AID-Initiated Purposeful Mutations in Immunoglobulin Genes

Myron F. Goodman, Matthew D. Scharff, Floyd E. Romesberg

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Exposure brings risk to all living organisms. Using a remarkably effective strategy, higher vertebrates mitigate risk by mounting a complex and sophisticated immune response to counter the potentially toxic invasion by a virtually limitless army of chemical and biological antagonists. Mutations are almost always deleterious, but in the case of antibody diversification there are mutations occurring at hugely elevated rates within the variable (V) and switch regions (SR) of the immunoglobulin (Ig) genes that are responsible for binding to and neutralizing foreign antigens throughout the body. These mutations are truly purposeful. This chapter is centered on activation-induced cytidine deaminase (AID). AID is required for initiating somatic hypermutation (SHM) in the V regions and class switch recombination (CSR) in the SR portions of Ig genes. By converting C → U, while transcription takes place, AID instigates a cascade of mutational events involving error-prone DNA polymerases, base excision and mismatch repair enzymes, and recombination pathways. Together, these processes culminate in highly mutated antibody genes and the B cells expressing antibodies that have achieved optimal antigenic binding undergo positive selection in germinal centers. We will discuss the biological role of AID in this complex process, primarily in terms of its biochemical properties in relation to SHM in vivo. The chapter also discusses recent advances in experimental methods to characterize antibody dynamics as a function of SHM to help elucidate the role that the AID-induced mutations play in tailoring molecular recognition. The emerging experimental techniques help to address long-standing conundrums concerning evolution-imposed constraints on antibody structure and function.

Original languageEnglish (US)
Pages (from-to)127-155
Number of pages29
JournalAdvances in Immunology
Volume94
DOIs
StatePublished - 2007

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Immunoglobulin Genes
Mutation
Antibodies
Genetic Recombination
DNA Mismatch Repair
Germinal Center
Poisons
DNA-Directed DNA Polymerase
Antigen-Antibody Complex
DNA Repair
Vertebrates
B-Lymphocytes
AICDA (activation-induced cytidine deaminase)
Antigens
Enzymes
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

AID-Initiated Purposeful Mutations in Immunoglobulin Genes. / Goodman, Myron F.; Scharff, Matthew D.; Romesberg, Floyd E.

In: Advances in Immunology, Vol. 94, 2007, p. 127-155.

Research output: Contribution to journalArticle

Goodman, Myron F. ; Scharff, Matthew D. ; Romesberg, Floyd E. / AID-Initiated Purposeful Mutations in Immunoglobulin Genes. In: Advances in Immunology. 2007 ; Vol. 94. pp. 127-155.
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