The acquired immune system: a vantage from beneath.

The invention of acquired immunity was like escalating a war with an omnipotent opponent, one that just deflects your energy or maybe even turns it back upon you. How does this knowledge affect the way we think about disease and immunity? For many years the study of immunology was carried out with little regard for infectious agents. With apologies to immunopathologists, much of what we've learned about immunology came from studying the immune response in inbred mice to dextran, sheep red blood cells, bovine serum albumin, keyhole limpet hemocyanin, ovalbumin, hen egg lysozyme, or cytochrome c—antigens that don't fight back. Only recently have immunologists, en masse, discovered the way infection with pathogens informs our understanding of the immune response. Even now, the strains of virus or bacteria used are laboratory strains selected to invoke huge responses before being cleared by the immune system of C57BL/6 mice. We do this despite the knowledge that species variation with respect to pathogen resistance is well documented (Sorci et al. 1997xGenetics of host-parasite interactions. Sorci, G., Moller, A.P., and Boulinier, T. Trends Ecol. Evol. 1997; 12: 196–200Abstract | Full Text PDF | Scopus (104)See all References, Carius et al. 2001xGenetic variation in a host-parasite association (potential for coevolution and frequency-dependent selection) . Carius, H.J., Little, T.J., and Ebert, D. Evolution Int. J. Org. Evolution. 2001; 55: 1136–1145See all References, Smith et al. 1999xHeritable variation in resistance to gastro-intestinal nematodes in an unmanaged mammal population. Smith, J.A., Wilson, K., Pilkington, J.G., and Pemberton, J.M. Proc. R. Soc. Lond. B. Biol. Sci. 1999; 266: 1283–1290Crossref | Scopus (37)See all References). C57BL/6 mice clear an infection with Leishmania whereas BALB/c mice succumb (Sacks and Noben-Trauth, 2002xThe immunology of susceptibility and resistance to Leishmania major in mice. Sacks, D. and Noben-Trauth, N. Nat. Rev. Immunol. 2002; 2: 845–858Crossref | PubMed | Scopus (667)See all References(Sacks and Noben-Trauth, 2002); yet, the susceptibility pattern of the two mouse strains is exactly the reverse for infection with the parasitic protozoan Toxoplasma gondii (Suzuki et al., 1995xGenetic resistance against acute toxoplasmosis depends on the strain of Toxoplasma gondii. Suzuki, Y., Yang, Q., and Remington, J.S. J. Parasitol. 1995; 81: 1032–1034Crossref | Scopus (30)See all References(Suzuki et al., 1995). Now that we understand quite a lot about the components of the immune system, how would the immune response look different were we to use real mouse pathogens in wild mice? In experimental immunology we attempt to avoid variation as much as possible, but what is the variation in a natural population (or even among strains), and what are the mechanisms employed by variants that confer resistance? A combination of genomics and immunopathology will surely uncover the subtle changes in the immune system that can dramatically affect virulence and the outcome of an infection. Such changes may be identified with the acquired immune system, but a prediction is that they will often be associated with innate immunity.Given that parasites are so wonderfully diverse, devious, and determined, is a “complete” knowledge of the average immune system the most important goal for human disease control? Very clearly, some diseases lend themselves to control by vaccination, although thus far, our successes have been limited to diseases caused by infectious agents that induce an effective and lasting immune memory. When a parasite has produced a strategy that prevents a memory response, our ability to produce an effective vaccine is thus far, nil. That doesn't mean there is no possibility for an effective vaccine, it just means we face a steep uphill struggle, and perhaps this is where the study of species- and strain-specific resistance may be fruitful.I conclude that a clear evolutionary approach to the problem of host-pathogen interactions might encourage the field to reconsider some of its most closely held tenets. Perhaps we should not assume that each and every disease can be controlled by vaccination. Considering the biological invention that has been directed toward thwarting T cell responses and antibody reactions, the possibility exists that for some agents, the acquired immune system is not up to the task. Other avenues of treatment might be more efficacious, but in a more fatalistic vein, one might conclude that the most effective means of controlling disease, as it has always been, is public sanitation, vector control, and education. A parasite can't replicate in a host to which it has no access. It is antithetical to biomedical science as practiced in western countries, but technology may not be the answer to most of the world's infectious diseases.