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Immunoglobulin class-switch DNA recombination: induction, targeting and beyond.

ABSTRACT: Class-switch DNA recombination (CSR) of the immunoglobulin heavy chain (IGH) locus is central to the maturation of the antibody response and crucially requires the cytidine deaminase AID. CSR involves changes in the chromatin state and the transcriptional activation of the IGH locus at the upstream and downstream switch (S) regions that are to undergo S-S DNA recombination. In addition, CSR involves the induction of AID expression and the targeting of CSR factors to S regions by 14-3-3 adaptors, and it is facilitated by the transcription machinery and by histone modifications. In this Review, we focus on recent advances regarding the induction and targeting of CSR and outline an integrated model of the assembly of macromolecular complexes that transduce crucial epigenetic information to enzymatic effectors of the CSR machinery.

SUBMITTER: Xu Z

PROVIDER: S-EPMC3545482 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Immunoglobulin class-switch DNA recombination: induction, targeting and beyond.

Xu Zhenming Z Zan Hong H Pone Egest J EJ Mai Thach T Casali Paolo P

Nature reviews. Immunology 20120625 7

Class-switch DNA recombination (CSR) of the immunoglobulin heavy chain (IGH) locus is central to the maturation of the antibody response and crucially requires the cytidine deaminase AID. CSR involves changes in the chromatin state and the transcriptional activation of the IGH locus at the upstream and downstream switch (S) regions that are to undergo S-S DNA recombination. In addition, CSR involves the induction of AID expression and the targeting of CSR factors to S regions by 14-3-3 adaptors, ...[more]

PMID: 22728528

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Project description:Inflammation and tissue damage in systemic lupus erythematosus (SLE) are mediated by class-switched autoantibodies reactive with nucleic acids, nucleic acid-binding proteins, phospholipids and other self-antigens. While some healthy individuals produce IgM antibodies with specificities similar to those of lupus patients, immunoglobulin class switching to mature downstream isotypes appears to be required for the generation of pathogenic autoantibodies. To characterize the cellular and molecular basis of pathogenic autoantibody production in SLE, we studied the capacity of peripheral blood B cells of naive phenotype from patients with SLE, rheumatoid arthritis (RA) or healthy control subjects to spontaneously switch to IgG and IgA. In addition, we determined the DNA sequences of the upstream evolutionary conserved sequence (ECS)-Igamma promoter regulatory regions that control germline IH-CH transcription and class switch DNA recombination (CSR) to IgG1, IgG2 and IgG4. IgM+IgD+ B cells from patients with SLE, but not those from RA or healthy control subjects, underwent spontaneous CSR, as assessed by expression of germline Igamma1-Cgamma1, Igamma2-Cgamma2, Igamma3-Cgamma3, Igamma4-Cgamma4 and Ialpha1-Calpha1 transcripts, mature (switched) VHDJH-Cgamma1, VHDJH-Cgamma2, VHDJH-Cgamma3 and VHDJH-Calpha1 transcripts and secreted IgG and IgA. Although polymorphic DNA sequences were identified in the ECS-Igamma1, ECS-Igamma2 and ECS-Igamma4 promoter regions, the transcription factor-binding sites that mediate germline Igamma-Cgamma transcription were conserved in patients and controls. However, distinct patterns of nuclear protein binding to an ECS-Igamma promoter sequence that contains both positive and negative regulatory elements were observed in SLE patients and controls. These results support a role for exogenous signals, such as through CD40 ligation, rather than altered genomic sequence, in the increased production of class switched autoantibodies in SLE.

Dataset Information

Immunoglobulin class-switch DNA recombination: induction, targeting and beyond.

Publications

Immunoglobulin class-switch DNA recombination: induction, targeting and beyond.

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