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Immunoglobulin heavy chain variable region gene replacement As a mechanism for receptor revision in rheumatoid arthritis synovial tissue B lymphocytes.

Itoh K, Meffre E, Albesiano E, Farber A, Dines D, Stein P, Asnis SE, Furie RA, Jain RI, Chiorazzi N - J. Exp. Med. (2000)

Bottom Line: These secondary V(H) rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within V(H) (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.A relationship between these secondary V(H) gene rearrangements and the autoimmunity characteristic of RA should be considered.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, North Shore University Hospital, Manhasset, New York 11030, USA.

ABSTRACT
Mature B cells can alter their antibody repertoires by several mechanisms, including immunoglobulin heavy chain variable region (V(H)) replacement. This process changes the antigen combining site by replacing a portion of the original V(H)/diversity/heavy chain joining region (V(H)DJ(H)) rearrangement with a corresponding portion of a new V(H) segment. This exchange can involve cryptic heptamer-like sequences embedded in the coding regions of V(H) genes. While studying the B lymphocytes that expand in the synovial tissues of patients with rheumatoid arthritis (RA), clones with V(H)DJ(H) variants that were apparently generated by V(H) replacement were identified with surprising frequency (approximately 8%). Examples of multiple independent V(H) replacement events occurring in distinct progeny clones were also identified. These secondary V(H) rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within V(H) (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 V(H) 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 V(H) gene rearrangements and the autoimmunity characteristic of RA should be considered.

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Immunoglobulin heavy chain variable region gene replacement As a mechanism for receptor revision in rheumatoid arthritis synovial tissue B lymphocytes.

Itoh K, Meffre E, Albesiano E, Farber A, Dines D, Stein P, Asnis SE, Furie RA, Jain RI, Chiorazzi N - J. Exp. Med. (2000)

© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195868&req=5

Bottom Line: These secondary V(H) rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within V(H) (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.A relationship between these secondary V(H) gene rearrangements and the autoimmunity characteristic of RA should be considered.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, North Shore University Hospital, Manhasset, New York 11030, USA.

ABSTRACT
Mature B cells can alter their antibody repertoires by several mechanisms, including immunoglobulin heavy chain variable region (V(H)) replacement. This process changes the antigen combining site by replacing a portion of the original V(H)/diversity/heavy chain joining region (V(H)DJ(H)) rearrangement with a corresponding portion of a new V(H) segment. This exchange can involve cryptic heptamer-like sequences embedded in the coding regions of V(H) genes. While studying the B lymphocytes that expand in the synovial tissues of patients with rheumatoid arthritis (RA), clones with V(H)DJ(H) variants that were apparently generated by V(H) replacement were identified with surprising frequency (approximately 8%). Examples of multiple independent V(H) replacement events occurring in distinct progeny clones were also identified. These secondary V(H) rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within V(H) (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 V(H) 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 V(H) gene rearrangements and the autoimmunity characteristic of RA should be considered.

Show MeSH
Related in: MedlinePlus