Dr. Andy

Reflections on medicine and biology among other things

Monday, March 21, 2005

Evolution of Adaptive Immune Response

How did the adaptive immune system evolve? By adaptive I mean the ability to respond to specific antigens. Plants and invertebrates lack this capacity. They have generalized defenses including cells called phagocytes that can engulf invading microorganisms and small proteints (peptides) that can kill a variety of bacteria, but they don't generate an immune response that specifically recognzies a given microbe.

All vertebrates from the level of the jawed fish on up have the ability to mix and match immune genes to create a near infinite number of receptors, which should be capable of recognizing just about any protein (or other appropriately sized molecule).

How did such an ability suddenly appear?

Two RAG (recombination activating gene) genes are key in cutting the DNA so that it can then be spliced together to form new genes. These are expressed only in B and T cells which use recombination to generate antibodies (aka immunoglobulins) and T cell receptors (TCRs), the two components of the adaptive immune response.

It has been known for some time that the RAG genes have unusual features.They lack introns, stretches of DNA which don't code for the final protein, but are rather cut out at the RNA stage. This suggests they entered the genome late in evolution. They share several other features that suggest they may have evolved from transposons.

Transposons are pieces of DNA that can move around within and between cells. I think of them as the lowest level on which natural selection can operate (one might argue that prions operate on an even less complex level). A minimal transposon has two essential features: repeated DNA sequences at each end and a gene encoding transposase, an enzymes which recognizes the repeated DNA sequences and can cut out the transposase. Of course many can be more complex.

RAG genes recognize repeated sequences that flank the component sequences of antibodies and TCRs.

The transposons (aka jumping genes made famous by Barbara McClintock) hop around, inserting and leaving DNA, often when they sense stress in the cell (obviously I am leaving a lot out her) and can have effects on genes which they insert near.

One mystery is that RAG genes cleave DNA by a method different from that used by other transposases. This mystery is now solved as a transposase encoded by a transposon called Hermes which is found in the housefly uses an identical mechanism to cleave DNA (Zhou Nature 432:995). I won't go into the details, but to my mind this resolves beyond any reasonable doubt that RAG genes evolved from a transposase.

More later on an equally fascinating (ed equally fascinating? I'll be sure to caffeinate beforehand) topic: the immune system of lampreys, which of course are non-jawed fish.