What can a spineless, shallows-dwelling marine animal known as amphioxus tell us about the origin of the human immune system? Perhaps quite a lot, says NIAID grantee Gary Litman, Ph.D., who studies the worm-like creature, also called a lancelet, at the University of South Florida in Tampa. With colleagues including David Ostrov, Ph.D., of the University of Florida (Gainesville), Dr. Litman used X-rays to take an atomic-level “snapshot” of a crystallized lancelet protein that seems to straddle the divide between immune system molecules found in invertebrates (animals without backbones) and those of higher vertebrates, including humans.
Although it doesn’t have the bony spinal column that characterizes vertebrates, the lancelet does have a notochord—a flexible rod running from its tip to its tail. This feature places the animal near the base of the evolutionary tree separating vertebrates from invertebrates, but on the side of the divide occupied by jawed fish, birds, and mammals.
To repel disease-causing microbes, both vertebrates and invertebrates use a quick-acting and relatively non-specific form of defense called innate immunity. Vertebrates also have an adaptive immune system. Key elements of adaptive immunity include infection-fighting antibodies that are tailored to specific microbes, and white blood cells that can “remember” past attacks by particular germs and respond quickly to squelch subsequent infections. Scientists have long sought to better understand the origins of the adaptive immune system and to identify living organisms that possess examples of what precursors to the modern adaptive immune system might have looked like. The lowly lancelet may be just such a missing link.
Through X-ray crystallography, Dr. Litman and his colleagues created a three-dimensional picture of a lancelet protein called VCBP (variable region-containing chitin-binding protein) and determined that it shared some features of immune system receptor proteins—those capable of recognizing specific molecules on disease-causing microbes—found in vertebrates. The quality of the crystals was impressively high, notes Dr. Litman, allowing the scientists to pinpoint the exact location of each atom in the protein. This, in turn, gave them clues about the range of possible actions of VCBP and its potential as an immune protein with adaptive-system-like characteristics.
The lancelet feeds on plankton and other material that it extracts from the sea water. Its entire gullet is thus exposed constantly to innumerable germs, and it is not surprising that it would have evolved ways to defend itself, including some proteins that may be able to specifically recognize and attach to microbe-specific “antigens.” Indeed, says Dr. Litman, the lancelet should cause us to step back and keep an open mind about alternative avenues to immunity that have been taken by various animal groups when faced with the problem of defending themselves against constantly changing microbes.
An international group of researchers including Dr. Litman is currently deciphering the full genome of amphioxus. It appears to have the requisite genetic diversity to generate immune receptor-like proteins. Additional insights into its immune system—and perhaps into our own—await.
Hernandez JA et al. Ancient evolutionary origin of diversified variable regions demonstrated by crystal structure of an immune-type receptor in amphioxus. Nature Immunology DOI: 10.1038/ni1359 (2006).
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Last Updated May 03, 2007