Turned up to eleven: Fair and Balanced

Sunday, September 29, 2002

Remembrances (warning: may bore you to tears)
The comment about immunological differences reminds me of my graduate work, so if you will indulge me, here is a brief detour into that very, very boring (to most) realm. My graduate research was into the function of a set of exotoxins (that is, poisonous chemicals) produced by Staphylococcus aureus. In particular, the laboratory I worked in studied proteins called Superantigens. These proteins produce toxic effects by activating the immune system of the host animal in a dysfunctional manner. In a normal immune reaction, a T-cell might be highly specific toward a given antigen, and only ~1/10000 (0.01%) T-cells in the body might react to that particular stimulus. The response is thus tuned, so that only highly specific responses occur. A superantigen interferes with this by reacting with T-cells in a much less specific way, stimulating T-cells in a V-beta specific manner. In brief, there are three complementarity determining regions on the face of the T-cell receptor, and the V-beta (V stands for variable) chain is an important part of this determinant of T-cell receptor specificity. By specifically binding to this region, Superantigens are much more potent stimulants to the immune system. In particular, Toxic Shock Syndrome Toxin-1, one of the first superantigens discovered, is lethal when injected at a dose of 1 microgram in humans. However, in mice, superantigens are much less potent. Comparison of mice and rabbits as experimental models is instructive. Mice can withstand a dose of superantigen (usually Staphylococcal Enterotoxin B) much higher than rabbits. Research into this subject has shown that the responses are quite different, and that some of that difference is explained, not by the different structures in the immune systems themselves, but by differences in the microbial flora. This has been shown somewhat indirectly, by showing how the the different host animals respond to exposure to endotoxin, which is the outer cell membrane lipoprotein (mixture of fats and protein) of gram negative bacteria (like E. coli and Salmonella. It turns out that rabbit immune cells are largely tuned to the bacteria in their intestines, in contrast to other mammals (at least, that is what we know at this point). This may make them particularly sensitive to endotoxin. The reason this is important is that superantigens act to enhance the toxicity of endotoxin, in a mechanism that is as yet not well defined. It may turn out that the toxicity of superantigens is largely due to their "enhancement of endotoxin shock", rather than their specific effects on the immune system (or rather, as less direct consequence of this). An important note here, however, is that the actual structure of the immune system receptor, the immunoglobulin on the surface of the T-cell, is not the determinant. The main determinant of toxicity is not fully understood, but the nature of the microbial flora seems to be an important factor. There is also research that suggests that immune determinants play a role in specifying the bacteria in the gut, so the layers of complexity may continue to grow.