Immune system

The immune system of mammals is composed of a complex constellation of cells, organs and tissues, arranged in an elaborate and dynamic communications network and equipped to optimize the response against invasion by pathogenic organisms. The immune system is, in its simplest form, a cascade of detection and adaptation, culminating in a system that is remarkably effective.

The immune system protects the body from infection by employing three basic strategies:

• Creating and maintaining a barrier that prevents bacteria and viruses from entering the body.
• If a pathogen breaches the barriers, and gets into the body, the innate immune system is equipped with specialized cells that detect, and often eliminate, the invader before it is able to reproduce and cause potentially serious injury to the host.
• If a pathogen is able to successfully evade the innate immune cells, the immune system activates a second, adaptive immune response against the pathogen. It is through the adaptive immune response that the immune system gains the ability to recognize a pathogen, and to mount stronger attacks each time the pathogen is encountered.

A scanning electron microscope (SEM) image of a T-lymphocyte (right), a platelet (center), and a red blood cell (left). Image: The National Cancer Institute at Frederick

Macrophages have identified a cancer cell (the large, spiky mass). Upon fusing with the cancer cell, the macrophages (smaller white cells) will inject toxins that kill the tumor cell. Magnification: x8,000.

Surface barriers and Mucosal immunity

• The skin is the first line of immunological defence. The skin is made up of the epidermis, outer layer, and dermis. The epidermis is comprised of tightly packed cells rich in keratin, which impedes water from entering the skin, and is slightly acidic which inhibits bacterial growth. The dermis contains the sebaceous glands from which hairs grow, and from which sebum is secreted. Sebum inhibits the growth of some type of bacteria and fungi. Areas of the body not covered with hair (i.e. lacking sebaceous glands)such as the palms and the soles of the feet, are more susceptible to fungal growth, such as athlete’s foot.
• Pathogens are mechanically expelled from the lungs through a process known as ciliary action. Coughing and sneezing causes tiny hairs, called cilia, to move in an upward motion ejecting both living things and other irritants from the respiratory tract .
• The flushing action of saliva, tears, and urine also mechanically expel pathogens.
• In addition saliva and tears contain antibacterial enzymes, such as lysozyme, which destroy bacterial cell walls. Vaginal secretions become slightly acidic following menarche, while semen contains spermine and zinc which repels some pathogens. Mother’s milk contains the powerful enzyme lactoperoxidase.
• Mucus secreted by the respiratory and gastrointestinal tract serves to protect the host by trapping many microorganisms.
• Gastric acid, produced in the stomach, is a powerful defense against ingested pathogens. Few species are able to survive the low pH and destructive enzymes that exist in the stomach.
• Within the intestines, commensal flora are protective by competing with pathogenic bacteria for food and space, diminishing the probability that the pathogenic bacteria will be able to reach sufficient numbers to cause illness. Antibiotics do not discriminate between pathogenic bacteria and the normal gut flora. It is for this reason that ingestion of oral antibiotics can sometimes lead to an “overgrowth” of fungus (fungus is not affected by antibiotics), such as a yeast infection.

Lymphatic system

Main article: Lymphatic System

The lymphatic system is a complex network of organs, lymph nodes, lymph ducts, and lymph vessels that produce and transport fluid from tissues to the circulatory system. When micro-organisms invade the body or the body encounters other antigens (such as pollen), the antigens are transported from the tissue in the lymph fluid by the lymphatic system. The lymph is carried in the lymph vessels to regional lymph nodes. The lymph nodes filter the lymph fluid and remove foreign material, such as bacteria and cancer cells. The organs of the lymphatic system also serve as the site of final maturation for some white blood cells, and the initiation site of many innate and adaptive immune functions.

Innate immunity

The innate immune system is comprised of the cells and mechanisms that defend the host from infection by other organisms, in a non-specific manner. This means that the cells of the innate system recognize, and respond to, pathogens in a generic way. The innate system does not confer long-lasting or protective immunity to the host. The innate system is thought to constitute an evolutionarily older defense strategy, and is the dominant immune system found in plants, fungi, insects, and in primitive multicellular organisms.

The major functions of the innate immune system include:

• The recruitment of immune cells to sites of infection and inflammation, through the production of chemical factors; including specialized chemical mediators, called cytokines.
• The identification and removal of foreign substances; such as bacteria and toxins, present in organs, tissues, the blood and lymph, by specialized white blood cells. See also: Complement system.
• The activation of the adaptive immune system through a process known as antigen presentation.

Inflammation

Main article: Inflammation

Inflammation is one of the first responses of the immune system to infection or irritation. Inflammation is stimulated by chemical factors released by injured cells and serves to establish a physical barrier against the spread of infection, and to promote healing of any damaged tissue following the clearance of pathogens.

Mechanistically, the chemicals factors produced during inflamation (histamine, bradicine, serotonin, leutrienes) sensitize pain receptors, cause vasodilation of the blood vessels at the scene, and attract phagocytes, especially neutrophils. Neutrophils then trigger the immune system by releasing factors that summon other leukocytes and lymphocytes. The inflammatory response is characterized by the following quintet: redness (rubor), heat (calor), swelling (tumor), pain (dolor) and possible dysfunction of the organs or tissues involved (functio laesa).

Cells of the innate immune system

Main article: Leukocyte

A scanning electron microscope (SEM) image of normal circulating human blood. One can see red blood cells, several knobby white blood cells including lymphocytes , a monocyte, a neutrophil, and many small disc-shaped platelets.

All white blood cells (WBC) are known officially as leukocytes. Leukocytes are unlike other cells of the body, and are not exclusively associated with any organ or tissue- in fact they actually act like independent, single-celled organisms. Leukocytes are able to move, interact, and even capture things on their own. Unlike many other cells in the body, most innate immune leukocytes cannot divide or reproduce on their own, but rely on the pluripotential hemopoietic stem cells present in the bone marrow to produce new cells.

The innate leukocytes include: Natural killer cells, mast cells, eosinophils, basophils; and the phagocytic cells including macrophages, neutrophils and dendritic cells, and function within the immune system by identifying and eliminating pathogens that might cause infection.

Natural killer cells

Main article: Natural killer cell

Natural killer cells, or NK cells, are a component of the innate immune system, and are distinctive in that NK cells attack host cells that have been infected by microbes, but do not attack microbes themselves. NK cells attack and destroy tumor cells, and virally infected cells, through a process known as "missing-self", a term used to describe cells with low levels of a cell-surface marker called MHC (major histocompatibility complex)—a situation which can arise due to viral infection of host cells. They were named "natural killer" because of the initial notion that they do not require activation in order to kill cells that are "missing self."

Mast cells

Main article: Mast cell

Mast cells are a type of innate immune cell that resides in the connective tissue and in the mucous membranes, and are intimately associated with pathogen defense, wound healing, and are often associated with allergy and anaphylaxis. When activated, mast cells rapidly release characteristic granules, rich in histamine and heparin, along with various hormonal mediators, and chemokines, or chemotactic cytokines into the environment. Histamine dilates blood vessels, causing the characteristic signs of inflammation, and recruits neutrophils and macrophages.

Basophils and Eosinophils

Main articles: Basophil granulocyte and Eosinophil granulocyte

Basophils and Eosinophils are cells related to the neutrophil (see below). When activated by a pathogen encounter, basophils release histamine, are important in defense against parasites, and play a role in allergic reactions (such as asthma). Upon activation, eosinophils secrete a range of highly toxic proteins and free radicals that are highly effective against bacteria and parasites, but are also responsible for most tissue damage occuring during allergic reactions. Activation and toxin release by eosiniphils is tightly regulated to prevent any inappropriate tissue destruction.

Phagocytes

Main article: Phagocytosis

The word 'phagocyte' literally means 'eating cell'. These are immune cells that engulf, or eat, pathogens or particles. To engulf a particle or pathogen, a phagocyte extends portions of its plasma membrane, wrapping the membrane around the particle until it is enveloped (i.e. the particle is now inside the cell). Once inside the cell, the invading pathogen is contained inside a endosome which merges with a lysosome. The lysosome contains enzymes and acids that kill and digest the particle or organism. Phagocytes generally patrol the body searching for pathogens, but are also able to react to a group of highly specialized molecular signals produced by other cells, called cytokines. The phagocytic cells of the immune system include Macrophages, Neutrophils and Dendritic cells.

Phagocytes often engulf the hosts’ own cells. When cells die, either during normal processes (called apoptosis) or due to a bacterial or viral infection of the cell, phagocytic cells are responsible for their removal from the system. By helping to remove dead cells, to make room for the new healthy cells, phagocytosis is an important part of the healing process following tissue injury.

A macrophage

Macrophages, from the Greek, meaning "large eating cell", are large phagocytic leukocytes, which are able to travel outside of the circulatory system by moving across the cell membrane of capillary vessels and entering the areas between cells in pursuit of invading pathogens. Macrophages are the most efficient phagocytes, and can eat substantial numbers of bacteria or other cells. The binding of bacterial molecules to receptors on the surface of a macrophage triggers it to engulf and destroy the bacteria through the generation of a “respiratory burst”. Pathogens also stimulate the macrophage to produce chemokines, which summons cells to the site of infection.

Neutrophils, along with two other cell types; eosinophils and basophils, are known as granulocytes or polymorphonuclear cells (PMNs), due to their distinctive lobed nuclei. Neutrophils are the most abundant type of phagocyte, normally representing 50 to 60% of the total circulating leukocytes, and are usually the first cells to arrive at the scene of infection. Similar to macrophages, neutrophils destroy foreign substances or pathogens by activating a "respiratory burst". The main products of the neutrophil respiratory burst are strong oxidizing agents including hydrogen peroxide, free oxygen radicals and hypochlorite.

Dendritic cell

The bone marrow of a normal healthy adult produces more than 100 billion neutrophils per day, and more than 10 times that many per day during acute inflammation.

Dendritic cells (DC) are phagocytic cells present in tissues that are in contact with the external environment, mainly the skin (where they are often called Langerhans cells), the inner lining of the nose, lungs, stomach and intestines. They are named for their resemblance to neuronal dendrites, but dendritic cells are in no way connected to nervous system function. Dendritic cells are very important in the process of antigen presentation (see below), and serve as a link between the innate and adaptive immune systems.

Innate immune evasion

Cells of the innate immune system effectivly prevent free growth of bacteria within the body, however many species of bacteria have evolved mechanisms allowing them to evade the innate immune system. Some of these strategies involve:

• Inhibiting phagocytosis, by affecting the receptors that the phagocytes use to engulf bacteria, or by mimicking host cells, so that the immune system does not perceive them to be foreign (Bacteroides)
• Inhibiting the ability of the phagocyte to respond to chemokines signals (Staphylococcus aureus)
• Inhibiting the mechanisms that phagocytes use to destroy the bacteria (Mycobacterium tuberculosis), and multiplying within the phagocyte.
• Directly killing the phagocyte (M. tuberculosis, Streptococcus pyogenes and Bacillus anthracis).

Specific or Adaptive immunity

The innate immune system is brought into play at the earliest stages of infection and often effectively prevents the free growth of most bacteria within the body. Many pathogens, however, have developed strategies that allow them to elude or escape from innate immune control. Under these circumstances the early innate response to infection sets the scene for the specialized functions of the adaptive immune system.

Adaptive immunity is triggered when a pathogen evades the innate immune system and generates a threshold level of antigen. The major functions of the adaptive immune system include:

• The recognition of specific “non-self” antigens in the presence of “self”, during the process of antigen presentation.
• The generation of responses that are tailored to maximally eliminate specific pathogens or pathogen infected cells.
• The development of immunological memory, in which each pathogen is “remembered” by a signature antigen. These memory cells can be called upon to quickly eliminate a pathogen should subsequent infections occur.

Cells of the adaptive immune system

Main article: Lymphocyte

A scanning electron microscope (SEM) image of a single human lymphocyte.

The cells of the adaptive immune system are a type of leukocyte, called a lymphocyte. B cells and T cells are the two major types of lymphocytes. In the human body there are about 2 trillion lymphocytes, constituting 20–40% of the body’s WBCs; their total mass is about the same as that of the brain or liver. The peripheral blood contains 20–50% of circulating lymphocytes; the rest move within the lymphatic system.

B cells and T cells are derived from the same pluripotential hemopoietic stem cells, and are indistinguishable from one another until after they are activated. B cells play a large role in the humoral immune response, whereas T-cells are intimately involved in cell-mediated immune responses. B-cells may be named for the bursa of Fabricius, an organ unique to birds, where the cells were first found to develop. However, in nearly all other vertebrates, B cells (and T-cells) are produced by stem cells in the bone marrow. T-cells travel to and develop in, the thymus, from which they derive their name. In an adult animal, the peripheral lymphoid organs contain a mixture of B- and T cells in at least three stages of differentiation:

• naive cells that have matured, left the bone marrow or thymus, and have entered the lymphatic system, but that have yet to encounter their cognate antigen,
• effector cells that have been actived by their cognate antigen, and are actively involved in eliminating a pathogen and,
• memory cells- the long-lived survivors of past infections.

Antigen presentation

Main article: Antigen presentation

The basis of adaptive immunity lies in the capacity of immune cells to distinguish between the body's own cells and the unwanted invaders. The host’s cells express “self” antigens that identify them as such. These antigens are different from those on the surface of bacteria ("non-self" antigens) or on the surface of virally infected host cells (“missing self”). The adaptive immune system is triggered through a process known as antigen presentation.

With the exception of some cell types, such as non-nucleated cells (including erythrocytes), all cells are capable of presenting antigen and activating the adaptive response. Some cells, however, are specially equipped to present antigen, and to prime naive T cells. Dendritic cells and B-cells (and to a lesser extent macrophages), while playing a major role in the innate response, also act as professional antigen presenting cells (APC). These professional APCs are equipped with special immunostimulatory receptors that allow for enhanced activation of T cells.

Several different types of T cell can be activated by professional APCs, and each type of T cell is specially equipped to deal with different pathogens, whether the pathogen is bacterial, viral or a toxin. The type of T cell activated, and therefore the type of response generated, depends, in part, on the context in which the antigen was first encountered by the APC.

Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells .

Exogenous antigens

Dendritic cells engulf exogenous (outside the cell) pathogens, such as bacteria, parasites or toxins in the tissues and then migrate, via chemotactic signals, to the T cell enriched lymph nodes. During migration, DCs undergo a process of maturation in which they lose most of their ability to engulf other pathogens and develop an increased ability to communicate with T-cells in the lymph nodes. The DC also uses enzymes to chop the pathogen into smaller pieces, called antigens. In the lymph node the DC will display these "non-self" antigens on its surface by coupling them to a "self"-receptor called the Major histocompatibility complex, or MHC (also known in humans as Human leukocyte antigen (HLA)). This MHC:antigen complex is then recognized by T-cells passing through the lymph node. Exogenous antigens are usually displayed on MHC Class II molecules, which interact with CD4+ helper T-cells.

Endogenous antigens

Endogenous antigens (from inside the cell) are produced by viruses replicating within a host cell. Like the DC, the host cells use enzymes to digest virally associated proteins. The infected cell displays these small pieces of the virus, coupled to MHC, on its surface, to T-cells. Endogenous antigens are typically displayed on MHC Class I molecules, which interact with CD8+ cytotoxic T-cells. With the exception of some cell types, such as non-nucleated cells (including erythrocytes), Class I MHC is expressed by all host cells.

CD8+ T lymphocytes and cytotoxicity

Main article: Cytotoxic T cell

Cytotoxic T cells (also known as TC, killer T cell, or cytotoxic T-lymphocyte (CTL)) are a sub-group of T cells which are capable of inducing the death of other cells, and are thus defined as "cyto"- or cell -toxic. CTL function to kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional.

Cytotoxic T cells express T-cell receptors (TCR) that recognize, and have high affinity for, a specific peptide antigen bound to Class I MHC molecules. This affinity is what keeps the CTL and the infected cell bound closely together, and allows for antigen-specific activation or the CTL.

File:Cytotoxic T cell.jpg

Killer T cells—also called cytotoxic T lymphocytes or CTL-directly attack other cells carrying certain foreign or abnormal molecules on their surfaces.

Naive cytotoxic T cells are activated when their TCR strongly interacts with a peptide-bound MHC class I molecule. Once activated CTL undergoes a process called clonal expansion in which the cell divides rapidly and becomes an “armed”-effector cell. The activated CTL will then travel throughout the body in search of other cells bearing the same MHC Class I + peptide complex that initially activated it.

When exposed to these infected or dysfunctional host somatic cells, effector CTL release perforin and granulysin: cytotoxins which form pores in the target cell's plasma membrane, causing ions and water to flow into the infected cell, causing it to burst or lyse. CTL also release granzyme, a serine protease that enters target cells via the perforin-formed pore and induces apoptosis (cell death). To limit extensive tissue damage during an infection, CTL activation is tightly controlled and generally requires either a very strong MHC/peptide activation signal, or additional activation signals provided by "helper" T-cells (see below).

Upon resolution of the infection, most of the effector cells will die and be cleared away by phagocytes, but a few of these cells will be retained as memory cells. These memory cells are able to quickly differentiate into effector cells upon a later encounter with the same antigen, dramatically shortening the time required to mount an effective immune response.

CD4+ “helper” T-cells

Main article: T helper cell

File:T cell activation.jpg

The T lymphocyte activation pathway. T cells contribute to immune defenses in two major ways: some direct and regulate immune responses; others directly attack infected or cancerous cells.

CD4+ Lymphocytes, or helper T cells, are immune response mediators, and play an important role in establishing and maximizing the capabilities of the adaptive immune response. These cells have no cytotoxic or phagocytic activity; and cannot kill infected cells or clear pathogens, but, in essence "manage" the immune response, by directing other cells to perform these tasks.

Helper T cells express T-cell receptors (TCR) that recognize a specific peptide antigen bound to Class II MHC molecules. The activation of a naive helper T-cell causes it to release cytokines, which in turn, influence the activity of many other cell types, including the APC that activated it. Helper T-cells require a much milder stimulus than do cytotoxic T-cells, thus, helper T-cells are sometimes required to provide extra signals that activate the cytotoxic cells. Like cytotoxic T-cells, most of the effector CD4+ helper cells will die upon the resolution of infection, with a few cells remaining as CD4+ memory cells.

HIV is able to subvert the immune system by directly attacking the CD4+ T cells, precisely the cells that could drive the destruction of the virus, but also the cells that drive immunity against all of the other pathogens encountered during an organisms' lifetime.

Th1 and Th2: helper T cell responses

There are essentially two types of CD4+ T helper cell responses that can be induced by a professional APC, each designed to eliminate different types of pathogens. The factors that dictate whether an infection will trigger a Th1 or Th2 type response are not fully understood, but the type of response generated plays an important role in the clearance of different kinds of pathogens.

The Th1 response is characterized by the production of cytokines, namely Interferon-gamma, which activates the bactericidal activities of macrophages, and induces B-cells to make opsonizing (coating) antibodies, leading to "cell-mediated immunity" . The Th2 response is characterized by the release of Interleukin 4, which results in the activation of B-cells to make neutralizing (killing) antibodies, leading to "humoral immunity". Generally, Th1 responses are invloved in eliminating intracellular pathogens (viruses and bacteria that are inside host cells), while Th2 responses are more effective against pathogens present outside of cells, such as extracellular bacteria, parasites and toxins.

A third type of T lymphocyte, the regulatory T cells (Treg), limits and suppresses the immune system, and may control aberrant immune responses to self-antigens; an important mechanism in controlling the development of autoimmune diseases.

B lymphocytes and antibody production

Main article: B cell

File:B cell activation.jpg

The B lymphocyte activation pathway. B cells function to protect the host by producing antibodies that identify and neutralize foreign objects like bacteria and viruses.

B Cells are the major cell type involved in humoral immunity. Humoral immunity is defined as the creation of antibodies that circulate in blood plasma and lymph. Antibodies (or immunoglobulin, Ig), are large Y-shaped proteins used by the immune system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target. In mammals there are five types of antibody: IgA, IgD, IgE, IgG, and IgM, each of which differ in biological properties and have evolved to handle different types of antigens. Upon activation, B cells produce antibodies that serve to identify and neutralize specific pathogens.

Like T-cells, each B cell has a unique receptor protein, an antibody molecule that is bound to the surface of the B cell and referred to as the B cell receptor (BCR). The BCR will recognize and bind to only one particular antigen. A critical difference between B cells and T cells is how each cell "sees" an antigen. B cells recognize their cognate antigen in its native form. In contrast, T cells recognize their cognate antigen in a processed form - as a peptide in the context of an MHC molecule. Once a B cell encounters its cognate (or specific) antigen and receives additional signal from a helper T cell (predominately Th2 type), it can further differentiate into an effector cell, known as a plasma cell.

Plasma cells are short lived cells (2-3 days) which secrete antibodies that assist in the destruction of antigens by binding to them and making them easier targets for phagocytes or by triggering the complement cascade. About 10% of these plasma cells will survive to become long-lived memory B cells, which are specific to the pathogen derrived antigens encountered during infection. If the same pathogen infects the host again, these cells can be called upon to respond quickly to this second exposure to the pathogenic antigen. Already having been primed to produce specific antibodies, the memory B cell can rapidly eliminate the infectious agent; the host experiencing few, if any, of the symptoms experienced during the primary infection.

Immunological memory & diversity

Most large molecules, including virtually all proteins and many polysaccharides, can serve as antigens. The parts of an antigen that combine with the antigen-binding site, either on an antibody molecule or a lymphocyte receptor, are called epitopes. Most antigens contain a variety of epitopes that can stimulate the production of antibodies, specific T cell responses, or both.

An antibody is made up of two heavy chains and two light chains. The unique variable region allows an antibody to recognize its matching antigen.

Only a very small proportion (less than 0.01%) of the total lymphocytes in the body are able to bind to each antigen, suggesting that only a very small number of cells are responsive to each specific antigen.

For the adaptive response to efficiently "remember" and eliminate a large number of pathogens the immune system must be able to distinguish between many different antigens. Therefore, the receptors used to recognize these antigens must be produced in a huge variety of configurations, essentially one receptor for each different pathogen that might ever be encountered. Even in the absence of antigen stimulation, a human is capable of producing more than 1 trillion different antibody molecules. The amount of genetic information needed to produce the sum total of these receptors would require millions of genes, while in reality, the entire human genome contains fewer than 50,000 genes. So how are so many different antibodies and antigen receptors produced?

This myriad of receptors are produced through a process known as clonal selection. According to the clonal selection theory, at birth, an animal will randomly generate a vast diversity of lymphocytes (each bearing a unique antigen receptor) from information encoded in a small family of genes. In order to generate each unique antigen receptor, these genes have undergone a process called combinatorial diversification, in which one gene segment from each gene family recombines with other gene segments to form a single unique gene. This assembly process effectively generates the enormous diversity of receptors and antibodies, even before the body encounters any antigens, enabling the immune system to respond to an almost unlimited diversity of antigens. Throughout the lifetime of an animal, those lymphocytes that can react against the foreign antigens that the animal actually encounters are specifically selected for action, directed against anything that expresses that antigen.

It is important to note that the innate and adaptive portions of the immune system work together and not in spite of each other. The adaptive arm, B and T cells, would be unable to function without the input of the innate system. T cells are useless without antigen-presenting cells to activate them, and B cells are crippled without T-cell help. On the other hand, the innate system would likely be overrun with pathogens without the specialized action of the adaptive immune response.

Immunity during pregnancy and infancy

The cornerstone of the immune system is the recognition of “self” versus “non-self”. Therefore, the mechanisms which protect the human fetus (which is clearly not “self”) from attack by the immune system, are particularly interesting. Although no comprehensive explanation has emerged to explain this mysterious, and often repeated, lack of rejection, two classical reasons have been presented that may explain how the fetus is tolerated. The first is that the fetus occupies a portion of the body that is protected by a non-immunological barrier, the uterus, which the immune system does not routinely patrol. The second is that the fetus itself likely promotes local immunosuppression in the mother, perhaps by a process of active nutrient depletion (see malnutrition). A more modern explanation for this induction of tolerance is that specific glycoproteins expressed in the uterus during pregnancy suppress the uterine immune response (see eu-FEDS).

Because they have had no prior exposure to microbes, newborn infants are particularly vulnerable to infection. However, the mother provides her baby several layers of protection against infection. In utero, maternal IgG is transported directly across the placenta, so that at birth, human babies have high levels of antibodies, with the same range of antigen specificities as their mother. Further, breast milk contains antibodies that are transferred to the gut of the infant, protecting against bacterial infections, until the newborn can synthesize its own antibodies.

Disorders of the human immune system

The immune system is a remarkably effective structure that incorporates specificity, induciblity and adaptation. That being said, failures of host defense do occur. These disorders fall into two broad categories: immunodeficiencies and autoimmunity/hypersensitivities.

Immunodeficiencies

Main article: immunodeficiency

Immunodeficiencies occur when one or more of the components of the immune system is defective.

• Nutrition is a critical determinant of immune system function and malnutrition the most common cause of immunodeficiency worldwide. Diets lacking sufficient protein sources are associated with a significant impairment of cell-mediated immunity, phagocyte function, the complement system, IgA antibody concentrations, and cytokine production. Deficiency of single nutrients such as zinc; selenium; iron; copper; vitamins A, C, E, and B-6; and folic acid (vitamin B-9) also results in inhibition of immune responses.
• Obesity, Alcohol and Drug abuse also contribute to poor immune function.
• The ability of the immune system to respond to pathogens is diminished in both the young and elderly. In fact, immune response to immunization begins to decline at around age 50.

• In developed countries, inherited (or 'congenital') and 'acquired' forms of immunodeficiencies are more common. Chronic granulomatous disease, in which phagocytes have trouble destroying pathogens, is an example of a congenital immunodeficiency. AIDS "Acquired Immune Deficiency Syndrome" and some types of cancer are examples of acquired immunodeficiency.

Autoimmunity and Hypersensitivity

Main articles: autoimmunity and hypersensitivity

Overactive immune responses comprise the other end of the immune dysfunction spectrum, particularly the autoimmune disorders. In this situation, the immune system fails to properly distinguish between self and non-self, and attacks a part of the host. Even under normal circumstances, many T cells and antibodies react with “self” peptides. One of the functions of specialized cells located in the thymus and bone marrow is to present the young lymphocytes with self antigens that might be produced throughout the body, and in an effort to reduce the potential for autoimmunity to develop, to eliminate those T-cells that react strongly with self-antigens.

Other examples of overzealous immune responses in disease include hypersensitivities, such as allergies and asthma.

Manipulation of the immune response

The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy and transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system.

Immunosupression

Main article: Immunosuppression

Immunosuppression (suppression of the immune system) is often used to control autoimmune disorders or inflammation when excessive tissue damage occurs, and to prevent transplant rejection after an organ transplant.

The drugs most commonly used to negatively regulate the immune system are anti-inflammatory drugs, which control the effects of inflammation. The corticosteroids are the most powerful of these drugs, however the use of these drugs must be tightly controlled as they can have many toxic side-effects. Therefore, anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs. Cytotoxic drugs inhibit the immune response by killing dividing cells. However, the cell killing induced by these drugs is indiscriminate and other organ systems may be affected. Immunosuppressive drugs act by inhibiting the ability of T-cells to respond to signals correctly. These drugs are usually less harmful but affect all T-cells regardless of antigen specificity, and are generally more expensive than the cytotoxic drugs.

Immunization

Main article: Immunization

Historically, infectious disease has been the leading cause of death in the human population. Over the last century however, two important factors have been developed to combat the spread of infectious diseases; sanitation and [[immunization. Immunization (commonly referred to as vaccination) is the deliberate induction of an immune response, and represents the single most effective manipulation of the immune system mankind has developed. Immunizations are so successful because they utilize the immune system's natural specificity as well as its inducibility.

The principle behind immunization is to introduce an antigen, derived from a disease causing organism, that stimulates the immune system to develop protective immunity against that organism, but which does not itself cause the pathogenic effects of that organism. An antigen (short for antibody generator), is defined as any substance that binds to a specific antibody and elicits an adaptive immune response.

Most viral vaccines are based on live attenuated viruses, while many bacterial vaccines are based on the acellular components of a micro-organism, including harmless components of the toxins that it produces. Many of the antigens derived from acellular vaccines do not strongly induce an adaptive immune response, and most bacterial vaccines require the addition of substances, known as adjuvants, which enhance the immunogenicity of the vaccine by activating the antigen presenting cells of the innate immune system.

See also

• Antigenic determinant
• Epitope
• Hapten
• Apoptosis
• Clonal selection
• Immunostimulator
• Immunosuppression
• Immunotherapy
• Monoclonal antibodies
• Polyclonal antibody
• Eu-FEDS

Host defense in non-mammalian species

• Antimicrobial peptides are an evolutionarily conserved component of the innate immune response and are found among all classes of life.
• Pattern recognition receptors are proteins used by organisms to identify molecules associated with microbial pathogens.
• Toll-like receptors are a major class of pattern recognition receptor.
• The Complement system is a biochemical cascade of the immune system that helps clear pathogens from an organism.

References and further reading