The specificities of innate immune recognition have evolved to combat microbes and are different from the specificities of the adaptive immune system in several respects (Table 1).

• The innate immune response is activated by recognition of a relatively limited set of molecular structures that either are products of microbes or are expressed by injured or dead host cells. It is estimated that the innate immune system recognizes only about 1000 products of microbes and damaged cells. By contrast, the adaptive immune system potentially can recognize millions of different microbial antigens and can also recognize nonmicrobial environmental antigens as well as self antigens that are normally present in healthy tissues.

 • The innate immune system uses germline-encoded invariant receptors to recognize microbial and other products. By contrast, the adaptive immune system uses highly variable and diverse receptors encoded by somatically rearranged genes to recognize foreign antigens. The specificity and receptors of innate immunity are described later.

Table1. Specificity of Innate and Adaptive Immunity

The innate immune system recognizes molecular structures that are produced by microbial pathogens. The microbial substances that stimulate innate immunity are often shared by classes of microbes and are called pathogen associated molecular patterns (PAMPs). Different types of microbes (e.g., viruses, gram-negative bacteria, gram-positive bacteria, fungi) express different PAMPs (Table 2). These structures include nucleic acids that are unique to or more abundant in microbes than in host cells, such as long double-stranded RNA found in replicating viruses and unmethylated CpG DNA sequences found in bacteria; features of proteins that are found in microbes, such as initiation by N-formylmethionine, which is typical of bacterial proteins; and complex lipids and carbohydrates that are synthesized by microbes but not by mammalian cells, such as lipopolysaccharide (LPS) in gram-negative bacteria, lipoteichoic acid in gram-positive bacteria, and oligosaccharides with terminal mannose residues found in microbial but not in mammalian glycoproteins.

Table2. Examples of Pathogen-Associated Molecular Patterns and Damage-Associated Molecular Patterns

The innate immune system detects the presence of infection but not the specific pathogens. By recognizing PAMPs, which are produced by broad classes of microbes, and products of cell damage that is often but not necessarily induced by pathogens, the innate immune system triggers host defense regardless of the particular species of microbe. In contrast, the adaptive immune system is capable of recognizing many more and diverse foreign substances (antigens). These may be unique to different individual microbial species and even variants of a single species or they may be unrelated to microbial infection or tissue injury.

The innate immune system recognizes microbial products that are often essential for survival of the microbes. This evolutionary adaptation of innate immune recognition is important because it ensures that microbes usually cannot evade innate immunity by eliminating molecules that may be recognized by the host. An example of a target of innate immunity that is indispensable for microbes is double-stranded viral RNA, which is an essential intermediate in the life cycle of many 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. Nonetheless, some microbes, especially viruses, have evolved mechanisms to alter PAMPs in ways that diminish innate immune recognition. In contrast, as we will see in Chapter 16, in response to the selective pressures of adaptive immunity, microbes often lose expression of the antigens that are recognized by antibodies and T cells, thereby evading 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 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 many insults, such as chemical toxins, burns, trauma, or loss of blood supply. DAMPs are generally not released from cells dying by apoptosis. In some cases, endogenous molecules, including some cytokines, that are produced by healthy cells are released when the cells are damaged or die, and they then stimulate innate responses. These cytokines are a subset of DAMPs and are sometimes called alarmins because their presence outside cells sends an alarm to the immune system that something is causing cell damage or death.

To recognize PAMPs and DAMPs, 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 (Table 3). The cellular receptors for pathogen- and damage-associated molecular patterns are called pat tern recognition receptors. They are expressed in phagocytes (primarily macrophages and neutrophils), DCs, epithelial cells that form the barrier interface between the body and the external environment, mast cells, and many other types of cells that reside in tissues. These receptors are located on the surfaces, in phagocytic vesicles, and in the cytosol of various cell types, all of which are cellular compartments where microbes or their products may be present (Fig. 1). When these cell-associated pattern recognition receptors bind to PAMPs and DAMPs, they activate signal transduction pathways that promote the antimicrobial and proinflammatory functions of the cells in which they are expressed. In addition, many proteins present in the blood and extracellular fluids recognize PAMPs (see Table 3). These soluble molecules are responsible for facilitating the clearance of microbes from the blood and extracellular fluids by enhancing uptake into phagocytes or by activating extracellular killing mechanisms. Immunologists refer to cellular and humoral arms of the innate immune system, describing cell associated versus soluble recognition molecules and the effector responses they are linked to, analogous to cellular and humoral arms of adaptive immunity.

Table3. Pattern Recognition Molecules of the Innate Immune System

Fig1. Cellular locations of pattern recognition receptors of the innate immune system. Some pat tern recognition molecules, including members of the TLR family and lectin-like receptors, are expressed on the cell surface, where they may bind extracellular pathogen-associated molecular patterns. Other TLRs are expressed on endosomal membranes and recognize nucleic acids of microbes that have been phagocytosed by cells. Cells also contain cytosolic sensors of microbial infection, including the NOD like receptors (NLRs), RIG-like receptors (RLRs), and cytosolic DNA sensors (CDSs). Only selected examples of microbial PAMPs recognized by these receptors are shown. Cytosolic receptors that recognize products of damaged cells (damage-associated molecular patterns).

The receptors of the innate immune system are encoded by inherited (germline) genes, whereas the genes encoding receptors of adaptive immunity are formed by somatic recombination of gene segments in the precursors of mature lymphocytes. As a result, the diversity of innate immune system receptors and the range of their specificities are small compared with those of B and T cells of the adaptive immune system. It is estimated that innate immune recognition is mediated by about 100 different receptors belonging to several protein families, whereas in the adaptive immune system there are only two families of receptors (immunoglobulins [Igs] and T-cell receptors), each with mil lions of variations that recognize a vast number of antigens.

The innate immune system does not react against nor mal healthy cells and tissues. This characteristic is, of course, essential for the health of the organism. The failure to recognize healthy self is due to three main mechanisms: normal cells do not produce ligands for most innate immune receptors, the receptors are located in cellular compartments where they do not encounter host molecules they could recognize, and regulatory proteins expressed by normal cells prevent activation of various components of innate immunity. We will discuss examples of such regulation later in this chapter.

With this introduction, we can proceed to a discussion of the large variety of molecules in the body that are capable of recognizing PAMPs and DAMPs, focusing on their specificity, location, and functions. We will begin with cell-associated receptors expressed on membranes or in the cytosol of cells. The soluble recognition and effector molecules of innate immunity, found in the blood and extracellular fluids, are described later.

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مواضيع ذات صلة

Antigens

NOD-Like Receptors: NOD1 and NOD2

Overview of Innate Immunity

Transplantation of Tissues and Organs

Rh Blood Types

O-A-B Blood Types

Allergy and Hypersensitivity

The Antiviral Response

Migration of B Lymphocytes

Migration of Effector T Lymphocytes to Sites of Infection

Exit of Naive and Effector T Cells from Lymph Nodes

Lymphocytes are Responsible for Acquired Immunity