Porth's Essentials of Pathophysiology, 4e

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Infection and Immunity

U N I T 4

multifunctional macrophage . Phagocytes are activated to engulf and digest microbes that attach to their cell membrane. Once the cell is activated and the microbe ingested, the cell generates digestive enzymes and toxic oxygen and nitrogen intermediates (e.g., hydrogen peroxide or nitric oxide) that kill the pathogen. The phagocytic killing of microorganisms helps prevent the spread of infectious agents until adaptive immunity can be marshaled. Dendritic cells , which are derived from bone mar- row cells and related in lineage to the macrophage, also play important roles in the innate immune response to infections and in linking innate and adaptive immune responses (to be discussed in section on antigen-present- ing cells). One subpopulation of dendritic cells governs the early response to viral infections. They recognize phagocytosed viruses and produce type 1 interferons that have potent antiviral actions. NK cells are a class of lymphocytes that recognize infected and stressed cells and respond by killing these cells. Activation of NK cells triggers the release of cytoplasmic granules toward the infected cells. These NK granules contain molecules that form pores in the cell membrane and other molecules that induce apop- tosis (programmed cell death). NK cells control their responses by using both activating and inhibitory receptors (Fig. 15-4). Their activating receptors (i.e., killer cell receptors) recognize altered host molecules expressed on stressed tissue cells that may be infected with intracellular microbes. The inhibitory receptors on NK cells recognize molecules on normal host cells and function to stop the killing response. This control ensures that normal body cells are not inappropri- ately destroyed. In contrast to the cytotoxic T lym- phocytes of the adaptive immune system, which need to undergo amplification and maturation to become cytotoxic, the NK cell is directly programmed to kill foreign cells. Pathogen Recognition The ability of leukocytes and epithelial cells to par- ticipate in innate immunity depends on their first rec- ognizing molecules that are a normal component of microbes but not host cells. These components are often essential for infectivity and cannot be mutated to allow the microbe to evade destruction. The receptors that the innate immune system uses to recognize and react against microbes are expressed on phagocytic leukocytes, NK cells, and other cells that participate in defense against various classes of microbes. These receptors are molecules that first tag the microbe and then bind it to the effector cell of the innate immune system. Microbial binding results in effector cell acti- vation, phagocytosis, and subsequent killing of the microbe. Several classes of receptors have been identi- fied that are specific for different types of microbial products including pattern receptors, Toll-like recep- tors, and serum proteins (e.g., complement proteins) that promote phagocytosis.

NK cell

Activating receptor

Inhibitory receptor

Ligands for activating receptor

MHC-I self-recognition peptide

No cell killing

A

Normal cell

Inhibitory receptor not engaged

Virus inhibits MHC-I expression

Virus-infected cell

Cell killing

B

Pattern Recognition Microbes typically bear repeating patterns of molecular structure on their surface. The cell walls of Gram-negative and Gram-positive bacteria are composed of a matrix of sugars, lipid molecules, proteins, or patterns of modified nucleic acids. The lipopolysaccharides of the outer wall of Gram-negative bacteria, for example, are important recognition sites for the innate immune system. Other microbial components also have repetitive structures. Bacterial DNA contains unmethylated cysteine-guanine (CpG) sequences and viruses invariably express double- stranded RNA as part of their life cycle. These repetitive FIGURE 15-4. Natural killer (NK) cell receptors. (A) NK cells express activating receptors that respond to ligands from virus-infected or injured cells and inhibiting receptors that bind to the class I major histocompatibility complex (MHC-I) self- recognition molecules expressed by normal cells. Normal cells are not killed because inhibitory signals from normal MHC-I molecules override activating signals. (B) In virus-infected or tumor cells, increased expression of ligands for activating receptors and reduced expression or alteration of MHC molecules interrupts the inhibitory signals, allowing activation of NK cells and lysis of target cells.