The basis of the adaptive immune system’s enormous capacity for antigen recognition has long been appreciated. In contrast, the basis of recognition of microbial products by innate immune sensors was discovered only in the late 1990s. Initially, innate recognition was considered to be restricted to relatively few pathogen-associated molecular patterns, or PAMPs, and we have already seen examples of such recognition of microbial surfaces by complement (see Chapter 2). In the last several years, with the discovery of an increasing number of innate receptors that are capable of discriminating among a number of closely related molecules, we have come to realize that a much greater flexibility in innate recognition exists than had been previously thought.
The first part of this chapter examines the cellular receptors that recognize pathogens and signal for a cellular innate immune response. Regular patterns of molecular structure are present on many microorganisms but do not occur on the host body’s own cells. Receptors that recognize such features are expressed on macrophages, neutrophils, and dendritic cells, and they are similar to the secreted molecules, such as ficolins and histatins, described in Chapter 2. The general characteristics of these pattern recognition receptors (PRRs) are contrasted with those of the antigen-specific receptors of adaptive immunity in Fig. 3.1. A new insight is that self-derived host molecules can be induced that indicate cellular infection, damage, stress, or transformation, and that some innate receptors recognize such proteins to mediate responses by innate immune cells. Such indicator molecules have been termed ‘damageassociated molecular patterns,’ or DAMPs, and some of the molecules in this class can be recognized by receptors also involved in pathogen recognition, such as the Toll-like receptors (TLRs).
Pattern recognition by cells of the innate immune system.
Induced innate responses to infection.
Fig. 3.1 Comparison of the characteristics of recognition molecules of the innate and adaptive immune systems. The innate immune system uses germline-encoded receptors while the adaptive immune system uses antigen receptors of unique specificity assembled from incomplete gene segments during lymphocyte development. Antigen receptors of the adaptive immune system are clonally distributed on individual lymphocytes and their progeny. Typically, receptors of the innate immune system are expressed non-clonally, that is, they are expressed on all the cells of a given cell type. However, NK cells express various combinations of NK receptors from several families, making individual NK cells different from one another. A particular NK receptor may not be expressed on all NK cells.
Coordination of the innate immune response relies on the information provided by many types of receptors. Pattern recognition receptors can be classified into four main groups on the basis of their cellular localization and their function: free receptors in the serum, such as ficolins and histatins (discussed in Chapter 2); membrane-bound phagocytic receptors; membrane-bound signaling receptors; and cytoplasmic signaling receptors. Phagocytic receptors primarily signal for phagocytosis of the microbes they recognize. A diverse group of receptors, including chemotactic receptors, help to guide cells to sites of infection, and other receptors, including PRRs and cytokine receptors, can control the activity of effector molecules at those sites.
In this part of the chapter we first look at the recognition properties of phagocytic receptors and of signaling receptors that activate phagocytic microbial killing mechanisms. Next we describe an evolutionarily ancient pathogen system of recognition and signaling, the Toll-like receptors (TLRs), the first of the innate sensor systems to be discovered, and several recently discovered systems that detect intracellular infections by sensing cytoplasmic microbial cell-wall components, foreign RNA, or foreign DNA.
3-1 After entering tissues, many microbes are recognized, ingested, and killed by phagocytes.