World Aquaculture 67 in which they are arranged, are shown in Figure 6A. Different 185 genes have different combinations of elements. The graphic shows three different 185 genes, each of which is comprised of different combinations of elements, shown as different colored boxes. Some 185 genes have all 27 elements, others have fewer. So far, researchers from the laboratory in Washington, have identified hundreds of different combinations of elements. But that’s not the limit of diversity among 185s. The molecular variability provided by element shuffling is magnified even further by variation within the elements themselves. There are multiple versions of each element based on changes in individual nucleotides, or letters of the genetic code, within each element. That sort of “single nucleotide polymorphism” is depicted in Figure 6B, which shows the changes that occur in the genetic code (represented by letters) in a small region of 15 different 185 genes. In the graphic, a dash means that the same letter of the genetic code is found in this position among all of the genes. We do not yet have a clear idea of what the proteins encoded by 185 genes do during sea urchin immune responses. But, we do know that they are synthesized by one particular population of sea urchin blood cells. These cells are obviously involved in defense responses similar to the encapsulation reactions that we described earlier and they may also participate in phagocytosis. The 185 proteins are located on the surface of these cells, suggesting that they may be involved in the interaction of these cells either with other sea urchin cells or infectious microbes. Whatever their role, it is clear that cells bearing 185 proteins on their surface are responsive to infection. The numbers of these cells in sea urchin blood increases dramatically when sea urchins are vaccinated with bacterial molecules. A different family of hypervarable molecules, called fibrinogen-related proteins (FREPs), have been discovered in pond snails by our colleagues Eric S. Loker and Coen Adema from the University of New Mexico in Albequrque (Flajnik and Du Pasquier 2004). Fibrinogen-related proteins were first identified during a long-term study of the relationship between pond snails and the human parasite, Schistosoma mansoni. Snails are an intermediate host for S. mansoni, which is a major public health problem, particularly in the developing world. During their studies, Loker, Adema and their team found that snails respond to S. mansoni infection by producing FREPs. Again, individual snails seem to be able to produce many different versions of FREPs. Similar to 185s from sea urchins, FREP diversity is based on the combination of different blocks of DNA and on variation within each block. While the exact function of FREPs is still unclear, it is known that they interact with the surface of S. mansoni parasites. Critically, the subsets of FREPs synthesized by individual snails changes in response to different microorganisms. In insects, hypervariability has been found among Down syndrome cell adhesion molecules (DSCAMs), which are involved in phagocytosis (Litman et al. 2005). A repertoire of more than 38,000 different DSCAMS is present in the vinegar fly, Drosophila. The molecules are constructed by similar forms of DNA shuffling to those seen in snail FREPs and sea urchins 185 proteins. Variable chitin binding proteins (VCBPs) from lancelets and tunicates are produced by similar molecular mechanisms. VCBPs seem to be designed to identify molecules like chitin, which is one of the key components in the shells of crustaceans and insects, and is also found in the cell walls of fungi, molds and yeast. Like FREPs and 185 proteins, the production of VCBPs is greatly increased when individuals are exposed to molecules from infectious microbes. One of the most important observations to come out of the discovery of these different classes of hypervariable defense molecules is that hypervariability is not particularly rare. There is nothing special about the evolution or life histories of vertebrates that provides evidence that these animals are the only ones to have developed molecular hypervariability. Indeed, the identification of hypervariable gene systems in relatively quick succession, among four different groups of invertebrates, indicates that similar systems will probably be discovered in many other animals in the coming decades. Another intriguing thing about the hypervariable systems discovered so far is how different they are from antibodies, and from each other. FREPs, DSCAMs and VCBPs have some regions that are distantly related to antibodies, but they are still very different molecules. And sea urchin 185 genes are entirely unique. No similar gene sequences have ever before been reported. This means that it is extremely difficult to predict what the next group of hypervariable genes will look like, or what exactly they will do during an immune response. Do Hypervariable Defense Molecules of Invertebrates Allow Them to Mount Disease Specific Immune Responses? One clue about the role of the newly discovered hypervariable genes in immune responses has come from recent work of Courtney Smith and her group in Washington DC. They have found that the types of hypervariable 185 molecules being synthesized by sea urchins changes when the urchins are vaccinated with different pathogen-associated molecules. Similar results are being uncovered by our work on 185 proteins and by Loker and Adema’s studies of FREP synthesis in snails. The data suggest that the repertoire of hypervariable proteins being synthesized by sea urchins or snails may change in response to infection. Perhaps the suite of genes responding to an infection is tailored to meet the demands of a particular infectious agent in much the same way that antibody responses are fine-tuned by clonal selection. If this is the case, it is likely that invertebrates are able to mount disease specific immune responses using hypervariable proteins to discriminate between infectious agents. Remarkably, the possibility that invertebrates can mount disease specific immune responses has never been tested exhaustively, until now. In the last few years, reports have begun to appear of New Immune Systems (Continued from page 49)
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