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CpG, cytidine-guanine dinucleotide; dsRNA, double-stranded RNA; HMGB1, high-mobility group box 1; HSPs, heat shock proteins; LPS, lipopolysaccharide; ssRNA, single-stranded RNA.

immunity that is essential for microbes is double-stranded viral RNA, which plays a critical role in the replication of certain viruses. Similarly, LPS and lipoteichoic acid are structural components of bacterial cell walls that are recognized by innate immune receptors; both are required for bacterial survival and cannot be discarded. In contrast, as we shall see in Chapter 15, microbes may mutate or lose many of the antigens that are recognized by the adaptive immune system, thereby enabling the microbes to evade host defense without compromising their own survival.

The innate immune system also recognizes endogenous molecules that are produced by or released from damaged and dying cells. These substances are called damage-associated molecular patterns (DAMPs) (see Table 4-2). DAMPs may be produced as a result of cell damage caused by infections, but they may also indicate sterile injury to cells caused by any of myriad reasons, such as chemical toxins, burns, trauma, or decreased blood supply. DAMPs are generally not released from cells dying by apoptosis. In some cases, healthy cells of the immune system are stimulated to produce and release DAMPs, which enhances an innate immune response to infections.

The innate immune system uses several types of cellular receptors, present in different locations in cells, and soluble molecules in the blood and mucosal secretions to recognize PAMPs and DAMPs (Table 4-3). Cell-associated recognition molecules of the innate immune system are expressed by phagocytes (primarily macrophages and neutrophils), dendritic cells, epithelial cells that compose the barrier interface between the body and the external environment, and many other types of cells that occupy tissues and organs. These cellular receptors for pathogens and damage-associated molecules are often called pattern recognition receptors. They are expressed on the plasma membrane or endosomal membranes of various cell types and also in the cytoplasm of these cells. These various locations of the receptors ensure that the innate immune system can respond to microbes that may be present outside cells or within different cellular compartments (Fig. 4-1). When these cell-associated pattern recognition molecules bind to PAMPs and DAMPs, they activate signal transduction events that promote the antimicrobial and proinflammatory functions of the cells in which they are expressed. In addition, there are many proteins present in the blood and extracellular fluids (see Table 4-3) that recognize PAMPs. These soluble molecules are responsible for facilitating the clearance of microbes from blood and extracellular fluids by enhancing uptake into cells or by activating extracellular killing mechanisms.

The receptors of the innate immune system are encoded in the germline, whereas the receptors of adaptive immunity are generated by somatic recombination of receptor genes in the precursors of mature lymphocytes. As a result, the repertoire of specificities of innate immune system receptors is small compared with that of B and

T cells of the adaptive immune system. It is estimated that the innate immune system can recognize about 103 molecular patterns. In contrast, the adaptive immune system is capable of recognizing 107 or more distinct antigens. Furthermore, whereas the adaptive immune system can distinguish between antigens of different microbes of the same class and even different antigens of one microbe, innate immunity can distinguish only classes of microbes, or only damaged cells from healthy cells, but not particular species of microbes or cell types.

The innate immune system does not react against normal, healthy cells and tissues. This characteristic is, of course, essential for the health of the organism. It is determined in part by the specificity of innate immune mechanisms for PAMPs and DAMPs and in part by regulatory proteins expressed by normal cells that prevent activation of various components of innate immunity. We will discuss examples of such regulation later in the chapter.

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