Porth's Essentials of Pathophysiology, 4e

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Infection and Immunity

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and the coating materials are called opsonins. Once the opsonin-coated microbe attaches to a complemen- tary receptor on a phagocytic cell, phagocytosis is acti- vated. Opsonins important in innate immunity and acute inflammation include acute-phase proteins, lec- tins (carbohydrate-binding proteins such as MBL), and complement. With the activation of adaptive humoral immunity, IgG and IgM antibodies can coat microbes and act as opsonins by binding to receptors on neutro- phils and macrophages. The adaptive immune response can thus enhance the phagocytic function of innate cells. Inflammatory Cytokines The cytokines involved in innate immunity include TNF- α ; the interleukins IL-1, IL-6, and IL-12; interfer- ons (IFN- γ , IFN- α , IFN- β ); and chemokines (see Table 15-1). These cytokines serve various functions. They influence the events of inflammation and innate immu- nity by producing chemotaxis of leukocytes, stimulating acute-phase protein production, inhibiting viral replica- tion, and affecting the development of cells of the innate and adaptive immune systems. A leukocyte exposed to an external stimulus (e.g., bacteria) can be activated through appropriately triggered receptors (e.g., TLRs) and can respond by secreting small amounts of cyto- kines and other soluble mediators. If many cells are acti- vated, the concentration of cytokines may be sufficient to influence the function of tissues distant from the site of infection, a true endocrine action. The short half-life of cytokines ensures that an excessive immune response and systemic activation do not usually occur. Other cytokines important in innate immunity are the interferons, so named because of their ability to interfere with virus infections. Although macrophages and NK cells are the major producers of these cytokines, they can also be secreted by tissue cells. Interferon- α and interferon- β are classified as type I IFNs and are made by fibroblasts and macrophages. They func- tion to inhibit the replication of viruses and improve the recognition of a virally infected cell by cells of the adaptive immune response. Type I IFNs interact with receptors on neighboring cells to stimulate the transla- tion of an antiviral protein that affects viral synthesis and its spread to uninfected cells. The actions of type I IFNs are effective against different types of viruses and intracellular parasites and are thus considered part of innate immunity. Interferon- γ can activate macro- phages in innate immunity and regulate lymphocytes in adaptive immunity. Interferon- γ is the most impor- tant cytokine produced by the T-helper 1 subclass of T lymphocytes. It is a potent activator of macrophages and enables them to destroy pathogens that prolifer- ate in their vesicles. Interferon- γ also stimulates the production of antibodies that promote phagocytosis of microbes through the complement system. In addition to their local effects, several of the inflam- matory cytokines (e.g., TNF- α , IL-1, and IL-6) have important long-range effects that contribute to host defense. One of the most important of these is the ini- tiation of the acute-phase response. This involves a shift

in the proteins synthesized by the liver into the plasma. Two of these, MBL and C-reactive protein (CRP), are of particular interest because they mimic the action of anti- bodies of the adaptive immune response, but unlike anti- bodies, these proteins have broad specificity for PAMPs and depend only on the presence of cytokines for their production. Mannose-binding lectin and CRP function as opsonins as well as activators of the complement system. The Complement System The complement system is an important effector of both innate and humoral immunity that enables the body to localize and destroy infectious pathogens. The comple- ment system, like the blood coagulation system, consists of a group of proteins that are present in the circulation as functionally inactive precursors. These proteins, mainly proteolytic enzymes, make up 10% to 15% of the plasma proteins. For a complement reaction to occur, the comple- ment components must be activated in the proper sequence. Uncontrolled activation of the complement system is pre- vented by inhibitor proteins and the instability of the acti- vated complement proteins at each step of the process. There are three parallel but independent pathways for recognizing microorganisms that result in activa- tion of the complement system: the classical, the lectin, and the alternative pathways. The classical pathway recognizes complement-fixing antibodies (IgG, IgM) of adaptive immunity bound to the surface of a microbe or other structure. The lectin pathway uses a plasma protein called the mannose-binding ligand (MBL) that binds to mannose residues on microbial glycoproteins or glycolipids. It is a component of innate immunity, as is the alternative pathway , which recognizes certain microbial molecules in the absence of antibody. The reactions of the complement systems can be divided into three phases: (1) initial activation, (2) amplification of inflammation, and (3) membrane attack response (See Understanding the Complement System). Although the classical, lectin, and alternative path- ways differ slightly in the proteins they use in the initial activation phase, all converge in the process by acting on the key complement protein C3, essential for the amplification phase. All generate a series of enzymatic reactions that prompt enzymatic cleavage of C3 into two fragments. The larger C3b fragment is a key opso- nin that coats microbes and allows them to be phagocy- tized after binding to the type 1 complement receptor on leukocytes. The smaller C3a fragment triggers an influx of neutrophils to enhance the inflammatory response. Production of C3a and C5a also leads to the activation of basophils and mast cells and the release of inflam- matory mediators that produce smooth muscle contrac- tion, increased vascular permeability, and changes in endothelial cells to enhance migration of phagocytes. The late phase of the complement cascade triggers the assembly of a membrane attack complex (MAC) made up of complement proteins C5 to C9. As its name sug- gests, the membrane attack complex leads to the lytic destruction of many kinds of cells, including bacteria and altered blood cells. The multiple functions of the