First AID (Activation-induced Cytidine Deaminase) Is Needed to Produce High Affinity Isotype-switched Antibodies

Abstract

An answer to the question "why don't you die when I sneeze?" resides in the ability of higher organisms to mount an aggressive defense in response to an invasion by foreign substances called antigens. In part this defense mechanism is accomplished through the synthesis of high affinity antibody (Ab) 2 proteins that effectively defuse the attack. Initially, lymphoid B cells rearrange immunoglobulin (Ig) genes using V(D)J recombination to generate a diverse repertoire of low affinity Abs. Subsequently these Ig genes undergo somatic hypermutation (SHM) and class switch recombination (CSR) to generate high affinity Ab molecules of different isotypes. Activation-induced cytidine deaminase (AID) is required to initiate both CSR and SHM. The current understanding of immunological diversification can be attributed to the contributions made by cellular and molecular immunologists with biochemical enzymology recently entering the arena. This minireview discusses advances in the understanding ofAb diversification from a biochemical perspective emphasizing the enzymatic properties of AID in initiating SHM and CSR and exploring the role of downstream mutation fixation events mediated by mismatch repair (MMR), basic excision repair (BER), and error-prone DNA polymerases (EP pols).