Self and Non-Self

Thanks to the health-conscious times in which we live, most of us have picked up a basic immunological vocabulary from mass media. Terms like cancer, AIDS, autoimmune disorder, stem cell, gene therapy, antibody, leukocyte, retrovirus, and T-cell receptor have become almost as familiar as the names of the latest Hollywood stars. A great deal has been learned about how the human immune system functions, and barely a week goes by without at least one news-bite announcing some new immunological discovery or treatment. What may surprise many people, however, is that sharks have an immune system remarkably similar to our own.

The main function of any immune system is distinguishing self from non-self. The essence of immunological response is a two part system: recognition and destruction. Pathogenic microbes or other foreign bodies that trigger an immune response are termed antigens. There are four basic players that compose the human immune system: antibodies, T-cells, Major Histocompatability Complexes (or MHC's), and RAG proteins. Recognizing foreign bodies is the primary function of antibodies. Antibodies are Y-shaped proteins that chemically 'read' surface proteins of every cell they encounter and 'stick' to any that are foreign, thereby marking the antigen for destruction by macrophages and other leukocytes (white blood cells). T-cells are another type of immunological marker, which - together with MHC's - bind to foreign proteins, setting off a complex chain of events leading to their destruction. RAG proteins are enzymes that 'cut and paste' antibody genes like a word-processor. This ability gives the human immune system much of its adaptability in the face of a continual stream of new antigens. All four of these immunological players have been found in sharks. And, as in humans, sharks have both a spleen and thymus glands, which - among other functions - produce cells of immunological importance.

But the shark immune system also exhibits some fascinating differences from our own. Sharks have two accessory immunological structures that humans do not: the epigonal organ and Leydig's organ. The epigonal organ is an elongate, paired, pinkish-white structure located beneath the dark red kidneys (which are themselves underneath the backbone). The anterior part of the epigonal organ is wrapped around the gonads (testes in male sharks, ovaries in females), hence its name. Leydig's organ is nestled along the top and bottom of the esophagus of most sharks. It is named after the German histologist who first described this structure in 1857. The epigonal organ becomes more extensive with growth and can be rather difficult to differentiate from the kidneys in younger sharks. In contrast, Leydig's organ can be quite large - a 3.5-pound (1.6-kilogram) one was reported in a 6-foot- (1.8-metre-) long Bluntnose Sixgill Shark (Hexanchus griseus). Most shark species have both epigonal and Leydig's organs, but a few have one or the other. I know from my own dissections that the White Shark has well-developed epigonal organs, but I cannot confirm that Leydig's organ is or is not present. Despite having had opportunities to examine White Sharks for this organ, I simply never thought to look until just this moment.

What makes the epigonal and Leydig's organs particularly astonishing is that they are absolutely unique to sharks. If you were to dissect most any vertebrate - from kangaroo to King Cobra - you would find a simple and straight-forward, one-to-one correlation among organ systems: a heart is a heart, a liver a liver, a spleen a spleen, and so on. Sharks have all the internal organs one would expect of a gill-breathing vertebrate . . . plus one or two extras. These 'extra' organs are, of course, the epigonal and Leydig's. Think of it: in sharks we have two complete, well-developed internal organs, yet we do not know from where they come, or even much about what they do. Recent studies suggest that the both organs seem to be composed of lymphoid tissue and seem to be involved with leukocyte formation. No one is sure what, exactly, Leydig's organ does. But recent data indicate that the epigonal organ is the site of T-cell differentiation in elasmobranchs, and thus plays an important role in the immune system of these fishes. Without long bones to serve as a site for leukocyte development, sharks have apparently jury-rigged a scrap of available tissue to assume that function.

Another intriguing difference between the shark and human immune system concerns the way antibodies are coded genetically. In humans, the genes coding for various structural regions on a given antibody are separated by relatively large gaps of non-coding genes. Making a human antibody requires that RAG proteins 'cut and paste' together antibody-coding genes, eliminating the intervening DNA. This process creates the tremendous diversity of antibodies that form an important part of the human immune system. But in sharks, the genes coding for the various functional regions of a given antibody are clustered, lying somewhat to much closer together than in humans. As a result, some of these genes are fused to begin with, not requiring any 'cutting' or 'pasting'. The end result of all this genetic shuffling and non-shuffling is that sharks enjoy the best of both immunologic worlds: they can 'cut and paste' genes to enhance antibody diversity, but they also have 'ready to wear' antibody genes, allowing a much faster response to certain pathogens.

Originating at least 425 million years ago, sharks are apparently the earliest creatures to develop a complex, multi-stage immunological response. This immune response is remarkably similar to that found in humans. Much has been learned in recent years about the probable origin of the human immune system and many of these studies have far-reaching implications for human medical health. Sharks appear to be remarkably resistant to cancers and a wide variety of other diseases and pathogens that are generally lethal to humans. Immunological researchers are cautiously optimistic about possibilities for applying what we learn from studying the shark immune system to human medicine. Squalamine, for example, derived from the stomach lining of the Spiny Dogfish (Squalus acanthias) has been demonstrated to be an astonishingly broad-spectrum antibiotic, effective against a constellation of otherwise drug-resistant pathogenic bacteria.

Recently, some over-confident or unscrupulous opportunists have begun selling drugs or 'dietary supplements' made from shark liver oil or cartilage, claiming them as a cure-all for everything from constipation to cancer. The clinical evidence supporting the efficacy of these purported 'drugs' is at best inconclusive and at worst downright negative. But there is little doubt that the shark immune system - including that of the Great White, which has received relatively little study - holds many more surprises and potential medical benefits for humankind. Astonishing as it may seem, someday a Great White Shark may save your life.

 

ReefQuest Centre for Shark Research
Text and illustrations R. Aidan Martin
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