Rheumatoid factor isotype switch and somatic mutation variants within rheumatoid arthritis synovium

The presence of clonally-related B-lymphocyte aggregates within synovial li ning tisue of rheumatoid arthritis (RA) patients suggests a germinal centre -like reaction, which may hold implications for disease pathogenesis and th e causes of chronic inflammation. We studied 250 rheumatoid factor (RF) hea vy-chain sequences cloned from the synovium of three patients with RA, to d etermine whether they undergo both somatic mutation and isotype switching c onsistent with this hypothesis. Size analysis of immunoglobulin heavy-chain cDNAs from synovial RF+ B cells revealed oligoclonal RF+ populations and i dentically-sized V-H-D-J(H) transcripts of different immunoglobulin isotype s. Sequencing of individual inserts selected from cloned immunoglobulin hea vy-chain cDNAs demonstrated a clonal relationship between immunoglobulin M (IgM) RF and IgA RF, suggesting that this isotype switch occurred in synovi um. Furthermore, most somatic mutations were found to have occurred after t his isotype switch. This finding suggests that the RA synovial microenviron ment sustains somatic mutation and isotype switching in RF-specific B lymph ocytes akin to secondary lymphoid organs.