Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes
Open Access
- 16 October 2000
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 192 (8), 1151-1164
- https://doi.org/10.1084/jem.192.8.1151
Abstract
Mature B cells can alter their antibody repertoires by several mechanisms, including immunoglobulin heavy chain variable region (VH) replacement. This process changes the antigen combining site by replacing a portion of the original VH/diversity/heavy chain joining region (VHDJH) rearrangement with a corresponding portion of a new VH segment. This exchange can involve cryptic heptamer-like sequences embedded in the coding regions of VH genes. While studying the B lymphocytes that expand in the synovial tissues of patients with rheumatoid arthritis (RA), clones with VHDJH variants that were apparently generated by VH replacement were identified with surprising frequency (∼8%). Examples of multiple independent VH replacement events occurring in distinct progeny clones were also identified. These secondary VH rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within VH (three sites in framework region 3 and one in complementarity determining region 2). The identification of blunt-ended double-stranded DNA breaks at the embedded heptamers and the demonstration of recombinase activating gene (RAG) expression suggested that these rearrangements could occur in the synovial tissues, presumably in pseudo-germinal centers, and that they could be mediated by RAG in a recognition signal sequence–specific manner. The presence of VH mutations in the clones that had undergone replacement indicated that these B cells were immunocompetent and could receive and respond to diversification signals. A relationship between these secondary VH gene rearrangements and the autoimmunity characteristic of RA should be considered.Keywords
This publication has 91 references indexed in Scilit:
- On The Occurrence Of A Factor In Human Serum Activating The Specific Agglutintion of Sheep Blood CorpusclesAPMIS, 2007
- Receptor Revision of Immunoglobulin Heavy Chain Variable Region Genes in Normal Human B LymphocytesThe Journal of Experimental Medicine, 2000
- Revising B Cell ReceptorsThe Journal of Experimental Medicine, 2000
- Analysis of Heavy and Light Chain Pairings Indicates that Receptor Editing Shapes the Human Antibody RepertoireJournal of Molecular Biology, 1999
- The Normal Counterpart of IgD Myeloma Cells in Germinal Center Displays Extensively Mutated IgVH Gene, Cμ–Cδ Switch, and λ Light Chain ExpressionThe Journal of Experimental Medicine, 1998
- Lupus-specific antibodies reveal an altered pattern of somatic mutation.JCI Insight, 1997
- VDJ recombinationImmunology Today, 1992
- Rheumatoid ArthritisNew England Journal of Medicine, 1990
- The american rheumatism association 1987 revised criteria for the classification of rheumatoid arthritisArthritis & Rheumatism, 1988
- Recombination between an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a Ly 1+ B-cell lymphomaNature, 1986