Innate immunity is one of two main immunologic strategies found in animals, the other being adaptive immunity. Major functions of the innate immune subsystem include anatomic defenses against infectious agents; inflammation; chemical defenses, such as activation of the complement cascade; and nonspecific immune cells.
Unlike adaptive immunity, innate immunity is nonspecific and does not improve with experience.
Anatomic Defenses in Innate Immunity in Animals
Anatomic defenses of an animal's immune system include physical barriers (eg, skin and mucosa), mechanical defenses (eg, expulsion of mucus via the mucociliary escalator and excretion of feces by peristalsis), and the microbiome (eg, resident bacteria of the skin and gut).
The physical barriers on the surface of the body play a critical role in slowing or blocking microbial invasion. Very few microorganisms can penetrate intact skin; instead, invaders usually enter via wounds or by injections such as insect bites. Skin wounds heal rapidly to reestablish the protective barrier.
A complex skin microbiota tends to exclude new invaders, while antimicrobial molecules in sweat kill many would-be invaders.
In the airways, the structure of the upper respiratory tract serves as an effective filter of small particles. The airways themselves are lined by a layer of adhesive mucus that can trap these particles. Mucus also contains antimicrobial proteins such as defensins, lysozyme, and surfactants.
“Dirty” mucus in the airways is continuously being replaced by clean material as ciliary action carries it to the pharynx, where it is swallowed. Coughing and sneezing remove larger irritants from the airways and nasal passages and are essential defensive responses.
The defense of the GI tract centers largely on the presence of the huge, complex commensal microbiota. A large, well-adapted microbial population excludes many potential pathogens through competition.
More importantly, the constant stimulus provided by the presence of these organisms stimulates the development of the adaptive immune system and regulates the intensity of inflammation mediated by the innate immune system.
The intestinal microbiota also plays a key role in maintaining animal health. It is a source of energy, especially in herbivores, where it provides a means of exploiting a cellulose-rich diet and a source of essential vitamins.
Additionally, invaders may be rapidly removed from the GI tract by vomiting and diarrhea.
Inflammation in Innate Immunity in Animals
Acute inflammation, although it causes discomfort, is an essential mechanism 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 cells bearing pattern-recognition receptors that bind and recognize conserved molecules expressed on microbial surfaces. These pathogen-associated molecular patterns (PAMPs) are one type of initiating trigger.
The second type of trigger consists of molecules released from broken or damaged cells. These are called damage-associated molecular patterns (DAMPs) or alarmins.
There are a variety of pattern-recognition receptors; however, the most important are the toll-like receptors (TLRs). TLRs are a family of 10 different receptors found on the surface or in the cytoplasm of cells such as macrophages, intestinal epithelial cells, and mast cells.
The TLRs bind to PAMPs commonly expressed by bacteria, such as lipopolysaccharides, flagellin, and lipoproteins. The cytoplasmic TLRs, in contrast, bind the nucleic acids of intracellular viruses. Once they bind these ligands, the TLRs trigger the production of inflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha).
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 in huge numbers 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 by phagocytosis, and kill them. This is largely mediated by a metabolic pathway called the respiratory burst that generates potent oxidants such as hydrogen peroxide and hypochlorite ions. Neutrophils, however, have minimal energy reserves and can only undertake a few phagocytic events before they are depleted.
Even when the inflammatory response is successful in killing invading microbes, the body must still remove cell debris and dying cells and repair any damage. This is the task of macrophages.
Tissue macrophages originate from blood monocytes. They, like neutrophils, are attracted to sites of microbial invasion and tissue damage by chemokines, DAMPs, and PAMPs, where they finish off any surviving invaders.
Tissue macrophages 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 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 TNF, can leak into the bloodstream, where they circulate.
When these molecules enter the brain, they trigger sickness behavior; for example, they cause a fever, suppress appetite, and produce sleepiness and lethargy. They also mobilize energy reserves from fat and muscle. 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 concentrations in blood climb steeply when acute inflammation develops.
Different mammals produce different acute-phase proteins, including serum amyloid A, C-reactive protein, and various iron-binding proteins.
Chemical Defenses in Innate Immunity in Animals
Tissues contain many antimicrobial peptides. These include the following:
detergent-like proteins, such as the defensins or cathelicidins that can lyse bacterial cell walls
enzymes such as lysozyme that kill many gram-positive bacteria
iron-binding proteins such as hepcidin or haptoglobin that prevent bacterial growth by depriving them of essential iron
The Complement System
The most important of these innate chemical defenses is the complement system. It consists of ~30 proteins (designated alphanumerically [C1, C2, etc], numbered in the order of their activity) that act collectively to kill invading microbes. The primary role of the complement system is to bind C3 and C4 covalently, and hence irreversibly, to microbial surfaces.
The complement system can be activated in three ways:
The classic pathway of complement activation is triggered when antibodies bind to microbial surfaces. It is thus triggered by adaptive immune responses. This binding activates an enzyme pathway that leads, in turn, to activation of C3 or C9.
A second complement-activating pathway is triggered when bacterial surface carbohydrates bind to a mannose-binding protein in serum. Like the classic pathway, this eventually leads to activation of C3 and C9.
A third pathway of complement activation, called the alternative pathway, is triggered by bacterial surfaces that bind C3. Once bound, 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 C9 to insert itself into bacterial cell walls, where it causes bacterial rupture.
Because of its potential to cause severe tissue damage, the complement system is carefully controlled via multiple complex regulatory pathways.
Cells of Innate Immunity in Animals
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. The most important are macrophages, dendritic cells, mast cells, and innate lymphoid cells. Macrophages, dendritic cells, and mast cells express pattern recognition receptors and can sense the presence of PAMPs and DAMPs.
When these receptors are engaged, they signal through a molecule called NF-kappaB to turn on the production of cytokines such as IL-1, interferon (IFN)-alpha, and TNF-alpha. They also release vasoactive and pain molecules such as histamine, leukotrienes, prostaglandins, and specialized peptides that initiate the vascular events in inflammation.
The purpose of inflammation is to ensure that leukocytes converge in large numbers 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.
Three major leukocyte populations can kill invaders:
Neutrophils are especially effective at killing invading bacteria. They engulf the invaders, activate the respiratory burst, and generate lethal oxidizing molecules such as hydrogen peroxide and hypochlorite ions that kill most ingested bacteria.
Eosinophils are specialized killers of invading parasites. They contain enzyme mixtures optimized to kill migrating helminth larvae.
M1 macrophages are the third major killing-cell population. 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 activates macrophages, they secrete a cytokine called IL-23. This, in turn, acts on a subset of T cells (called Th17 cells), causing them to secrete IL-17. IL-17 recruits even more neutrophils to sites of inflammation, infection, and tissue damage and thus promotes immunity.
Although many leukocytes are optimized to kill invading bacteria, viruses also present a potent threat. Animals possess at least four populations of innate lymphoid cells (ILCs) that participate in innate immunity:
Group 1 innate lymphoid cells are found in large numbers in the intestinal wall. They secrete macrophage-activating cytokines and play a key role in antiviral immunity.
Group 2 innate lymphoid cells are scattered through the body and secrete cytokines that are important in antiparasite immunity.
Group 3 innate lymphoid cells act like Th17 cells and promote inflammation by releasing IL-17.
Natural killer (NK) cells are a population of innate lymphoid cells optimized to kill virus-infected cells.
NK cells can kill virus-infected or other abnormal cells that fail to express major histocompatibility complex (MHC) class I molecules. MHC class I molecules are present normally on all nucleated cells of the body. They bind to NK cell receptors and switch off their killing abilities.
Some viruses and cancer cells downregulate expression of MHC class I molecules on the surface of cells. In the absence of this MHC class I binding signal, the NK cells bind to the virus-infected or neoplastic target cells, inject them with proteins that induce cell death, and thus eliminate them.
Key Points
Innate immunity is one of two main immunologic strategies found in animals, the other being adaptive immunity.
Innate immunity includes anatomic defenses, inflammation, chemical defenses, and nonspecific immune cells.
