Eileen L. Thacker Dept. of Veterinary Microbiology & Preventive Medicine Associate Professor Extracted from: Order your copy here! View Vol. 54 here

1. Immunology: The innate immune system
   The Pig Journal (2003) Vol. 52 p. 111-123.
2. Lymphocyte development and maturation
   The Pig Journal (2004) Vol. 53, p. 75-91.
3. The battle between the immune system and pathogens
   The Pig Journal (2004) Vol. 54, p 55-69.

Part 3: Immunology - The battle between the immune system and pathogens

In the previous two articles of this three part series, the development and action of the various components of the innate and adaptive immune systems was discussed. This provides the background information required to successfully develop intervention, control and elimination strategies for most of the pathogens pigs encounter. However, as we identify the mechanisms used by the immune system to control pathogens, it is also necessary to recognise the ways pathogens evade, alter or modulate the immune system in order to replicate and survive. Knowledge of the mechanisms used by pathogens to cause disease provides insight into how microbes influence the outcome of infection. In the case of bacteria, the interaction with the host is thought to consist of 3 stages: bacterial invasion and colonisation of host tissues, growth in tissues with the production of toxic substances, and the inflammatory response of the host. In contrast, viruses that consist of either RNA or DNA, replicate inside living cells. Viruses typically enter cells through receptors on their surface and are dependent on the host cell machinery for replication. Because viruses are contained within cells of the host, detection is often more difficult and thus constant surveillance by the immune system for viral infections is required to enable a rapid response by both innate and acquired immune systems. However, for each mechanism utilised by the host immune system to prevent and control infection and disease, successful pathogens have developed counter measures to ensure their ability to replicate and survive. The contest between microbial survival mechanisms and the host immune system results in the disease that veterinarians combat on a daily basis. Understanding these battles further enables veterinarians to develop successful strategies to aid the immune system in fighting to keep the pig free of pathogens and disease.

The purpose of this article is to provide general information on how the immune system controls and eliminates pathogens, as well as the mechanisms used to circumvent the process. Entire textbooks are written on this subject so it is obvious that not every mechanism used by every pathogen can be covered in this brief article. However, the goal is to provide an overview that can be used by swine practitioners to further their understanding of why some pathogens are easily controlled, while others remain a challenge.

Pathogens replicate in different components of the body, either intracellular or extracellular. Obligate intracellular microbes can only replicate within cells. Facultative intracellular pathogens, which include mycobacteria, can replicate either within cells or in the extracellular spaces. In addition, microbes that replicate intracellularly can be further divided into those that replicate in the cytoplasm of a cell or in the vesicles within the cells. The mechanisms used by the immune system to control the pathogens vary by their location. Neutralising antibodies are important in preventing pathogens from infecting cells, while cytotoxic T lymphocytes (CTLs) destroy the cells after infection by intracellular mechanisms. Pathogens that infect macrophages require pathogen-specific Th1 cells to activate the macrophages to destroy the pathogens. Pathogens that replicate in the extracellular spaces are primarily controlled by antibodies and cells of the innate immune system. Knowledge of the site of replication of the pathogen assists the practitioner in knowing and understanding what type of intervention strategy and immune response is required to control and/or eliminate the microbe.

Infection is defined as the presence of an organism in the host, while disease is the reaction to the infection. Although the terms are often used interchangeably, when signs and symptoms of disease, such as fever and increased respiratory rate, are present, the term infection is incorrect. Many organisms can infect the host without causing disease. Pathogenicity is the term used to indicate the potential ability of a microbe to cause disease or elicit inflammation consistent with disease. The pathogenic potential of an organism is based on a wide variety of virulence factors as well as control of the pathogen and disease by the host. The ability of a microbe to induce disease is defined by its capability to infect the host, by the virulence factors of the organism and the ability of the host to control the organism. These factors must be considered when determining the effect of a pathogen as well as what intervention strategies have the potential to control disease.

Bacterial Infections

The innate immune effectors described in Part 1 are important mediators for control of bacterial infections. In fact, the vast majority of bacteria encountered by the pig are readily controlled by the innate immune system. The first line of defence consists of the epithelial cells of the skin and mucosal surfaces, which have a number of mechanisms used to control pathogens. These include the physical barriers of mucus and cilia, as well as a number of enzymes and molecules that act to control bacteria as they attempt to colonise the host. In order to circumvent the protective mechanism of the epithelial cells and the mucosal surfaces, bacteria have developed strategies of their own. One common mechanism used by bacteria to successfully infect the host is through the use of massive numbers of organisms. By infecting the host in large numbers, the pathogens can overwhelm the initial immune response, allowing colonisation and production of other factors that ensure the survival of the microbes. Bacteria use a number of virulence mechanisms, such as pili, adhesion proteins, surface polysaccharides, and lipoteichoic acids, to infect and colonise the host. Production of various proteins, glycolipids, carbohydrates, teichoic acids, peptidoglycan, metabolites, enzymes and toxins are produced by bacteria to disable the various parts of the innate immune response. Glycolipids of gram negative bacteria, such as LPS, and the cell wall structures of gram positive bacteria that include teichoic acid can overstimulate the host immune response, resulting in increased levels of inflammation that reduces or renders the defence system of the pig ineffective. Proteins, enzymes and toxins work further to impede the function of lymphocytes and granulocytes that would phagocytise and destroy the bacterial invaders.

For bacteria to invade the host, they must be able to evade the innate host defences that include macrophages and complement. Cell surface polysaccharides, either in the form of capsules or long antigens on the surface of the bacteria, are examples of some of the more common mechanisms used to evade the immune system. These molecules prevent the activation and/or deposition of complement on the bacterial surfaces or limit access to the complement receptors on phagocytic cells. Intracellular bacteria such as Mycobacterium spp. may resist destruction within the macrophages by preventing fusion of the phagolysosomes, thus allowing them to replicate within the cells without being destroyed by the enzymes and metabolites contained within the lysosomes.

Phagocytosis by macrophages is an important mechanism for controlling bacterial pathogens. By producing capsules, bacteria such as Streptococcus spp, inhibit phagocytosis until the immune system produces opsonising antibodies, which combines with complement to facilitate their uptake by the macrophages. This allows the bacteria to replicate and potentially change antigenically or produce other toxins capable of inactivating the immune system. The different strains of Streptococcus have antigenically distinct polysaccharides on their capsules. Thus, antibody against one strain of Streptococcus does not cross-react with others so no cross-protection occurs. A new immune response must be generated each time an individual is infected with a different strain of the organism. Thus, the same pathogen can cause disease many times in the same individual.

Production of antibodies is a primary countermeasure used by the adaptive immune system against bacteria. As described in Part 2 of this series, antibodies are produced by B cells with receptors that can recognise specific epitopes or antigens on the surface of the foreign invaders. While this is the most apparent mechanism used to prevent colonisation and tissue invasion by bacteria, there is little evidence that this mechanism of immune action is a primary contributor to resistance to infection and colonisation by bacteria. Bacteria frequently use multiple colonisation mechanisms that constantly change at the genetic level so antibodies and the immune system do not prevent colonisation and invasion of tissues. Bacteria, such as Salmonella sp, have developed elaborate systems of antigenic variation of their surface structures, such as pili and flagellae, which allows them to evade cells of the immune system. To further decrease the effectiveness of an antibody response to the various bacterial antigens, if the affinity of the antibody to the antigens is lower than the affinity of the bacteria to the host cell, little can be done to prevent adherence and colonisation. Currently there are few successful vaccines produced to any of the adhesins or colonisation factors of bacteria in either veterinary or human medicine.

Invasion of tissue by bacteria is accomplished by the production of extracellular enzymes such as hyaluronidase, lipases, nucleases and hemolysins that break down the cellular and matrix structures of the host. Some bacteria that normally do not induce disease, progress from local commensal colonisation to disseminated disease through loss in the integrity of the mucosal or epithelial barrier by injury or a secondary pathogen, or when the normal flora is altered, as is observed with antibiotic therapy.

In order to infect a host effectively, bacteria must often neutralise both the innate and adaptive immune responses long enough for colonisation and invasion to occur. One common technique used by gram negative bacteria is the use of a type III secretion mechanism which makes a hole in the cells that enables the microbe to enter, infect and replicate. Yersina pestis, the cause of bubonic plague, uses a type III secretion mechanism to cause disease. Proteins produced by Y. pestis produce a pore in the phagocytic cell's membrane allowing the entrance of the bacteria into the host cell cytoplasm. To prevent disease from Y. pestis, substantial amounts of the pro-inflammatory cytokines, interferon gamma (IFN-?) and tumor necrosis factor (TNF) are required. These cytokines are produced as a result of the interaction of the bacterial lipopolysaccharide (LPS) with the host's LPS binding protein, CD14, and toll like receptor (TLR) 4, all of which were discussed in Part I. Additional proteins produced by Y. pestis, which entered the macrophage via the type III secretion mechanism, interfere with the ability of the phagocytic cells to move or produce the IFN-? and TNF required for controlling the infection. The type III secretion proteins of Y. pestis and other gram negative bacteria are likely vaccine candidates and could possibly be effective in controlling many of the bacteria that use this as a virulence factor for invasion and induction of disease.

Toxin elaboration is one of the best-characterised molecular mechanisms by which bacteria damage the hosts. However, production of host factors including IL-1, IL-6, TNF, complement products, mediators derived from arachidonic acid metabolites (leukotrienes) and inflammatory cell degranulation products, such as histamine, further contribute to the disease. The interplay of these agents, produced by both the host and the pathogen, often dictates the severity of disease, which can vary between pigs infected with the same organism. Often the severity of disease is determined more by the host immune response than the toxins produced by the bacteria. Actinobacillus pleuropneumoniae (APP) is an example of bacteria that induces disease through the combination of toxin and host response. Following either adherence to, or phagocytosis by, macrophages, APP produces a number of toxins, including ApxI, ApxII and ApxIII. All three toxins are potentially toxic to the cells of the respiratory tract, including macrophages, endothelial cells of the lung and blood vessels and the epithelial cells of the alveoli. The damage to lungs by APP is the result of both toxin production and the induction of pro-inflammatory cytokines by the host. Neutralisation by the immune system of the toxins induced by APP toxins is critical for prevention of disease. Recent APP vaccines have concentrated on inducing the production of neutralising antibodies to the toxins. As our knowledge of the specific toxins and virulence factors utilised by bacteria to induce disease are identified, improved vaccines will follow.

As discussed above with APP, the damage induced by some bacteria is primarily caused by the host's own immune response. The inflammation and influx of inflammatory cells and lymphocytes in response to infection with Mycoplasma hyopneumoniae is an example of this type of disease. It is currently unknown what stimulus is used by M. hyopneumoniae that results in the influx of cells, but the resulting pneumonia is due to the activation and inflammation induced by the host cells that are attracted to the site of infection. M. hyopneumoniae binds to the ciliated epithelial cells of the lower airways of pigs and colonises the host by disrupting the mucociliary apparatus. M. hyopneumoniae colonisation also allows secondary bacterial pathogens, such as Pasteurella multocida, to infect and colonise in the respiratory tract. Infection with M. hyopneumoniae induces the production of pro-inflammatory cytokines, including TNF, Il-1 and IL-6 by the pig. Additionally, M. hyopneumoniae infection induces the production of IL-10, which reduces the activation of macrophages, further diminishing the effectiveness of the respiratory immune system in the control of bacteria and viruses.

Bacteria that survive in the intracellular spaces, such as Mycobacterium spp, pose a special challenge to the immune system. Few antigenic targets are present on the surface of infected cells, resulting in a low identification rate by the cellular immune system. Uptake of bacteria by phagocytic cells is critical for the induction of any immune response that will control and/or eliminate the organisms. When bacteria replicate intracellularly, this important control mechanism is avoided. If bacterial antigens are presented on the surface of the infected cell, T cell immunity can induce the secretion of cytokines that activate phagocytic cells. Also, CTLs appear to have some antibacterial activity and through the use of the granzymes can kill bacteria-infected cells. Stimulation of the appropriate immune response is critical to eliminating bacteria that infect and replicate in macrophages. Activation of infected macrophages by Th1 CD4+T cells results in the generation of oxygen radicals and other toxic substances within the macrophages and the release of the antimicrobial peptides such as defensins, resulting in destruction of the bacteria. While phagocytic activation has long been recognised as important in the control of extracellular bacteria, the genetic, molecular and cellular factors that activate the immune system and provide protection against intracellular bacteria are just beginning to be identified.

The molecular mechanisms used by bacteria are varied and diverse. Each step of the process requires the interaction between the host and pathogen that can result in either resolution of the infection or disease. Identification of the various bacterial virulence factors at the molecular level will enhance our ability to develop intervention strategies. However, bacteria typically use more than one mechanism for colonisation and disease, so a large number of potential therapies need to be investigated and developed for disease control.

In summary, there are many mechanisms used by bacterial pathogens to colonise pigs, resulting in infection and disease. Some secrete toxins, others infect in large numbers, so that the metabolic and toxic affects of bacterial metabolism cause tissue damage. In other cases, it is not the infection and growth of the bacteria that result in disease, but the activation of the host immune effector system that results in damage to the host tissues causing disease. The mechanisms used by the immune system to control bacterial infection vary depending on the location of the organism, the structural properties of the bacterial cell wall and the mechanism by which the organism causes disease. Typically, extracellular bacteria are destroyed by antibodies and complement. Both mechanisms are ineffective against intracellular bacteria, which require identification and destruction of the infected cells by T cells. In the case of infected macrophages, activation of their killing mechanisms is required to control and eliminate intracellular organisms. Disease caused by toxin producing bacteria can often be controlled by the development of antibodies to the toxins. However, for every mechanism used by the immune system to control bacteria, pathogens have developed mechanisms to circumvent these host strategies. As we learn more about the molecular and genetic aspects of bacteria, improved intervention strategies, including vaccines and antibiotics, can be developed.

Viral Immune Strategies

As with bacterial pathogens, control of viruses requires both the innate and adaptive immune system to respond. In a similar manner as bacteria, the disease induced by a viral infection can consist of direct tissue damage by the virus, as well as damage induced by the host immune response. In contrast to bacteria, which are primarily extracellular pathogens, viral pathogens are exclusively intracellular pathogens. Therefore, many of the mechanisms of immune defence used against bacteria are useless. However, the immune system has both innate and adaptive strategies designed to control and eliminate viral invaders. The external barriers of epithelial cells, mucus and cilia are minimally effective in preventing viral pathogens from invading the host. Instead, cells have devised other mechanisms to prevent infection, replication and spread once a virus has infected a cell. Natural killer (NK) T cells are members of the innate immune system that recognise foreign antigens expressed on the surface of viral infected cells without prior exposure. The presence of specific receptors on the surface of cells, including the major histocompatibility complex (MHC) molecules, are required for NK cells to differentiate between normal cells belonging to self and abnormal cells. Viruses often decrease the level of MHC molecules on the cell surface in order to decrease the antigens on the surface of infected cells, thus evading detection by T cells. NK cells detect cells that lack the normal expression of MHC molecules (as well as several other important proteins) on their surface. Once NK cells detect altered cells surface proteins, they induce the cell to undergo apoptosis and die. This ability of the NK cells to detect cells early in viral infection is valuable in preventing the spread of the virus to other susceptible cells. However, as with other protective immune responses, viral pathogens have devised mechanisms to hide from detection by NK cells. One mechanism of preventing detection by NK cells is for the viral antigens to mimic normal cellular proteins, reducing the number of foreign peptides expressed on the surface of the infected cells. In addition, viruses may decrease the number of MHC molecules on the surface of the cell to a level that is not detected by NK cells and yet reduces the presentation of viral antigens to the immune system. The viruses may also produce proteins and signals that prevent the cells from undergoing apoptosis in response to the NK cells, thus allowing replication and spread of the virus.

Production of type I interferons (IFN) that include IFN α and β is another innate immune mechanism induced early in viral infections. Type I IFNs are produced in the cell in response to virus infection and prevent the virus from using the cellular machinery to replicate. Production of type I IFNs can also induce the cell to undergo apoptosis in response to the viral infection, thus preventing virus replication and spread. Production of IFN α and β by virus infected cells can also increase the resistance of neighbouring cells to infection, thus reducing the spread of the virus in the host. Production of type I IFNs play an important role in the rapid elimination of influenza virus from the pig's respiratory tract. Typically, within 5 to 7 days following infection, the virus can no longer be isolated from the pig's respiratory tract due to the rapid production and control by the type I IFNs and other members of the innate immune system. In contrast, it has been demonstrated that while administration of the type I IFNs are effective in reducing the ability of PRRSV to infect cells in vitro, PRRSV infection is a poor inducer of type I IFN in the pig. This is probably an important mechanism for infection and persistence of the virus in the host. The mechanism used by PRRSV to prevent the induction of the type I IFN is currently unknown.

Induction of an adaptive immune response to virus infection is important for both eliminating virus infected cells by T cells and to develop antibodies that prevent future infections. Both neutralising and opsonising antibodies are important in the control of viral infections. Optimally, neutralising antibodies will bind to the virus and prevent the virus from binding to its receptor, thus preventing infection. Opsonising antibodies can coat the surface of the virons and enhance uptake by phagocytic cells in a similar fashion, as with bacteria. Typically however, the development of neutralising antibodies is a more effective control method. Viruses prevent the development of neutralising antibodies by hiding and altering their antigens. Antigenic variation is an important evasion technique used by viruses to evade the immune system. Influenza viruses induce antigenic variation by both antigenic drift and shift. Antigenic drift is caused by small changes in the genes that encode the surface proteins of the virus, which include haemagglutinin and neuraminidase. These small changes occur during virus replication and finally accumulate to a level that the antibodies produced against the viral proteins no longer recognise their epitopes. When this occurs, a new immune response must be induced, which allows time for the virus to replicate. Antigenic shift occurs when gene segments re-assort, resulting in a new genome in the virus. Often this results in a complete change in viral isotype. Again, a new immune response must occur to eliminate the virus and protect against disease. These changes have recently been observed in the U.S. swine system with the emergence of a new H3N2 subtype of the virus in addition to the original subtype of H1N1. The introduction of the H3N2 virus has facilitated recombination of viruses to occur, resulting in the production of new genetically diverse variants including H1N2 viruses, as well as genetically diverse isolates of the H1N1 and H3N2 subtypes. This allows the virus to change enough that the immune response to the original virus is no longer effective and a new immune response to the virus must develop.

Development of a cell-mediated immune response is typically considered the most important immune response for virus control. As outlined in Part 2, the viral antigens are processed within the infected cell into peptides, enter into the endoplasmic reticulum using transporter (TAP) proteins, where they bind to the MHC class I molecules and are exported to the surface of the cell. Once on the surface, T cells with the appropriate T cell receptor (TCR) bind the MHC molecule that contains the viral peptides and, with the assistance of either the CD4+ or CD8+ molecules, activate the T cells. Additional co-stimulatory molecules are required for cell activation in order to ensure that T cells are not activated inappropriately. In the case of a T cell bearing the CD4+ accessory molecules (T helper or Th cells), further differentiation into either Th1 or Th2 cells occurs. The type of Th cell produced is determined by the cytokines present in the environment at the time the antigen is presented to the T cells. The cytokines produced by the Th cells will determine which cells of the adaptive immune response will become activated. In the presence of IL-4, a predominantly Th2-type of immune response may occur. This will favour the production of cytokines that decrease macrophage activation (IL-10), and cytokines that direct the development of B cells into plasma cells producing specific types of antibodies such as IgE. In contrast, the development of a Th1-type of response will produce cytokines such as IFN-? that will activate macrophages and cytotoxic T lymphocytes (CTLs). In addition, opsonising and neutralising antibodies are produced by B cells with the help of Th1 cells. This is the type of immune response that appears most effective in the control of viral infections. However, the development of either a Th1 or Th2 type of response is not a clear-cut process. Because the activation of any immune response must be carefully controlled, the Th1 and Th2 responses are important in controlling each other. So, whenever the immune system is activated, both types of response will be present; however, one type of response will be predominant. In addition, over time, the immune system can direct the response to one of the two types of Th response. An immune response to a pathogen is constantly evolving in order to develop the optimal response for disease control. With the production of Th1 cells, macrophages are activated to engulf, destroy and present viral peptides to the immune system and CTLs that recognise and destroy the viral infected cells expressing the foreign peptides on their surface within the MHC molecules are activated. In addition, neutralising antibodies may be produced by activated B cells. These responses result in the development of an effective immune response that controls the viral infection.

As expected, even though the immune system has devised elaborate and sophisticated methods to control intracellular invaders such as viruses, the pathogens have developed strategies to circumvent these measures. For every type of virus that successfully infects the host resulting in disease, different mechanisms are used to evade the immune response. Some are very simplistic, others are extremely sophisticated. One important mechanism used to evade the immune system is by diverting the immune response away from an effective immune response against the pathogen to a less effective response by changing a more effective Th1 response to a Th2 type of response. A number of pathogens, both bacterial and more commonly viral, use this as a method to survive and replicate within the host. The mechanisms by which the pathogens of pigs divert the immune system often remain unknown. The Epstein-Barr virus effectively inhibits a Th1 response by producing a virally encoded cytokine homolog of IL-10, which decreases macrophage activation and induces more of a Th2-type response. Infection with PRRSV has also been shown to induce the production of IL-10, although the mechanism is unidentified. Induction of a Th2 response results in decreased amounts of IFN-γ, which further reduces a cell mediated immune response. This may also be a mechanism for the delayed production of serum neutralising antibodies observed with PRRSV.

Other mechanisms for immune evasion by viruses include inhibition of the presentation of viral antigens on the MHC molecules. Viruses have been shown to inhibit each step of the process by which antigens are loaded onto the MHC molecules. Viruses have been shown to prevent the TAP proteins from carrying viral peptides into the endoplasmic reticulum to bind with the MHC molecules. They can prevent the normal formation of MHC molecules within the endoplasmic reticulum, and prevent the migration of MHC molecules to the cell surface. Alteration of their genetic composition so that the viral peptides that bind in the MHC groove resemble host peptides is also an effective mechanism to prevent the immune system from recognising infected cells. The goal of these steps is to prevent the expression of viral proteins on the surface of cells and thus recognition and destruction by the cellular immune system. Thus, the MHC is a frequent target for viral interference in the immune process.

The mechanisms used by a number of human viruses to circumvent the immune system have been well identified. Less is known about veterinary pathogens. However, as viral genes are identified, more information will be emerging on mechanisms used by swine and veterinary pathogens to survive in the host. As this information becomes known, increased intervention strategies and vaccine targets will be identified.

Summary

As can be expected, there are many mechanisms used by the immune system to control pathogens. All of the various immune systems described in this series of articles are utilised in the control of pathogens. However, for each action by the immune system, a counter move is made by the pathogen. The immune system typically eliminates, or at least controls, the damage done by the pathogen. However, we know that some pathogens are capable of persisting and surviving in the host using many different techniques. Successful pathogens cause minimal disease to their host and either change or evade the immune response, allowing the organism to live and replicate. Severe disease or damage to host tissues is not in the best interest for pathogen survival so the induction of a significant immune response that may cause further damage to the host is to be avoided. Therefore, the balancing act between infection, disease and the immune response is always in flux. The information about the immune response to pathogens, as well as the specific mechanisms used by the problem pathogens for evasion, remains minimal in many cases. As we are better able to understand how the pathogens cause disease, how the immune system responds and what is required for the successful clearance of the pathogen, improved intervention strategies will be developed.

Associated figures

Figure 1. Immune responses associated with infection and pathogen clearance

Figure 2. Antigenic shift and drift

Glossary

Antigenic drift - small changes or point mutations in the viral genes that alter the structure of viral surface proteins. When enough mutations occur, a new immune response is required to control the virus.

Antigenic shift - obtaining new genes from another genetically different virus resulting in a change in the structure of viral surface proteins. When genes are switched or undergo "re-assortment," a new subtype of virus may emerge that must be controlled with a new immune response.

Antigen presentation - the display of antigen fragments bound to the MHC molecules on the surface of cells. This is how T cells recognise antigens. Apoptosis - or "programmed cell death" is a type of cell death that occurs when the cell activates an internal death program. This is in contrast to necrosis, which is death due to external factors.

CD (clusters of differentiation) - a cell-surface molecule that is identified by a group of monoclonal antibodies that all recognise the same molecule.

Epitope - a site on an antigen that is recognised by an antibody or a T cell receptor. T-cell epitopes are short peptides derived from proteins and bound to a MHC molecule. B-cell epitopes used for antibody production can either be to linear sections of the protein or conformational, based on different spots on a folded protein.

Granzymes - are proteases produced by cytotoxic T cells (CTL) and are involved in inducing apoptosis in the target cell.

Interferons - Type 1 (α and β) are cytokines that induce cells to resist viral replication. Interferon gamma (IFN-γ) is produced by Th1 cells, CD8+ cells and NK cells and activates macrophages and increases the expression of the MHC on the surface of cells.

MHC (major histocompatibility complex) molecules - membrane glycoproteins that bind to antigens and take them to the surface of the cell to present them to T cells. MHC class I molecules are present on all cells and present peptides to CD8+ T (CTLs) cells. MHC class II molecules present peptides to CD4+ Th cells. Neutralising antibodies - antibodies that reduce or prevent infection by a virus or the activity of a bacterial toxin.

Opsonisation - alteration of the surface of a pathogen that facilitates uptake by phagocytic cells. Antibody and complement opsonise extracellular bacteria and occasionally viruses for uptake and destruction by macrophages and neutrophils.

TAP proteins (transporters associated with antigen processing) - proteins involved in transporting antigen peptides from the cell cytoplasm into the endoplasmic reticulum where they bind to MHC molecules.

Th cells - CD4+ cells that are characterised by the cytokines they produce. Th1 cells produce IFN-? and activate macrophages. Th2 cells produce IL-10 and decrease macrophage activity and induce production of antibodies such as IgE.

TLR-4 - is a mammalian toll-like receptor that in conjunction with the macrophage LPS receptor, recognises bacterial lipopolysaccharide (LPS). Tumor necrosis factor alpha (TNF) - a cytokine produced by macrophages and T cells that is a pro-inflammatory cytokine. Small amounts induce antigen presenting cells to migrate to the peripheral lymph nodes for an adaptive immune response. Large amounts can lead to septic shock.

Source: Pig Journal - February 2005