INNATE IMMUNITY

Innate immunity is a protective system involving a variety of mechanisms that are always in place and do not depend on previ­ous exposure to infectious agents, toxins, or other foreign chemicals (Clough and Roth 1998).

Some aspects of the innate immune sys­tem act simply as passive physical barriers and impediments to infection. These include intact skin and mucous membranes, the nor­mal microbial flora living on host tissues, many fatty acids of the skin, a low stomach pH, and the cilia of the respiratory and urinary tracts (Wilson and Miles 1964). Other aspects of the innate immune system involve specific antimi­crobial components. This more active aspect involves the complement system, interferon, antimicrobial peptides, phagocytic cells, and natural killer (NK) lymphocytes (Clough and Roth 1998).

For example, inflammation is a specific pro­cess using many of the innate immune system tools, and in which many host cell types work cooperatively in response to infection or injury, including release of histamine. Inflammation typically results in pain, heat, redness, swelling of affected tissues, and loss of function.

Passive Barriers

The skin and mucous membranes provide a very effective physical and chemical barricade to foreign agents (Wilson and Miles 1964, Janeway and Travers 1997). Very few invading organisms can penetrate intact skin, despite the important exceptions of infective stages (cer- cariae) of some trematodes (Bush et al. 2001) and bacteria such as Francisella tularensis, the cause of tularemia (Hopla and Hopla 1994). Hair, feathers, and scales can further reduce success of parasites penetrating host skin. If parasites do reach the skin, they encounter a variety of excreted salts, organic acids, and fatty acids that have antiparasite effects.

The acid pH of the stomach is very effec­tive at killing many invading bacteria. Further, enzymes in the intestine, saliva, and tears have antibacterial effects. The normal bacte­rial flora of the skin, digestive tract, and other mucous membranes essentially fill those sites with microorganisms to which hosts are well adapted, and which inhibit the successful colonization of those sites by invading, foreign organisms (Wilson and Miles 1964).

Antimicrobial Defenses

Cytokines are a very extensive group of small proteins produced by leukocytes that act as cel­lular growth and differentiation factors, and also influence the immune responses of the host. Cytokines affect those cells that have specific receptor molecules for them; in host defense they often destroy target cells such as microbe- infected cells or tumor cells (Bellanti 1978, Buisseret 1982). Examples of cytokines include histamine, serotonin, prostaglandins, at least 30 types of interleukins, several types ofinterfer- ons, as well as tumor necrosis factors and some growth factors; there are many others. Interleu­kins are cytokines that regulate the interactions between lymphocytes and other leukocytes (Tizard 2004). Many individual cytokines affect a variety of cells and organs, and many cytokines appear to be redundant in their biological activi­ties; this complexity has given rise to the concept of a cytokine network, a web of signals among all the cell types of the immune system medi­ated by complex mixtures of cytokines (Tizard 2004). Cells producing cytokines include baso­phils, platelets, mast cells, neutrophils, macro­phages, monocytes, and lymphocytes; cytokines produced by lymphocytes sometimes are called lymphokines. Macrophages secrete at least five different types of cytokines and most leukocytes secrete more than one type.

The complement system is a multiple­enzyme system present in the blood that rap­idly responds to and attacks some infectious agents, as well as attracting other host defense mechanisms to the site of infection (Clough and Roth 1998).

In the event of a bacterial infection, mem­bers of a complement system may damage bac­terial membranes, attract neutrophils, increase blood flow to the site of infection (vasodilation), and also facilitate leakage of protective plasma proteins from blood vessels into the site of infection. Complement chemicals combine with antibodies already attached on the surface of the invading bacteria to make those bacteria more susceptible to phagocytosis; this process is called opsonization (Hayden 1995, Swierkosz and Hodinka 1999). Complement sometimes interacts with disease agents in such a way as to cause harm to the host as well (Leslie 2012).

Interferon is a group of chemicals among the cytokines tied to antiviral and anticancer defense. Some interferons are produced by virus-infected macrophages, dendritic cells, or fibroblasts, and bind to uninfected host cells in a way that prevents virus replication from occurring in those cells (Clough and Roth 1998). Other interferons are produced by lym­phocytes and regulate the immune response by stimulating T-lymphocytes, macrophages, and neutrophils, as well as influencing the classes of antibodies that B-lymphocytes secrete (Clough and Roth 1998).

Basophils release histamine and other vaso­active substances, and are active in moderating the process of inflammation (Wedemeyer et al. 2000). Mast cells sometimes are considered “chemical factories” that produce a multitude of compounds; these include histamines to make the blood vessels leaky, protein-slicing enzymes such as chymase and tryptase, and other cytokines to incite inflammation and attract other leukocytes.

Although not addressed in this summary, there are many animal antimicrobial pep­tides having protective effects against disease agents. These gene-encoded antimicrobial pep­tides have significant roles in animal defense systems at all taxonomic levels (Andreu and Rivas 1999).

Another important component of the innate immune system is phagocytosis, the process whereby some leukocytes ingest foreign particles. The major types of phagocytic cells among mam­mals are neutrophils, eosinophils, monocytes, and macrophages (Tizard 2004); in birds, hetero­phils function in place of neutrophils (Andreasen et al. 1991). Neutrophils contain several types of chemicals important for killing microorgan­isms and breaking down complex chemicals; for example, lysosomes are intracellular granules of neutrophils containing lysozyme, a very effective chemical for rupturing bacterial cell walls. Neu­trophils are attracted by a number of cytokines and complement to injured and infected sites of the host; in turn, they also produce some cyto­kines that influence host responses.

Eosinophils are phagocytic, but less efficient than neutrophils or mononuclear cells. Their functions are not fully clear, but they appear to ingest antigen-antibody complexes, remove products of mast cell degranulation, and attack multicelled parasites, (Meeusen and Balic 2000, Klion and Nutman 2004) They also limit inflammatory reactions by inactivating histamine and inhibiting edema. Eosinophils have receptors on their membranes for a type of antibody called immunoglobulin E, and there is evidence that eosinophils kill some helminth parasites after binding to them; eosinophils also detoxify some inflammation­inducing substances released by the mast cells and basophils (Clough and Roth 1998).

There are two closely related mononuclear cell types: monocytes and macrophages. After their production from stem cells, monocytes circulate in the blood for a few days and then migrate to the tissues to develop into macro­phages. Both cell types remove and destroy invading organisms, including those that mul­tiply intracellularly, and also attack damaged and worn out cells and tumor cells; their role in removing tumor cells is considered very impor­tant (Schultz et al. 1977). Like neutrophils, monocytes and macrophages also are attracted to an infected site by cytokines and comple­ment, and they are further stimulated to phago­cytize when an object is coated with antibody, complement, or with a chemical combination of antibody and complement (Tizard 2004).

Phagocytic cells such as neutrophils and monocytes are important for providing a rapid response to reduce the impact of bac­terial infections while the slower humoral and cell-mediated immune systems of the host develop their responses (Clough and Roth 1998); they are particularly effec­tive against extracellular bacteria (Baxt et al. 2013). Neutrophils are attracted to a number of chemicals produced by infect­ing bacteria. After ingesting these invading bacteria, neutrophils kill the bacteria with lysozyme and other chemicals they carry. However, as the neutrophils themselves often die at a site of infection, the lysozyme and other toxic chemicals they produce may spill out and exacerbate the damage to local host cells. Bacterial cells also have several mecha­nisms to evade phagocytosis (Baxt et al. 2013).

Natural killer (NK) cells, another defensive cell, are a type of small lymphocyte that can recognize and kill some virally infected cells and cancer cells; they also play an important role in tumor rejection. These NK cells are so named because they are active naturally without previous exposure to antigen (Clough and Roth 1998).

Inflammation

Inflammation is the host response to tissue damage or invading microorganisms, and is a means by which defensive cells and molecules are concentrated rapidly at injured or infected host sites (Tizard 2004). The innate immune system recognizes generic classes of foreign molecules produced by a variety of pathogens. When such foreign molecules are detected by a host, the innate system triggers an inflam­matory response in which various cells of the immune system attempt to wall off' the invader and halt its spread (O’Neill 2005). An important role of inflammation is facilitating the move­ment of defensive cells from the blood stream into sites of infection or injury (Tizard 2004).

Inflammation also involves the process of returning an injured site to a condition of homeostasis and may include scar formation, the replacement of dead cells with connective tissue, and regeneration of some cells such as skin. Inflammation is a very complex array of responses coordinated primarily by the innate immune system. Its overt physical features tra­ditionally are described as redness, swelling, heat, pain, and loss of function.

Much work of the innate immune system contributes to both enhancing and eventually reducing the inflammatory process. In addi­tion to the benefits provided to the host, excess activity by complement, and leukocytes such as neutrophils and mast cells, also may cause tissue damage and exacerbate problems for the host (Tizard 2004).

The inflammatory response is initiated by Toll-like receptors (TLRs), an ancient family of proteins that mediate innate immunity in a wide variety of vertebrates and invertebrates; these TLRs are made by many leukocytes of the innate system (O’Neill 2005). Most TLRs recog­nize molecules important to the survival of bac­teria, viruses, fungi, and other parasites, such as bacterial lipopolysaccharide, the lipoteichoic acid found in bacterial cell walls, a protein of bacterial flagella, and the genetic material of viruses (O’Neill 2004). Approximately 10 dif­ferent TLRs appear to protect humans from virtually every know pathogen (O’Neill 2004).

Besides the specialized immune cells, there also is the capacity of most cells to defend themselves against infections. This host pro­tection is termed cell-autonomous immunity and operates across all domains of life (Randow et al. 2013).

Summary

Collectively, the various cells and processes of innate immunity are part of a host’s first line of defense against infective agents and play a pow­erful protective role for hosts. Innate immunity also interacts extensively with the acquired immune system, helping to determine the antigens to which the acquired immune sys­tem responds and the nature of that response (Fearon and Locksley 1996).