recent years by the evidence that rheumatoid factors (RF) variable regions are encoded by a restricted set of V genes, with little or no somatic mutations, that are often overexpressed in the fetal repertoire. This is reminiscent of what has been observed for natural autoantibodies. However, these data come from studies of monoclonal RF (mRF) isolated from patients with lymphoproliferative disorders who usually do not present autoimmune symptoms. The molecular characterization of RF during autoimmune diseases such as rheumatoid arthritis (RA) has been hampered for some time because of their polyclonality; recently using the polymerase chain reaction method, we have demonstrated that RFχ variable regions from a patient with RA were encoded by VχIII genes known to code for mRF but that these genes had undergone somatic mutations with a pattern suggesting an antigen‐driven maturation. Because an important role of the light chain third complementarity‐determining region (CDR3) in anti‐IgG reactivity and idiotype expression has already been suspected for RF, we now report the molecular characterization of the junction regions of these rearranged Vχ genes. Surprisingly, our data show that in 55% of the cases there is addition of a proline and/or glycine amino acid residue at the recombination site between Vχ and Jχ. The sequence analysis of our patients' germ‐line Vg and Jχ4 gene segments and their flanking regions demonstrates that the additional codons are not readily explicable by recombination between germ‐line sequences and probably result from an N addition process. Since we could not find such an additional codon in 15 previously published mRF χ chains we suggest that “pathogenic” RF during RA and mRF derive from different, although overlapping, B cell subsets. Moreover, since additional codons at the recombination site of Vχ and Jχ seem exceptional in expressed human χ chains and because the resulting amino acid residue is a proline in most cases, we think that RFχ chain CDR3 is under a very strong selective pressure during RA.