Sir Joseph Norman Lockyer — the founding editor of Nature. Credit: Hulton-Deutsch Collection/CORBIS

Our immune system uses some fascinating genetic mechanisms to generate the huge diversity of antibodies necessary to fight infection — combinatorial diversity, class-switching and somatic hypermutation. And now RNA editing can be added to the list.

Antibody genes are assembled from DNA segments (V, D and J) by site-directed recombination: because there are many copies of each segment, this generates combinatorial diversity. Class-switching swaps a segment encoding the constant region of the antibody for another segment. This alters the functionality of the antibody — changing an IgM antibody to an IgG antibody, for example. The antibody is then finely tuned by somatic hypermutation. As the antibody gene is expressed in maturing B cells, mutations are generated at high frequency and the antibodies with the highest affinities for antigen are selected.

As far as the mechanisms are concerned, quite a bit is known about V(D)J recombination, but we know little about the molecules responsible for class-switching and somatic hypermutation. In previous work, Tasuku Honjo and colleagues have used a cell-based assay to look for new genes expressed during class-switching and identified a new RNA editing enzyme known as activation-induced cytidine deaminase ( AID). In the latest work, gain-of-function and loss-of-function analyses establish a clear role for AID in class-switching and somatic hypermutation.

Muramatsu et al. have now shown that increased expression of AID can induce class-switching in the cell-based assay. Furthermore, when they knocked out AID, the homozygous mice lost all class-switching, in vivo and in vitro. The authors also assayed for hypermutation by screening antibody gene transcripts for mutations in the AID mutants. They found a tenfold reduction in mutation rate in mutants, relative to wild-type littermates.

In an accompanying paper, Revy et al. present the human story. They mapped an autosomal recessive form of an immune abnormality known as hyper IgM syndrome, and by a positional candidate approach, they found that the human AID gene carries causative mutations in 12 families. Like the knockout mice, AID deficient humans have no class-switching and severely reduced hypermutation. The evidence is watertight — AID is necessary for class-switching and somatic hypermutation.

But how does an enzyme that changes C's to U's in RNA transcripts contribute to antibody diversity? At this stage, it is only possible to speculate. The closest homologue to AID is the RNA editing enzyme, APOBEC1, which has one specific target — the apolipoprotein B transcript. Does AID just modify the transcript of one gene, leading to the synthesis of a protein that plays a specific role in switching and hypermutation? Or, does AID have multiple targets? Whatever they are, antibody gene expression has just become even more interesting, and like Lockyer back in 1869, AID is one editor we couldn't do without.