Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes
| Autor: | David M. Dines, Peter Stein, Richard A. Furie, Andrew Farber, Kenji Itoh, Nicholas Chiorazzi, Rita I. Jain, Emilia Albesiano, Stanley E. Asnis, Eric Meffre |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2000 |
| Předmět: |
Adult
Male immune tolerance antibody diversity Knee Joint Immunology Molecular Sequence Data Gene Rearrangement B-Lymphocyte Heavy Chain Immunoglobulin Variable Region Complementarity determining region Biology Polymerase Chain Reaction recombinase activating genes rheumatoid factor Arthritis Rheumatoid medicine Immunology and Allergy Coding region Humans Genomic library Framework region Gene Library B-Lymphocytes Base Sequence Genes Immunoglobulin autoimmunity Synovial Membrane Genetic Variation Gene rearrangement Molecular biology Immunoglobulin Isotypes medicine.anatomical_structure Immunoglobulin M Mutation biology.protein Immunoglobulin heavy chain Original Article Female Hip Joint Antibody Synovial membrane Immunoglobulin Heavy Chains Sequence Alignment |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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