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Equine Summer 2006 (Vol 1, No 2)

Abstract Thoughts—"Danger, Will Robinson!" The True Function of the Innate Immune System

by James N. Moore, DVM, PhD, David J. Hurley, PhD

    Werling D, Jungi TW: TOLL-like receptors linking innate and adaptive immune response. Vet Immunol Immunopathol 91:1-12, 2003.

    Abstract: Invading pathogens are controlled by the innate and adaptive arms of the immune system. Adaptive immunity, which is mediated by B and T lymphocytes, recognizes pathogens by rearranged high-affinity receptors. However, the establishment of adaptive immunity is often not rapid enough to eradicate microorganisms as it involves cell proliferation, gene activation, and protein synthesis. More rapid defense mechanisms are provided by innate immunity, which recognizes invading pathogens by germ-line-encoded pattern recognition receptors. Recent evidence shows that this recognition can mainly be attributed to the family of TOLL-like receptors (TLR). Binding of pathogen-associated molecular patterns to TLR induces the production of reactive oxygen and nitrogen intermediates as well as pro-inflammatory cytokines and up-regulates expression of co-stimulatory molecules, subsequently initiating the adaptive immunity. This article summarizes the discovery and the critical roles of the TLR family in host defense, briefly alludes to signaling mechanisms mediating the response to TLR ligands, and provides an update on current knowledge regarding the ligand specificity of these receptors and their role in immunity of domestic animals, particularly cattle.

    This abstract has been adapted with permission from Elsevier.

    Commentary: When we were in school, we were taught that the immune system was essentially divided into two parts—one that responded specifically to "chemically defined antigens" and another that was "nonspecific." Of the two, the "nonspecific immunity" concept was always more difficult to envision. Things have changed a lot since we were in school, especially concerning the nonspecific immunity side of the equation. The article by Werling and Jungi is an excellent vehicle for getting up-to-date on nonspecific immunity and how it is really regulated.

    The key to understanding the nonspecific side of immunity became evident in the late 1990s when a family of the body's "field sensors" was first discovered. These sensors recognize chemical patterns, otherwise known as pathogen-associated molecular patterns, that are shared by a number of groups of pathogens. Furthermore, these sensors are located on the surface of the cells that make up the body's first line of defense, namely neutro­phils, monocytes, dendritic cells, and macrophages, and are connected to the machinery within those cells that drives inflammation. This machinery produces local inflammatory responses and provides the context for the regional and systemic immune re­sponses induced by the perceived level of "danger" associated with the particular pathogen-associated molecular patterns. Rather than being unfocused as its name might imply, the nonspecific component of the immune response is quite complex and effective.

    Another thing we were taught in our immunology classes was that the world of the immune system was made up of self and nonself. That does not appear to be a valid belief any longer. Now we are learning that the immune system views things in the world as being either dangerous or not. Consequently, the body's network of field sensors has a very focused task: Rather than having to maintain a catalog of all things in the body that are self and thus must be ignored, it must only detect the presence of danger within different local environments in the body. This seems a much saner and more manageable approach.

    Equine veterinarians regularly face problems with their patients as a result of inflammation. In fact, there are not many equine diseases—at least the ones that keep you up at night—that do not involve inflammation as an important part of their pathogenesis. So why is inflammation so important in horses? Part of the answer may be that neutrophils often comprise 75% to 80% of the circulating leukocytes in horses. Neutrophils carry a relatively high density of field sensors for pathogen-associated molecular patterns and are highly responsive to the "hormone-like" signals that epithelial cells, endothelial cells, and tissue-resident macrophages send out as a "call to arms" when they encounter the molecular patterns of pathogens.

    Unlike the more "reflective" mononuclear phagocytes, neutrophils are inflammatory hotheads. When they are triggered, they pour out the contents of their cytoplasmic granules and activate their "defensive" enzyme systems, yielding an environment full of oxygen radicals, destructive enzymes, and molecules designed to starve out the danger. Once they are triggered, it is hard to turn them off. It is almost like horses agree with Nietzsche:

    For believe me: The secret for harvesting from existence the greatest fruitfulness and greatest enjoyment is to live dangerously.—Friedrich Nietzsche, The Gay Science, section 283

    Thus horses seem to approach life armed and ready to act. They carry a large number of cells that respond to danger with danger. They seem to be filled with the thought that "As soon as there is life there is danger" (Ralph Waldo Emerson, Society and Solitude, 1870).

    Clearly there are real dangers in the environment, and the wise course of action is for the field sensors to re­spond. For some reason, however, it appears that horses have stronger, longer-lasting inflammatory responses than cattle that live in very similar environments. Perhaps this reflects essential differences in how these two species deal with their environment, or maybe the "artificial setting" we place horses in today causes part of this problem. As we protect and shelter horses from the outside world and "refine" their diet more to our liking, we may be trying too hard to protect them from danger. Sir Winston Churchill once said:

    One ought never to turn one's back on a threatened danger and try to run away from it. If you do that, you will double the danger. But if you meet it promptly and without flinching, you will reduce the danger by half.

    Thus horses might be better off if they were to meet danger head on.

    NEXT: Clinical Snapshot: Tongue Laceration


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