IMMUNOLOGY:
Jawless Fish Have Form of Adaptive Immunity

Evolution doesn't like to do things just once. It came up with flight three times, for example--in insects, birds, and bats. Now it appears that evolutionarily distinct immune systems have exploited a similar genetic trick to battle microbes. New research on page 1970 reveals that the immune defenses of jawless fish such as lampreys generate as much diversity as the immune system that organisms from sharks onward in evolution use. And both employ a similar technique: rearranging DNA.

Researchers don't yet know whether the lamprey's immune system arose before our own or if it spun off from its own evolutionary tangent, but they're impressed by its sophistication. "It's just fascinating that there's another adaptive immune system," says David Davies of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, who studies Toll-like receptors, other immune proteins that recognize pathogens.

Jaw-dropping find. These lampreys make key immune proteins by shuffling bits of DNA. CREDIT: DAVE BRENNER/MICHIGAN SEA GRANT ARCHIVES

Comparative immunologist Zeev Pancer of the Center of Marine Biotechnology Institute in Baltimore, clinical immunologist Max Cooper, a Howard Hughes Medical Institute investigator at the University of Alabama, Birmingham, and colleagues knew that lampreys responded to invading microbes by generating their own diverse set of proteins called variable lymphocyte receptors (VLRs). These proteins contain varying numbers of different leucine-rich segments, which are often involved in binding to other molecules.

But just how diverse are VLRs? In one experiment, the team identified hundreds of unique VLRs by immunizing lampreys with anthrax spores and collecting the fish's immune cells. Other experiments and a close look at the predicted protein sequence for each identified VLR allowed the researchers to estimate all the possible sequences for a VLR. They calculated that lampreys can make as many as 10¹⁴ different immune proteins.

Yet there's only a single VLR gene in the germline of lampreys, for example, and two in hagfish. So, "we hypothesized that the genes rearrange" in each immune cell to create distinct VLRs, Pancer says.

They then looked at the actual VLR gene in dozens of lamprey immune cells and found that each was unique, having been formed by shuffling around nearby DNA sequences, each of which encode short leucine-rich segments.

Finally, the team looked closely at the types of VLRs in blood after the fish were immunized. The amount of VLR protein that could bind the anthrax rose over 8 weeks, but these same proteins did not attach to spores from another bacterium. This indicated that the lamprey could tailor its production of VLRs to a particular microbe, the hallmark of an adaptive immune response.

Whether vertebrates started out with a VLR system and later gave it up for the antibody-based immunity is anybody's bet. The study authors are looking both in invertebrates--squid and octopus--and in bony fish for remnants of such a system. "It may well be that this exists in us because nature very rarely throws things away," says Davies. But immunologist Gary Litman of All Children's Hospital in St. Petersburg, Florida, is skeptical that VLRs represent a forerunner to antibody-based immunity in vertebrates. "The jawless fish are not a simple step from jawed vertebrates," he says. "There's a huge transition, and the jawless fish are highly derived and specialized."

In any event, the lamprey work "deserves a lot of attention," says Litman. "It seems to be that the [adaptive] immune system has been reinvented by any number of mechanisms."