Q J Med 2003; 96: 385-386
© 2003 Association of Physicians
Biologic |
The Eurofighter and infections
It is said that no one can fly the Eurofighter; it is designed to be unstable and to have control surfaces managed by computer. That way it is more manoeuvrable and quicker to respond to challenge. To some extent, it's the same with B-cells.
Despite realizing that genetic change happens much faster than we thought (around 5% of our genome is composed of segmental duplications that have arisen in the last 35 million years),1 we know that new proteins have appeared over evolutionary time by mutation and selection, and generally have become established rather slowly (despite Stephen Jay Gould and punctuated equilibrium). But the genes that produce antibodies are like the Eurofighter—basically unstable.
The initial response to infection (or immunization) is to produce a wide range of antibodies of low affinity. These have their origins in the early differentiation of B-cells, where genetic re-arrangement of basic antibody-producing genes occurs. You will remember that the other half of each antibody molecule is encoded by variable genes, and that these genes have a tremendous mutation rate. This is exploited to permit the production of high-affinity antibodies produced by cells that undergo the so-called hypermutation, which permits the production of many new protein sequences. The hypermutation is targeted specifically at the variable part of the imunoglobulin genes, causing relatively little damage to other loci (clearly diffuse activity would be intolerable). Antigen-mediated selection then allows the preferential expansion of those mutants expressing antibodies displaying improved binding characteristics.
How is it done? We owe the explanation to a beautiful series of experiments by Neuberger (see, for example reference 2). It has been known for a while that activation-induced cytosine deaminase (AID) an RNA-editing enzyme, leads to DNA mutations when expressed in bacteria, and that it is expressed in hypermutating cells. There is a bias towards more mutations in the cytosines in bacteria that lack the enzyme uracil glycosylase, suggesting that AID converts cytosines to uracils—the uracils that should not be there are normally removed by the glycolsylase. What happens in Man is that the formation of uracil from cytosine in B-cell DNA sets off hypermutation, and this is exploited as cells try to correct the errors. Remember, the normal bases in DNA are cytosine, guanine, thymine and adenine, so the appearance of a uracil provokes a repair attempt. When this happens, mistakes occur—uracil can be read as thymine, and an error is thus perpetuated. Some of the other correction methods depend on the uracil being removed by its glycolase, leaving a gap that may be filled by a number of pathways. The one so clearly defined by Di Noia and Neuberger is replication-based. In DNA replication, transversion-type mutations are generated in the variable genes (a transversion is where a pyrimidine base is swapped for a purine, i.e. cytosine, adenine or uracil for adenine or guanine) and in this case cytosine or guanine is usually replaced. Transitional mutations are where one pyrimidine is replaced by another or a purine is swapped.
In human hypermutating cells, all of the nucleotides are mutated at similar rates, and transitions are the commonest form of mutation found. All of the available repair and replication pathways may be used to deal with AID-generated uracils, and after they are removed the repair pathways will act, allowing mutations involving adenine and thymine to occur, rather than just those involving cytosine and guanine (this process is clearly illustrated by Gerhardt3). Other repair mechanisms may result in polymerase-driven errors, resulting in thymine opposite guanine, and mismatch repair enzymes may cause further change. Interestingly, Gerhardt points out that we need an explanation for the replacement of the usually accurate base-excision repair mechanism (using polymerase ß) by mutation-generating repair (using polymerase 
) in variable genes. Whatever is the case, here is a superb example of a series of mechanisms to guarantee diversity.
This story would have delighted Darwin. He considered that natural selection relied entirely on small isotropic, non-directional variation as the raw material for natural selection. In his book on earthworms, he refutes an argument by the splendidly named Mr Fish (who considered that earthworms were not up to much) thus: ‘Here we have an instance of that inability to sum up the effects of a continually recurrent cause, which has often retarded the progress of science, as formerly in the case of geology, and more recently in that of the principle of evolution’. This variability in mammals might well underlie resistance to plagues, and thus be a powerful selective force. There are those who cannot hypermutate—they get infections and don't respond to immunization.
References
1. Berry C. Variety. Q J Med 2002; 95:261–2.
2. Di Noia J, Neuberger MS. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 2002; 419:43–8.[CrossRef][Medline]
3. Gearhart P. The roots of antibody diversity. Nature 2002; 419:29–31.[CrossRef][Medline]
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