The term innate immunity refers to defense mechanisms that are always present, ready to combat microbes and other offending agents. The innate immune system, which was introduced in Chapter 1, consists of many types of cells and soluble molecules in tissues and blood that prevent microbes from invading and establishing infections. If microbes do establish a foothold, innate immune responses provide an early defense, before adaptive immune responses can develop. In this chapter, we will describe in more detail the components, specificity, and antimicrobial mechanisms of innate immunity. The focus of much of the subsequent chapters is on the role of the adaptive immune response in host defense and disease.

Functions of Innate Immune Responses

 Innate immunity serves several essential functions that protect us against microbes, clear damaged tissues, and initiate repair. The major components of the innate immune system are: barrier epithelia, which block the entry of microbes; tissue-resident sentinel cells, including dendritic cells (DCs), macrophages, and mast cells, which detect microbes that have breached epithelia and initiate host responses; white blood cells (leukocytes), including neutrophils and monocytes, which enter the tissues from the blood and eliminate microbes that have invaded through epithelia and also remove damaged host cells; natural killer (NK) cells and other lymphoid cells with diverse functions; and several types of plasma proteins that combat microbes within and outside the circulation. We discuss the functions of each of these later in the chapter. The cells and soluble molecules are sometimes called the cellular and humoral arms of innate immunity, respectively, analogous to the two main arms of adaptive immunity.

The two major types of protective reactions of the innate immune system are inflammation and antiviral defense. Inflammation is the process by which circulating leukocytes and plasma proteins are brought into sites of infection in tissues and are activated to destroy and eliminate the offending agents. Inflammation is also the major reaction to damaged or dead cells whether or not the damage is related to infection. Antiviral defense mechanisms prevent virus replication and promote killing of infected cells independent of inflammation, thus eliminating reservoirs of viral infection, although inflammation may also contribute to defense against viruses.

The functions of innate immune responses have some important general features.

• Physical and chemical defenses at epithelial barriers, such as the skin and lining of the gastrointestinal and respiratory tracts, block microbial entry. Although the outer sur faces of epithelial barriers are colonized from birth with large numbers of different microbes, colonization of internal tissues with these microbes usually does not occur because the microbes are unable to cross the barrier epithelia. If the barriers are damaged, allowing the microbes to cross, or the microbes have evolved mechanisms to cross undamaged epithelia, innate and adaptive immune responses are activated to provide the next lines of defense.

 • Innate immune responses are the initial reactions to microbes that serve to control or eliminate infection of the host by many pathogens. These responses are activated by microbes that infect or traverse epithelial barriers. Epithelial cells and tissue-resident cells inside the barrier can eradicate some microbes that infect these cells. If the microbes are able to cross the epithelial barriers, tissue-resident cells that reside under the epithelia and other cells and plasma proteins recruited from the blood provide defense. The importance of innate immunity in host defense is illustrated by clinical observations and experimental studies showing that deficiencies, inhibition, or elimination of any of several mechanisms of innate immunity increase susceptibility to infections, even when the adaptive immune system is intact and functional. Many pathogenic microbes have evolved strategies to resist innate immunity, and these strategies are crucial for the virulence of the microbes. Innate immune responses to such microbes may keep the infection in check until adaptive immune responses are activated. Adaptive immune responses typically are more potent and specialized and therefore able to eliminate microbes that resist the defense mechanisms of innate immunity.

• Innate immunity eliminates damaged cells and initiates the process of tissue repair. These functions involve recognition and response to host molecules that are produced by, released from, or accumulate in stressed, damaged, and dead host cells. The injury that elicits these innate responses may occur as a result of infection, or it may be sterile cell and tis sue damage in the absence of infection.

• Innate immune responses stimulate adaptive immune responses and can influence the nature of the adaptive responses to make them optimally effective against different types of microbes. Thus, innate immunity not only serves as the initial line of defense early after infection but also provides the danger signals that alert the adaptive immune system to respond. Moreover, different components of the innate immune system often react in distinct ways to different microbes (e.g., extracellular bacteria vs. intracellular viruses) and thereby influence the type of adaptive immune response that develops. We will return to this concept at the end of the chapter.

Comparative Features of Innate and Adaptive Immunity

To understand how innate and adaptive immunity complement each other to protect against pathogens, it is instructive to high light their important differences.

• Innate immune responses to a microbe develop rapidly and do not require prior exposure to the microbe. In other words, innate immune effector cells and molecules are present in sufficient quantities, even before infection, and are fully functional or quickly become activated by microbes to prevent, control, or eliminate infections. In contrast, effective adaptive immune responses to a newly introduced microbe develop over several days as clones of naive antigen-specific lymphocytes expand and differentiate into functional effector cells.

• For most innate responses to microbes, there is no appreciable change in the quality or magnitude of the response upon repeated exposure; that is, there is little or no memory. In contrast, repeated exposure to a microbe enhances the rapidity, magnitude, and effectiveness of adaptive immune responses. There is emerging evidence for some memory in innate immunity, in that macrophage and NK cell responses to certain infections are increased in magnitude upon subsequent infections. It is not clear how specific these memory-like innate responses are, which and how many microbes are capable of eliciting them, or how much such responses contribute to increased protection against repeat infections.

 • The innate and adaptive immune systems differ greatly in specificity for microbial structures and in the diversity of their receptors, as discussed later.

Evolution of Innate Immunity

 Innate immunity is phylogenetically the oldest part of the immune system. It co-evolved with microbes to protect all organ isms from infections. Some components of the mammalian innate immune system are remarkably similar to components in plants and insects, suggesting that these appeared in common ancestors long ago in evolution. For example, peptides that are toxic to bacteria and fungi, called defensins, are found in plants and mammals and have essentially the same tertiary structure in both life forms. A family of receptors that we will discuss in detail later in this chapter, called Toll-like receptors, recognize pathogenic microbes and activate antimicrobial defense mechanisms. Toll-like receptors are found in every life form in the evolution arytree, from insects up to mammals. The major signal trans duction pathway that Toll-like receptors engage to activate cells, called the NF-κB (nuclear factor kappa B) pathway in mammals, also shows remarkable evolutionary conservation. In fact, most of the mechanisms of innate immune defense that we will discuss in this chapter appeared very early in evolution, when the first multicellular organisms appeared, about 750 million years ago. An adaptive immune system, in contrast, is clearly recognizable only in vertebrates that developed about 350 to 500 million years ago. A testament to the importance of innate immunity is that the human genome contains approximately 850 genes that are directly related to innate immune responses, compared to about 575 for adaptive immunity.

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مواضيع ذات صلة

Antigens

NOD-Like Receptors: NOD1 and NOD2

Recognition of Microbes and Damaged Tissue by the Innate Immune System

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