Immunoglobulin VDJ recombination occurs in B lymphocytes in the absence of AID expression. The expression of AID controls antibody diversity through multiple gene rearrangements involving mutation of DNA sequence and recombination. The initial expression of antibodies requires immunoglobulin (Ig) gene rearrangement that is AID-independent (1). This occurs in immature B lymphocytes developing in fetal liver or adult bone marrow and requires DNA double strand breaks at the Ig heavy chain locus whose ends are rejoined by non-homologous end joining. The rearranged immunoglobulin V (variable), D (diversity) and J (joining) gene segments encode a variable region that is expressed initially with the mu (µ) constant region (Cµ) to form a primary antibody repertoire composed of IgM antibodies. In humans and many mammals, AID-dependent gene alterations occur in B lymphocytes that are growing in germinal centers of secondary lymphoid organs following antigen activation. This involves multiple mutations of the variable region through Somatic Hypermutation (SHM) as well as removing the Cµ and replacing it with one of several other constant regions (Ca, Cd, Ce or Cg) through a recombination process known as Class Switch Recombination, CSR. In sheep, rabbits and chickens, pre-immune Ig gene diversification is mediated by an AID-dependent process known as gene conversion (GC) in which stretches of nucleotide sequences from one of several pseudogene V elements are recombined into the VDJ exon to generate diversity (for diagrams and further review see references 2 and 3). The mechanism of action of AID and its targets remain controversial. Although evidence is compelling that AID mutates DNA during SHM and CSR a role for AID in mRNA has not been ruled out (4,5).
- (1) Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y. and Honjo, T. (2000). Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102:553-563.
- (2) Fugmann, S.D. and States, D.G. (2002). Immunology. One AID to unite them all. Science 295:1244-1245.
- (3) Honjo, T., Kinoshita, K. and Muramatsu, M. (2002). Molecular Mechanism of Class Switch Recombination: Linkage with Somatic Hypermutation. Ann. Rev. Immunol. 20:165-196.
- (4) Galloway, C.A., Sowden, M.P. & Smith, H.C. Increasing the Yield of Soluble Recombinant Protein Expressed in E. coli by Induction During Late Log Phase. BioTechniques 34: 524-530 (2003).
- (5) Smith, H.C., Bottaro, A, Sowden, M.P. & Wedekind, J.E. Activation induced deaminase: the importance of being specific. Trends in Genetics 20:224-227 (2004).