Adaptive Immunity Goes Back in Time

Immune insight.
The simple purple sea urchin may shed light on the origins of the complex human immune system.

Jonathan Rast

Is the big bang of immunology a big mistake? A new study of DNA from the lowly purple sea urchin now threatens to spoil, or at least modify, a popular explanation for how the complex immune system of people and other vertebrates originated.

Almost all multicellular animals have an arsenal of cells or molecules that broadly target potentially dangerous microbes. But jawed vertebrates, such as sharks and humans, also possess a so-called adaptive immune system that tailors the body's defenses to thwart a specific pathogen. As part of this system, two enzymes called Rag1 and Rag2 cut apart and rearrange DNA within immune cells, helping to create the body's millions of unique antibodies and T cell receptors--each specific for a particular microbe.

But just where the genes for these enzymes came from has been a mystery. They had never been found in unjawed vertebrates or invertebrates, so some scientists speculated that Rag genes must have somehow "jumped" into the genome of a jawed vertebrate about 450 million years ago (ScienceNow, 19 August 1998:). According to the theory, this event, dubbed immunology's "big bang" by some, ultimately enabled lucky vertebrates to shuffle their immune genes--a process known as VDJ recombination.

The discovery of apparent Rag1 and Rag2 genes in the purple sea urchin (Strongylocentrotus purpuratas)--an invertebrate--promises to shake up this idea. Immunologist Jonathan Rast of University of Toronto in Canada initially noticed hints of a Rag1-like gene in the data produced by scientists sequencing the sea urchin's genome. Subsequent work with immunologist Sebastian Fugmann of the National Institute on Aging in Baltimore, Maryland, and other colleagues added further evidence for the presence of Rag1 and Rag2 genes. Although the function of these sea urchin genes is not yet known, their proteins form complexes in a manner similar to RAG1 and RAG2, says Fugmann.

The findings indicate that the RAG genes existed in animals long before vertebrates came on the scene. Instead of a big bang creating VDJ recombination, these results "allow for a longer, multistep process for the system to evolve," says Rast. The team presents its results online today in Proceedings of the National Academy of Sciences.

David Schatz of Yale University, who studies the origin of VDJ recombination, isn't yet totally convinced the sea urchin genes are in fact versions of RAG1 and RAG2. But if the work holds up, he says, it will demand a rewriting of the history of the adaptive immune system. "This sets the stage for a new paradigm," Schatz says.

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