Representative cytokines

TNF-«, IL-1« and (3, IL-6

IL-2, IL-12, I FN-7

IL-4, IL-10

Note. IFN = interferon; IL = interleukin; NK = natural killer; Th1 = T-helper 1; Th2 = T-helper 2; TNF = tumor necrosis factor.

Innate immunity begins with the skin and other mucosal surfaces lining the gastrointestinal and respiratory tracts, which provide a physiochemical barrier to invasion by foreign pathogens. When these surfaces are breached, phagocytic cells, such as macrophages, microglia (in the brain), and certain dendritic cells, recognize invading pathogens through relatively crude pattern-recognition molecules referred to as toll-like receptors and, depending on the cell type, ultimately engulf and destroy these foreign agents. Upon activation, these cells and other participants in the early innate immune response (e.g., natural killer [NK] cells) release soluble, proteinaceous, immune mediators known as cytokines. Cytokines that mediate innate immunity include the type I interferons, which have direct antiviral effects, and proinflammatory cytokines. Of these, interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-« (TNF-«) are important in inducing inflammation at the site of pathogen invasion or tissue damage. IL-6 also plays a central role in stimulating the liver to produce a host of acute-phase reactants, such as C-reactive protein; «i-acid glycoprotein; complement C3; haptoglobin; «2-macroglobulin; c i-antitrypsin; ceruloplasmin; and «-, [3-, and 7-fibrinogen (Baumann and Gauldie 1994). These proteins, which make up the acute-phase response, serve to both facilitate destruction of foreign substances and limit tissue damage from immune activation. In addition to the release of cytokines and acute-phase proteins, other molecules are induced, including chemokines and adhesion molecules, which assist in the recruitment of multiple cell types to the site of infection and/or tissue damage and destruction. Depending on the magnitude of the innate immune response, relevant cytokines can enter the peripheral blood or activate local afferent nerve fibers and have potent effects on the neuroendocrine system, especially the hypothalamic-pituitary-adrenal (HPA) axis and the central nervous system (CNS), where they mediate many symptoms of illness, including fever, loss of appetite, social withdrawal, and sleep changes (Maier et al. 1998). These behavioral changes are believed to subserve the metabolic demands inherent in the task of fighting infection and maintaining an elevated body temperature.

Acquired immunity relies on hematopoietically derived lymphocytes, which have the ability to specifically recognize an astoundingly wide array of foreign substances. These lymphocytes fall into two general categories. T lymphocytes mature in the thymus and mediate cellular immunity, which is essential for protection against intracellular pathogens, such as viruses and mycobacteria. B lymphocytes mature in the bone marrow and produce antibodies that are especially effective in neutralizing bloodborne and extracellular pathogens, such as parasites, viruses in replication phase, and many species of bacteria. A further key function of the acquired immune system is to screen out lymphocytes that might react against self molecules. When this essential function fails, autoimmune conditions can result.

Like innate immunity, acquired immunity utilizes soluble cytokine mediators. It is generally recognized that an acquired immune response develops along one of two lines, Th1 or Th2, on the basis of the cytokine profiles induced by T-helper CD4 cells (Elenkov and Chrousos 1999). A Th1 response is characterized by cytokines that promote cell-mediated inflammatory reactions, such as delayed-type hypersensitivity (DTH). These cytokines include interleukin-2 (IL-2), interleukin-12 (IL-12), tumor necrosis factor-E> (TNF-B), and interferon-T (IFN->). Cytokines generated by T-helper cells during a Th2 immune response include interleukin-4 (IL-4), interleukin-9 (IL-9), and interleukin-10 (IL-10). IL-6 is also produced by CD4 cells during a Th2-type acquired immune response. The development of a Th2 response favors antibody production, may provide protection against parasites, and is associated with allergic and hypersensitivity reactions.

An acquired immune system response consists of three phases: an induction phase, in which the system detects the presence of antigen; an activation phase, in which the presence of antigen triggers the expansion of antigen-specific T and B cells; and an effector phase, in which the foreign substance is cleared from the body (Miller et al. 2000). In this process, the acquired immune system utilizes and empowers many innate immune elements. For example, the coating of bacteria by B cell-produced antibodies enhances the ability of innate immune system phagocytes to destroy pathogens. Like other complicated physiological response systems, the immune response has built-in negative feedback elements that have evolved to limit immune reactivity once the pathogenic challenge has been met. Other bodily systems, including the HPA axis, perform important extrinsic immunomodulatory roles, and when functioning optimally, these systems limit inflammation and immune system proliferation. A final feature of the acquired immune system, which is central to its functioning, is the formation of long-lived B and T lymphocytes that serve as memory cells for recognizing an antigen should it be encountered in the future. This mechanism accounts for the ability of acquired immunity to mount far more rapid and effective responses to previously seen antigens. It also provides the physiological basis for the effectiveness of vaccines, which activate acquired immunity toward a specific pathogen without inducing illness.

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