Chapter 113. Introduction to Infectious Diseases: Host–Pathogen Interactions (Part 4) The Immune Response Innate Immunity As they have co-evolved with microbes, higher organisms have developed mechanisms for recognizing and responding to microorganisms. Many of these mechanisms, referred to together as innate immunity, are evolutionarily ancient, having been conserved from insects to humans. In general, innate immune mechanisms exploit molecular patterns found specifically in pathogenic microorganisms. These "pathogen signatures" are recognized by host molecules that either directly interfere with the pathogen or initiate a response that does so. Innate immunity serves to protect the host without prior exposure to an infectious agent—i.e., before specific or adaptive immunity has had a chance to develop. Innate immunity also functions as a warning system that activates components of adaptive immunity early in the course of infection. Toll-like receptors (TLRs) are instructive in illustrating how organisms are detected and send signals to the immune system. There are at least 11 TLRs, each specific to different biologic classes of molecules. For example, even minuscule amounts of lipopolysaccharide (LPS), a molecule found uniquely in gram-negative bacteria, are detected by LPS-binding protein, CD14, and TLR4 (see Fig. 114-3). The interaction of LPS with these components of the innate immune system prompts macrophages, via the transcriptional activator nuclear factor κB (NF-κB), to produce cytokines that lead to inflammation and enzymes that enhance the clearance of microbes. These initial responses serve not only to limit infection but also to initiate specific or adaptive immune responses. Adaptive Immunity Once in contact with the host immune system, the microorganism faces the host's tightly integrated cellular and humoral immune responses. Cellular immunity (Chap. 308), comprising T lymphocytes, macrophages, and natural killer cells, primarily recognizes and combats pathogens that proliferate intracellularly. Cellular immune mechanisms are important in immunity to all classes of infectious agents, including most viruses and many bacteria (e.g., Mycoplasma, Chlamydophila, Listeria, Salmonella, and Mycobacterium), parasites (e.g., Trypanosoma, Toxoplasma, and Leishmania), and fungi (e.g., Histoplasma, Cryptococcus, and Coccidioides). Usually, T lymphocytes are activated by macrophages and B lymphocytes, which present foreign antigens along with the host's own major histocompatibility complex antigen to the T cell receptor. Activated T cells may then act in several ways to fight infection. Cytotoxic T cells may directly attack and lyse host cells that express foreign antigens. Helper T cells stimulate the proliferation of B cells and the production of immunoglobulins. Antigen-presenting cells and T cells communicate with each other via a variety of signals, acting coordinately to instruct the immune system to respond in a specific fashion. T cells elaborate cytokines (e.g., interferon) that directly inhibit the growth of pathogens or stimulate killing by host macrophages and cytotoxic cells. Cytokines also augment the host's immunity by stimulating the inflammatory response (fever, the production of acute-phase serum components, and the proliferation of leukocytes). Cytokine stimulation does not always result in a favorable response in the host; septic shock (Chap. 265) and toxic shock syndrome (Chaps. 129 and 130) are among the conditions that are mediated by these inflammatory substances. The immune system has also developed cells that specialize in controlling or downregulating immune responses. For example, T reg cells, a subgroup of CD4+ T cells, prevent autoimmune responses by other T cells and are thought to be important in downregulating immune responses to foreign antigens. There appear to be both naturally occurring and acquired T reg cells. The reticuloendothelial system comprises monocyte-derived phagocytic cells that are located in the liver (Kupffer cells), lung (alveolar macrophages), spleen (macrophages and dendritic cells), kidney (mesangial cells), brain (microglia), and lymph nodes (macrophages and dendritic cells) and that clear circulating microorganisms. Although these tissue macrophages and polymorphonuclear leukocytes (PMNs) are capable of killing microorganisms without help, they function much more efficiently when pathogens are first opsonized (Greek, "to prepare for eating") by components of the complement system such as C3b and/or by antibodies. Extracellular pathogens, including most encapsulated bacteria (those surrounded by a complex polysaccharide coat), are attacked by the humoral immune system, which includes antibodies, the complement cascade, and phagocytic cells. Antibodies are complex glycoproteins (also called immunoglobulins) that are produced by mature B lymphocytes, circulate in body fluids, and are secreted on mucosal surfaces. Antibodies specifically recognize and bind to foreign antigens. One of the most impressive features of the immune system is the ability to generate an incredible diversity of antibodies capable of recognizing virtually every foreign antigen yet not reacting with self. In addition to being exquisitely specific for antigens, antibodies come in different structural and functional classes: IgG predominates in the circulation and persists for many years after exposure; IgM is the earliest specific antibody to appear in response to infection; secretory IgA is important in immunity at mucosal surfaces, while monomeric IgA appears in the serum; and IgE is important in allergic and parasitic diseases. Antibodies may directly impede the function of an invading organism, neutralize secreted toxins and enzymes, or facilitate the removal of the antigen (invading organism) by phagocytic cells. Immunoglobulins participate in cell- mediated immunity by promoting the antibody-dependent cellular cytotoxicity functions of certain T lymphocytes. Antibodies also promote the deposition of complement components on the surface of the invader. . Chapter 113. Introduction to Infectious Diseases: Host–Pathogen Interactions (Part 4) The Immune Response Innate Immunity As they have. transcriptional activator nuclear factor κB (NF-κB), to produce cytokines that lead to inflammation and enzymes that enhance the clearance of microbes. These initial responses serve not only to limit infection. host's own major histocompatibility complex antigen to the T cell receptor. Activated T cells may then act in several ways to fight infection. Cytotoxic T cells may directly attack and lyse host