THE MERCK VETERINARY MANUAL
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Innate Immunity

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Microbes that succeed in penetrating the physical barriers of the body are rapidly detected, and the innate defenses are activated. Although multiple innate mechanisms exist, acute inflammation is the central feature of innate immunity. The first step in the inflammatory process is the early detection of either invading organisms or damaged tissues. Most invaders are recognized by pattern-recognition receptors that bind and recognize conserved molecules expressed on microbial surfaces. There are many different pattern-recognition receptors, but the most important are the toll-like receptors (TLRs). TLRs are a family of at least 10 different receptors found on the surface or in the cytoplasm of cells such as macrophages, intestinal epithelial cells, and mast cells. The TLRs on cell surfaces bind to molecules commonly expressed by extracellular bacteria such as lipopolysaccharides or lipoproteins. The cytoplasmic TLRs, in contrast, bind to the nucleic acids of intracellular viruses. Once they bind their ligands, the TLRs trigger the production of proteins such as interleukin 1 (IL-1) or interferon α (IFN-α).

IL-1 and the other cytokines produced in response to TLR stimulation then trigger acute inflammation. They initiate the adherence of circulating leukocytes to blood vessel walls close to sites of invasion. These leukocytes, especially neutrophils, then leave the blood vessels and migrate to invasion sites, attracted by microbial products, small proteins called chemokines, and molecules from damaged cells. Once they arrive at the invasion site, the neutrophils bind invading bacteria, ingest them through the process of phagocytosis, and kill the ingested organisms. This killing is largely mediated by a metabolic pathway called the respiratory burst that generates potent oxidants such as hydrogen peroxide and hypochloride ions. Neutrophils, however, have minimal energy reserves and can undertake only few phagocytic events before they are depleted.

Even if the initial inflammatory response is successful in killing all invaders, the body must still remove cell debris, eliminate any surviving microbes and dying neutrophils, and repair the damage. This is the task of macrophages. Tissue macrophages originate as blood monocytes. They, like neutrophils, are attracted to sites of microbial invasion and tissue damage by chemokines and damaged tissues, where they finish off any surviving invaders. They also ingest and destroy any remaining neutrophils, thus ensuring that the neutrophil oxidants are removed without toxic spills occurring in the tissues. Finally, another population of these macrophages begins the process of tissue repair. Macrophages that complete the destructive process are optimized for microbial destruction and are called M1 cells. Macrophages optimized for tissue repair and removal of damaged tissues are called M2 cells.

Many of the molecules produced as a result of inflammation and tissue damage, such as IL-1 and tumor necrosis factor, can reach the bloodstream where they circulate. They enter the brain and trigger sickness behavior; for example, they alter the thermoregulatory centers to cause a fever, act on appetite-controlling centers to suppress appetite, and act on sleep centers to produce sleepiness and depression. They also mobilize energy reserves from adipose tissue and muscle. This sickness behavior is believed to enhance the defense of the body by redirecting energy toward fighting off invaders.

Circulating cytokines from inflammatory sites also act on liver cells, causing the cells to secrete a mixture of “acute-phase proteins,” so-called because their blood levels climb steeply when acute inflammation develops. Different species have different acute-phase proteins, including serum amyloid A, C-reactive protein, and many different iron-binding proteins. Acute-phase proteins also serve to promote innate immunity.

Complement

Although acute inflammation is central to the processes of innate immunity, the body possesses other innate defenses. Tissues contain antimicrobial peptides that can bind and kill invading bacteria. These include detergent-like molecules such as the defensins or cathelicidins that can lyse bacterial cell walls, enzymes such as lysozyme that kill many gram-positive bacteria, and iron-binding proteins such as hepcidin or haptoglobin that prevent bacterial growth by depriving them of essential iron supplies. Perhaps the most important of these innate defenses is the complement system, which consists of a complex group of ~30 proteins that act collectively to kill invading microbes. The primary function of the complement system is to bind two proteins called C3 and C4 irreversibly to microbial surfaces. Once bound, these complement components may either kill microbes by rupturing them using another protein called C9 or simply coat them so that they are rapidly and effectively phagocytized by leukocytes.

The complement system can be activated in three ways. One way, called the alternative pathway, is triggered by the presence of bacterial surfaces that consist largely of carbohydrates and can bind the complement protein C3. Once bound, the C3 acts as an enzyme to activate and bind more C3. These C3-coated bacteria are rapidly and effectively phagocytized and destroyed. Alternatively, surface-bound C3 can activate additional complement components that eventually cause a protein called C9 to insert itself within bacterial cell walls, where it causes bacterial rupture. A second complement-activating pathway is triggered when bacterial surface carbohydrates bind to a mannose-binding protein in serum. This binding activates an enzyme pathway that leads to activation of C3 or C9. The third, or classic, pathway of complement activation is triggered when antibodies bind to microbial surfaces. It is thus triggered by adaptive immune responses. As with the mannose pathway, this eventually leads to activation of C3 and C9. Because of its potential ability to cause severe tissue damage, the complement system is carefully regulated through multiple complex regulatory pathways.

Cells of Innate Immunity

The key to an effective innate immune response is prompt recognition of invasion and a rapid cellular response. Several cell types function as sentinel cells; three of the most important are macrophages, dendritic cells, and mast cells. These cell types express pattern recognition receptors such as TLRs and can sense the presence of microbial invaders. They also express multiple other receptors that can detect microbes and tissue damage. When these receptors are engaged, they signal through a molecule called NF-κB to turn on the production of cytokines such as IL-1, IFN-α, and TNF-α. They also release vasoactive and pain molecules such as histamine, leukotrienes, prostaglandin, and specialized peptides that initiate the vascular events in inflammation.

The purpose of inflammation is to ensure that leukocytes are delivered as promptly as possible to sites of microbial invasion. This involves attracting these cells from the bloodstream where they circulate and inducing them to migrate through the tissues to the invasion sites where they engulf and kill invaders. There are three major leukocyte populations that can kill invaders. Granulocytes are especially effective at killing invading bacteria. They engulf the invaders, activate a metabolic pathway called the respiratory burst, and generate lethal oxidizing molecules such as hydrogen peroxide and hypochloride ions that kill most ingested bacteria. Eosinophils are specialized killers of invading parasites. They contain enzymes that are optimized to kill migrating helminth larvae. The third major killing cell population are M1 macrophages. These cells migrate into areas of microbial invasion more slowly than granulocytes. However, they are capable of sustained and effective phagocytosis. They contain the highly lethal antimicrobial factor nitric oxide and thus can kill organisms resistant to neutrophil killing.

When inflammation leads to activation of macrophages, they secrete a cytokine called IL-23. This, in turn, acts on a population of T cells (called Thl7 cells), causing them to secrete IL-17. IL-17 recruits granulocytes to sites of inflammation, infection, and tissue damage.

While many leukocytes are optimized to kill invading bacteria, viruses also present a potent threat. Natural killer (NK) cells are a population of innate cells optimized to kill virus-infected cells. NK cells, a form of lymphocyte, can kill virus-infected or other “abnormal” cells that fail to express major histocompatibility complex (MHC) class I molecules. MHC class I molecules bind to NK cell receptors and switch off their killing abilities. In the absence of this signal, the NK cells bind to target cells, inject them with apoptosis-inducing proteins, and kill them.

Last full review/revision August 2013 by Ian Tizard, BVMS, PhD, DACVM

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