Rheumatoid factors in primary Sjogren's syndrome (pSS) use diverse V(H) region genes, the majority of which show no evidence of somatic hypermutation

Abstract

Rheumatoid factor (RF) is the most common autoantibody found in patients with Sjogren's syndrome (SS). To study the genetic origin and the mechanisms acting behind its generation we have characterized and sequenced the immunoglobulin V(H) genes used by 10 IgM RF MoAbs derived from peripheral blood of six female patients with pSS. We compared the structure of the RF immunoglobulin VH genes with those obtained previously from rheumatoid arthritis (RA) patients and healthy immunized donors (HID). V(H)1 and VH4 were each used by four RF clones, one clone was encoded by V(H)3 family gene and one by V(H)2 family gene. This distribution frequency was different from that observed in RA, where V(H)3 was the dominant family, followed by V(H)1. Eight different germ-line (GL) genes encoded the clones and all of these genes were seen previously in RA and/or HID RF. Five clones rearranged to J(H)6, four rearranged to J(H)4 and one to J(H)5, in contrast to RF from RA and HID, where J(H)4 was most frequently used. D segment use and CDR3 structure were diverse. Interestingly, three out of four V(H)4 clones used the GL gene DP-79 that was seen frequently in RA RF. The degree of somatic mutation in the pSS RF was very much lower than seen in RA and HID RF. All the pSS RF clones except three were in or very close to GL configuration. This indicates that there is little role for somatic hypermutation and a germinal centre reaction in the generation of RF from peripheral blood in pSS.