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AID and mismatch repair in antibody diversification

Nature Reviews Immunology volume 2, pages 605–614 (2002)Cite this article

Key Points

  • In response to antigen, antibody genes are diversified by three genetic events: somatic hypermutation (SHM) and/or gene conversion, which improve antibody affinity; and class-switch recombination, which alters the antibody isotype and, thereby, effector function.

  • SHM requires transcription; is targeted to particular regions or hotspots; is not restricted to immunoglobulin genes only; and might be associated with double- and/or single-stranded DNA breaks.

  • In mice that are deficient in mismatch repair (MMR), there is a bias for mutation of G–C base pairs in hotspot motifs. This indicates that MMR repair might preferentially correct mutations of G–C base pairs in hotspots, or that SHM might involve two phases — one that targets G–C base pairs in hotspots, and a MMR-dependent phase that mutates A–T base pairs and G–C base pairs outside hotspots.

  • Variable region (V) genes can also be diversified by gene conversion, whereby sequences from upstream V pseudogenes are copied into functional V genes. The mechanism of gene conversion seems to be similar to homologous recombination.

  • CSR involves recombination between switch regions. The cleaving enzyme is not known, but repair of the lesion probably involves the non-homologous end joining (NHEJ) pathway.

  • Activation-induced cytidine deaminase (AID) and MMR are involved in SHM, CSR and gene conversion.

  • AID is the only B-cell-specific factor that is required for SHM, gene conversion and CSR.

  • Two models for AID activity have been proposed: that AID is a messenger RNA editor, or that it is a DNA-specific cytidine deaminase. The MMR system might have an important role at latter stages in the repair process.

Abstract

In response to antigen, B cells undergo a series of specialized genetic events to produce the 'ideal' population of antibodies to prevent and eradicate infections. Although these events — somatic hypermutation, gene conversion and class-switch recombination — have been recognized for many years, the enzymes that are involved have remained elusive. The recent discovery that activation-induced cytidine deaminase (AID) and the mismatch repair (MMR) system are involved in these processes has led to new models of the biochemical events that generate antibody diversity. However, there is still considerable uncertainty about the mechanism of action of AID, and there are differing viewpoints about the role of MMR.

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Figure 1: Antibody-diversification mechanisms in mature B cells.
Figure 2: Two-stranded invasion in gene conversion.
Figure 3: Staggered cleavages and processing during class-switch recombination.
Figure 4: Putative modes of AID and MMR function in SHM, gene conversion and CSR.

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Acknowledgements

We thank M. Goodman, B. Birshtein, M. Sadofsky, P. Bardwell, R. Laskov and W. Edelmann for their critical review of this manuscript. This work was supported by grants from the National Institutes of Health to M.D.S., who is also supported by the Harry Eagle Chair provided by the National Women's Division of the Albert Einstein College of Medicine. A.M. is a recipient of Cancer Research Institute and Harry Eagle Fellowships.

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  1. Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Chanin 403, Bronx, 10461, New York, USA

    Alberto Martin & Matthew D. Scharff

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DATABASES

LocusLink

AID

APOB

APOBEC1

BCL6

CD40L

CD95L

DNA polymerase η

EXO1

GST

H2AX

interleukin-4

MLH1

MLH3

MSH2

MSH3

MSH4

MSH5

MSH6

NBS1

PCNA

phorbolin-1

PMS2

RAD51B

RAD54

Rag1

RAG1

RAG2

XRCC2

XRCC3

<i>Saccharomyces</i> Genome Database

Rad

Glossary

AFFINITY MATURATION

The mutation of antibody variable (V)-region genes followed by selection for higher-affinity variants in the germinal centre leads to an increase in average antibody affinity as an immune response progresses. The selection is thought to be a competitive process in which B cells compete with each other to capture decreasing amounts of antigen.

CENTROBLAST

A stage of B-cell development at which class-switch recombination and somatic hypermutation occur. These cells are rapidly cycling and reside in the dark zone of the germinal centre.

GERMINAL CENTRE

Located in peripheral lymphoid tissues (for example, the spleen), these structures are sites of B-cell proliferation, somatic hypermutation and selection for clones that produce antigen-specific antibodies of higher affinity.

INTRONIC ENHANCER

An ∼2 kb DNA sequence that lies between the V region and the μ-switch region that regulates the transcription of the heavy-chain antibody gene.

XERODERMA PIGMENTOSUM

(XP). A rare inherited human disorder, in which patients are sensitive to the DNA-damaging effects of sunlight. XP can be caused by disabling any of eight different genes. Seven of the genes, denoted XPA–XPG, encode components of the nucleotide-excision repair pathway. The XPV gene encodes DNA polymerase η.

ERROR-PRONE DNA POLYMERASES

Recently identified DNA polymerases that copy templates inaccurately. Some of these — including POLζ, POLη, POLι and POLμ — are candidates for enzymes that introduce base changes during somatic hypermutation.

V(D)J RECOMBINATION

To create a functional antibody variable (V) region, mouse pre-B cells must first recombine one of many V gene segments to one of 15 diversity (D) segments and one of four joining (J) segments.

HOMOLOGOUS RECOMBINATION

Genetic recombination that occurs between DNA strands that have long stretches of homology. Double-stranded breaks can be repaired if a chromosome or chromatid that is homologous to the broken DNA is available in the cell.

HYBRIDOMA

An antibody-secreting B-cell line that is generated by fusing splenic-derived B cells with a plasmacytoma.

DT40 CELLS

A chicken B-cell line that undergoes high rates of homologous recombination and immunoglobulin gene conversion.

STERILE TRANSCRIPTS

These transcripts, which are driven from I promoters located upstream of all switch regions, are not believed to encode proteins, but are spliced to form mature sterile transcripts that contain the constant-region exons and sequences upstream of the switch region.

3′ REGULATORY REGION

Sequences that are located 3′ of the last constant-region genes of the heavy-chain immunoglobulin cluster (that is, Cα in mice) that regulate transcription of the immunoglobulin locus.

NON-HOMOLOGOUS END JOINING

(NHEJ). A pathway that rejoins DNA strand breaks without relying on marked homology. The main known pathway uses the Ku-end-binding complex and is regulated by DNA protein kinase. The pathway is often used in mammalian cells to repair strand breaks that are caused by DNA-damaging agents, and some of the same enzymes are used during the strand-joining steps of V(D)J recombination.

HYPER-IGM SYNDROME

An immunodeficiency in which patients have high levels of serum IgM, but trace amounts of IgG, IgA and IgE, and suffer from opportunistic infections. The most common form, X-linked hyper-IgM, is caused by defects in CD40 ligand (CD154).

RAMOS CELLS

A Burkitt's lymphoma human B-cell line that constitutively undergoes high rates of somatic hypermutation.

RAG PROTEINS

Recombination-activating gene 1 (RAG1) and RAG2 are proteins that mediate V(D)J recombination in pre-B cells and thymocytes, which allows for the production of antibodies and T-cell receptors, respectively.

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Martin, A., Scharff, M. AID and mismatch repair in antibody diversification. Nat Rev Immunol 2, 605–614 (2002). https://doi.org/10.1038/nri858

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