Expression of recombination‐activating genes and terminal deoxynucleotidyl transferase and secondary rearrangement of immunoglobulin κ light chains in rheumatoid arthritis synovial tissue

• Published in: Arthritis and rheumatism 2001-10, Vol.44 (10), p.2275-2284
• Main Authors: Zhang, Zhixin, Wu, Xing, Limbaugh, Brent H., Bridges, S. Louis
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; DNA Nucleotidylexotransferase - genetics; Female; Gene Expression Regulation; Gene Rearrangement; Genes, Immunoglobulin; Humans; Immunoglobulin kappa-Chains - genetics; Male; Middle Aged; Polymerase Chain Reaction; Recombination, Genetic; Synovial Membrane - immunology; Synovial Membrane - pathology
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/1529-0131(200110)44:10<2275::AID-ART390>3.0.CO;2-K

Objective Lymphocytic infiltrates in rheumatoid arthritis (RA) synovium often resemble lymphoid follicles and contain clonally related Ig transcripts, suggesting in situ antigen‐dependent B cell selection. Recent reports have shown expression of recombination‐activating genes (RAGs) and concurrent secondary rearrangement of Ig genes in normal peripheral lymphoid organs (receptor revision). We sought to determine if RAG‐mediated receptor revision of Ig κ light chains occurs in B cells within the RA synovium. Because we previously reported enhanced N‐region addition at VL–JL joins in clonally expanded light‐chain transcripts from RA synovium, we also sought expression of terminal deoxynucleotidyl transferase (TdT), which is normally expressed only in B cell precursors or immature B cells. Methods Reverse transcription–polymerase chain reaction (PCR) was used to detect RAG and TdT transcripts from unselected and B cell–enriched synovial and peripheral blood mononuclear cells obtained from 12 RA patients. Activity of RAG protein was sought using ligation‐mediated PCR to detect recombination intermediates, and immunohistochemistry was performed to identify RAG+ cells within synovia. Results We found evidence of RAG‐mediated secondary Ig κ light chain rearrangements in about one‐third of RA synovia. TdT expression was found in several samples, but did not correlate with RAG expression. Conclusion RAG‐mediated secondary Ig rearrangements of κ light chains may contribute to the local production of antibodies to autoantigens (e.g., rheumatoid factor) or exogenous antigens, or it may represent a failed attempt at immune tolerance. TdT expression suggests the presence of immature B cells in RA synovia. These findings have important implications for the local generation of antibodies in RA and other chronic inflammatory diseases.