immune system: Definition from Answers.com

Concept

The immune system is a network of organs, glands, and tissues that protects the body from foreign substances. These substances include bacteria, viruses, and other infection-causing parasites and pathogens. Usually, the immune system is extremely effective in performing its work of defending the body, but sometimes an error occurs in this highly complex system, and it can lead to terrible mistakes. The result can be an allergic reaction, which can be as simple as a case of the sniffles and as serious as a fatal condition. Or the error can manifest as an autoimmune disorder, such as lupus, in which the body rejects its own constituents as foreign invaders.

How It Works

The Immune System in General

The human body is under near constant attack from pathogens, or disease-carrying parasites, of the type discussed in Infection, Infectious Diseases, and Parasites and Parasitology. No human would live very long without the immune system, which includes two levels or layers of protection, the nonspecific and the specific defenses. The nonspecific defenses, including the skin and mucous membranes, serve as a first defensive line for preventing pathogens from entering the body. The specific defenses are activated when these microorganisms get past the nonspecific defenses and invade the body.

For the immune system to work properly, two things must happen: first, the body must recognize that it has been invaded, either by pathogens or toxins or by some other outside threat. Second, the immune response must be activated quickly, before the invaders destroy many body tissue cells. For the immune system to respond effectively, several conditions must be in place, including the proper interaction of non-specific and specific defenses. The nonspecific defenses on the skin do not identify the antigen (a substance capable of stimulating an immune response or reaction) that is attacking or potentially attacking the body; instead, these defenses simply react to the presence of what it identifies as something foreign. Often, the nonspecific defenses effectively destroy microorganisms, but if these defenses prove ineffective and the microorganisms manage to infect tissues, the specific defenses go into action. The specific defenses function by detecting the antigen in question and mounting a response that targets it for destruction.

The Major Histocompatibility Complex

How does the specific system "know" what is foreign and what is part of the body? The cell membrane of every cell is studded with various proteins, which together are known as the major histocompatibility complex, or MHC. The MHC is a kind of pass code, since all cells in the body must possess an identical pattern so that the body will identify those cells as belonging to the "self." An invading microorganism, such as a bacterium, does not have the same MHC, and when the immune system encounters it, it alerts the body that it has been invaded by a foreign cell.

Every person has his or her nearly unique MHC, and the response of the immune system to foreign MHC can pose a problem where organ transplants are concerned. Because the immune system interprets the transplanted organ, with its foreign MHC, as an invader, the body may reject the transplant, and therefore organ recipients usually take immunosuppressant drugs to quell the immune response. Furthermore, doctors often attempt transplants only between close relatives, who are likely to have genetically similar MHCs, or try to find organs that match in the major histocompatibility antigens.

Parts of the Immune System

The organs of the immune system include the lymphatic vessels, lymph nodes, tonsils, thymus, Peyer's patch, and spleen. Each of these organs either produces the cells that participate in the immune response or serves as a site for immune function. Lymphocytes, a type of white blood cell, are concentrated in the lymph nodes, which are masses of tissue that act as filters for blood at various places throughout the body-most notably the neck, under the arms, and in the groin. As the lymph (white blood cells plus plasma) filters through the lymph nodes, foreign cells are detected and overpowered.

The tonsils, located at the back of the throat and under the tongue, contain large numbers of lymphocytes and filter out potentially harmful bacteria that might enter the body via the nose and mouth. Peyer's patches, scattered throughout the small intestine and appendix, are lymphatic tissues that perform this same function in the digestive system. The thymus gland, located within the upper chest region, is another site of lymphocyte production, though it is most active during childhood. The thymus gland continues to grow until puberty, protecting a child through the critical years of early development, but in adulthood it shrinks almost to the point of vanishing.

Marrow, the soft tissue at the core of bones, is a key producer both of lymphocytes and of another component of blood, the hemoglobin-containing red blood cells. Because of its critical role in the immune system, it is a very serious decision to allow marrow to be extracted (itself an extremely serious operation, of course) for use in a cancer treatment, as described in Noninfectious Diseases. The spleen, in addition to containing lymphatic tissue and producing lymphocytes, acts as a reservoir for blood and destroys worn-out red blood cells.

Antibodies, B Cells, and T Cells

The functioning of the immune system also calls into play a wide array of substances, most notably antibodies and the two significant varieties of lymphocyte: B cells and T cells. Antibodies, the most well known of the three, are proteins in the human immune system that help fight foreign invaders. B cells (B lymphocytes) are a type of white blood cell that gives rise to antibodies, whereas T cells (T lymphocytes), are a type of white blood cell that plays an important role in the immune response. T cells are a key component in the cell-mediated response, the specific immune response that utilizes T cells to neutralize cells that have been infected with viruses and certain bacteria. There are three types of T cells: cytotoxic, helper, and suppressor T cells. Cytotoxic T cells destroy virus-infected cells in the cell-mediated immune response, whereas helper T cells play a part in activating both the antibody and the cell-mediated immune responses. Suppressor T cells deactivate T cells and B cells when needed, and thus prevent the immune response from becoming too intense.

The intricacies of the immune system's functioning are far beyond the scope of this essay. The reader interested in a more in-depth review of the substances, organs, glands, and processes is encouraged to seek clarification from a textbook. On the other hand, a very basic and nontechnical example of how the body resists infection can help clarify, in general terms, how the immune system does its work.

Real-Life Applications

Protecting the Body

As discussed in Infection, not all bacteria are bad; in fact, many are helpful or even essential to humans. When the word bacteria is mentioned, however, most of us think of the "bad" bacteria, which is understandable, since there are so many of them and their effects can be so dramatic. Suppose such a bacterium enters the body, which is an easy situation to imagine—it happens all the time. Indeed, even as you are reading these words, literally trillions of bacteria the world over are attempting to invade human bodies, including your own. Their chances of success are determined by the immune system and response.

Most of the time, the skin provides us with sufficient protection from invaders, but if the skin is broken, it creates a pathway for invasion. Even a minor cut on a finger can serve as an opening for a microorganism that, once inside the body, will flourish in the body's warm, blood-washed interior. When it is established, the bacterium begins to divide rapidly, but already the specific immune system has begun to mount its resistance, and sometimes evidence of the battle can be seen on the outside—for example, in the form of a red, pus-exuding welt. In the bloodstream, lymphocytes engulf bacteria and carry them toward the lymph nodes. For this reason, when the body is under attack, it begins producing white blood cells at an accelerated rate, and for this reason doctors sometimes measure a patient's white blood cell count. If the number is high, the physician knows that an infection is active somewhere in the patient's body.

Killer blood cells, known by the generic name phagocyte, engulf the bacteria and digest-them, but even as this is occurring, the rapid reproduction of the bacterium provides a challenge to the immune system. If the infectious agent reproduces at a rate beyond the control of the immune system, the physician may provide help in the form of an antibiotic. Alternatively, he or she may lance (cut open) a superficial infection to allow it to drain and to provide access for an antiseptic agent. If the bacterial invasion is minor, the immune system soon dispatches the invader, and the system returns to normal.

Often, some of the white blood cells form antibodies against such invading bacteria, so that the immune system will be better armed to combat any future invasions by the same microorganism. The white blood cell count returns to its normal level, but still with the capability of mobilizing the immune defense on short notice. It is this response that is the basis for inoculations against certain infections, a topic discussed in Immunity. Sometimes, however, something goes wrong in the production of antibodies, and instead of properly protecting the body against invaders, the immune system creates an allergy.

Allergies

An allergy is a change in bodily reactivity to an antigen as a result of a first exposure. Allergies bring about an exaggerated reaction to substances or physical states that would normally have little significant effect on a healthy person. Although the immune system behaves as if it is fighting off a pathogen, in fact, it is launching a complex series of reactions against an irritant. The irritant, or allergen, may well be an otherwise innocuous substance that hardly bothers a person without the allergy. It could even be something that other people enjoy—for example, peanuts or bananas—or at least something, such as animal hair, that does not typically cause people undue discomfort. Allergies also may involve a substance, such as venom from a bee sting, that most people consider far from pleasant but which does not pose a serious threat to someone who is not allergic to it.

In extreme cases of allergic reaction, the situation that follows exposure to an allergen truly is one of life and death. The immune response may be accompanied by a number of stressful symptoms, ranging from mild reactions, such as hives (the formation of red, swollen areas on the surface of the skin) to a life-threatening situation known as anaphylactic shock. The latter, a condition characterized by a sudden drop in blood pressure and difficulty in breathing, can be accompanied by acute skin irritation in the form of angry red boils all over the body. Collapse or coma can ensue and may result in death.

Causes of Allergy

Pollens from grasses, trees, and weeds produce such allergic reactions as sneezing, runny nose, swollen nasal tissues, headaches, blocked sinuses, and watery, irritated eyes. Of the 46 million allergy sufferers in the United States, about 25 million have this form of allergy, known to scientists as rhinitis but to the populace as hay fever. Other common allergens are dust and dust mites, pet hair and fur, insect bites, certain foods or drugs, and skin contact with specific chemical substances. About 12 million Americans are allergic to a variety of chemicals.

Some people are allergic to a wide range of substances, while others are affected by only a few or none. Why the difference? The reasons can be found in the makeup of an individual's immune system, which may produce several chemical agents that cause allergic reactions. The main immune system substances responsible for the symptoms of allergy are the histamines that are produced after exposure to an allergen. When an allergen first enters the body, the lymphocytes make what are known as E antibodies. These antibodies attach to mast cells, large cells that are found in connective tissue and contain histamines. The histamines are chemicals released by basophils, a type of lymphocyte, during the inflammatory response.

The second time a given allergen enters the body of a person who has an allergy, it becomes attached to the E antibodies. They stimulate the mast cells to discharge their histamines and other anti-allergen substances. One type of histamine travels to various receptor sites in the nasal passages, respiratory system, and skin, dilating smaller blood vessels and constricting airways. The results include some of the reactions associated with allergies, for instance, sneezing or the formation of hives. Another type of histamine constricts the larger blood vessels and travels to the receptor sites found in the salivary and tear glands and in the stomach's mucosal lining. These histamines stimulate the release of stomach acid, thus creating a stomach ulcer condition.

Treatments

There are many treatments for allergy, including (obviously) avoidance of the substance to which the patient is allergic. Among these treatments are the administration of antihistamines, which either inhibit the production of histamine or block histamines at receptor sites. After the administration of anti-histamines, E antibody receptor sites on the mast cells are blocked, thereby preventing the release of the histamines that cause the allergic reactions. The allergens are still there, but the body's allergic reactions are suspended for the period of time that the antihistamines are active. Antihistamines, sold both in prescription and over-the-counter forms, also constrict the smaller blood vessels and capillaries, thereby removing excess fluids. Decongestants can bring relief as well, but they can be used for only a short time, since their continued use can irritate and intensify the allergic reaction.

In cases of extreme allergic reaction leading to anaphylactic shock, the patient may require an injection of epinephrine (also sometimes called adrenaline), a hormone that the body produces for responding to situations of fear and danger. In the case of anaphylactic shock, which involves such severe constriction of the breathing passages that the patient runs a risk of suffocation, epinephrine causes the passages to open, making it possible to breathe again. It also constricts the blood vessels, increasing the pressure and making the blood move more rapidly throughout the body. The body's own supply of epinephrine is not enough to counteract anaphylactic shock, however, and therefore a person experiencing that condition must receive an emergency injection containing many times the amount of the hormone naturally supplied by the body. It may be administered at a hospital, though doctors usually advise people with severe allergies to keep an emergency supply on hand.

Autoimmune Disorders

Allergies are one example of an immune system gone awry, and though they can be fatal, they typically are a reaction to only one or two substances. An autoimmune disorder, on the other hand, is an entirely different class of phenomenon: it a condition in which a person's body actually rejects itself. This condition comes about when the ability of the immune system to read MHCs becomes scrambled, such that it fails to recognize cells from within the body and instead rejects them as though they came from outside. As a result, the body sets in motion the same destructive operation against its own cells that it normally would carry out against bacteria, viruses, and other such harmful invaders.

The reasons why the immune system becomes dysfunctional are not well understood, but most researchers agree that a combination of genetic, environmental, and hormonal factors plays into autoimmunity. They also speculate that certain mechanisms may trigger it. First, a substance normally restricted to one part of the body, and therefore not usually exposed to the immune system, is released into other areas, where it is attacked. Second, the immune system may mistake a component of the body for a similar foreign component. Third, cells of the body may be altered in some way, by drugs, infection, or some other environmental factor, so that they are no longer recognizable as "self" to the immune system. Fourth, the immune system itself may be dysfunctional, for instance, because of a genetic mutation.

Some Autoimmune Diseases

Examples of autoimmune disorders include lupus, rheumatoid arthritis, autoimmune hemolytic anemia, pernicious anemia, and type 1 diabetes mellitus. (The last of these diseases is discussed in Noninfectious Diseases.) Lupus, or systemic lupus erythematosus, is seen mainly in young and middle-aged women, and its symptoms include fever, chills, fatigue, weight loss, skin rashes (especially a "butterfly" rash on the face), patchy hair loss, sores in the mouth or nose, enlargement of the lymph nodes, stomach problems, and irregular menstrual cycles. Lupus also may induce problems in the cardiopulmonary, urinary, and central nervous systems and can cause seizures, depression, and psychosis.

Rheumatoid arthritis, as its name suggests, is a type of both rheumatism and arthritis, which are general names for diseases associated with inflammation of connective tissue. Rheumatoid arthritis occurs when the immune system attacks and destroys the tissues that line bone joints and cartilage. The disease can affect any part of the body, although some joints may be more susceptible than others are. As it progresses, joint function diminishes sharply, and deformities arise.

Like rheumatism and arthritis, anemia is a general term for several conditions. Forms of it are marked either by a lack of red blood cells (hemoglobin) or by a shortage in total blood volume, and these deficiencies can produce effects that range from lethargy or sluggishness to death. Autoimmune hemolytic anemia occurs when the body makes antibodies that coat red blood cells. Patients have been known to experience a variety of symptoms, including jaundice, characterized by a yellowish coloration, before dying—sometimes just a few weeks after showing the first signs of the disease.

Pernicious anemia was so named at a time when it, too, was almost always fatal (pernicious means "deadly"), though treatments developed in the twentieth century have changed that situation. A disorder in which the immune system attacks the lining of the stomach in such a way that the body cannot metabolize vitamin B₁₂ (see Vitamins), pernicious anemia manifests symptoms that include weakness, sore tongue, bleeding gums, and tingling in the extremities. Because the disease leads to a decrease in stomach acid, nausea, vomiting, loss of appetite, weight loss, diarrhea, and constipation are also possible. Furthermore, since B₁₂ is essential to the functioning of the nervous system, a deficiency can result in a host of neurological problems, including weakness, lack of coordination, blurred vision, loss of fine motor skills, impaired sense of taste, ringing in the ears, and loss of bladder control.

Where to Learn More

All About Allergies. About.com (Web site). <http://gened.emc.maricopa.edu/bio/bio181/BIOBK/BioBookIMMUN.html>.

Clark, William R. At War Within: The Double-Edged Sword of Immunity. New York: Oxford University Press, 1995.

Davis, Joel. Defending the Body: Unraveling the Mysteries of Immunology. New York: Atheneum, 1989.

Deane, Peter M. G., and Robert H. Schwartz. Coping with Allergies. New York: Rosen Publishing Group, 1999.

Focus on Allergies (Web site). <http://www.focusonallergies.com/script/main/hp.asp>.

"Infection and Immunity." University of Leicester Microbiology and Immunology (Web site). <http://www-micro.msb.le.ac.uk/MBChB/MBChB.html>.

Joneja, Janice M. Vickerstaff, and Leonard Bielory. Understanding Allergy, Sensitivity, and Immunity: A Comprehensive Guide. New Brunswick, NJ: Rutgers University Press, 1990.

The Vaccine Page: Vaccine News and Database (Web site). <http://vaccines.org/>.

Vaccine Safety (Web site). <http://www.vaccines.net/>.

Young, Stuart H., Bruce S. Dobozin, and MargaretMiner. Allergies: The Complete Guide to Diagnosis, Treatment and Daily Management. New York: Plume, 1999.

A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange).

An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumour cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own healthy cells and tissues in order to function properly. Detection is complicated as pathogens can evolve rapidly, producing adaptations that avoid the immune system and allow the pathogens to successfully infect their hosts.

To survive this challenge, multiple mechanisms evolved that recognize and neutralize pathogens. Even simple unicellular organisms such as bacteria possess enzyme systems that protect against viral infections. Other basic immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants, fish, reptiles, and insects. These mechanisms include antimicrobial peptides called defensins, phagocytosis, and the complement system. Vertebrates such as humans have even more sophisticated defense mechanisms.^[1] The immune systems of vertebrates consist of many types of proteins, cells, organs, and tissues, which interact in an elaborate and dynamic network. As part of this more complex immune response, the human immune system adapts over time to recognize specific pathogens more efficiently. This adaptation process is referred to as "adaptive immunity" or "acquired immunity" and creates immunological memory. Immunological memory created from a primary response to a specific pathogen, provides an enhanced response to secondary encounters with that same, specific pathogen. This process of acquired immunity is the basis of vaccination.

Disorders in the immune system can result in disease. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. Immunodeficiency can either be the result of a genetic disease, such as severe combined immunodeficiency, or be produced by pharmaceuticals or an infection, such as the acquired immune deficiency syndrome (AIDS) that is caused by the retrovirus HIV. In contrast, autoimmune diseases result from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimoto's Thyroiditis, rheumatoid arthritis, diabetes mellitus type 1 and lupus erythematosus. Immunology covers the study of all aspects of the immune system which has significant relevance to human health and diseases. Further investigation in this field is expected to play a serious role in promotion of health and treatment of diseases.

Layered defense

The immune system protects organisms from infection with layered defenses of increasing specificity. Most simply, physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals.^[2] However, if pathogens successfully evade the innate response, vertebrates possess a third layer of protection, the adaptive immune system, which is activated by the innate response. Here the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.^[3]

**Components of the immune system**
Innate immune system	Adaptive immune system
Response is non-specific	Pathogen and antigen specific response
Exposure leads to immediate maximal response	Lag time between exposure and maximal response
Cell-mediated and humoral components	Cell-mediated and humoral components
No immunological memory	Exposure leads to immunological memory
Found in nearly all forms of life	Found only in jawed vertebrates

Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are those components of an organism's body that can be distinguished from foreign substances by the immune system.^[4] Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (short for antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response.^[5]

Surface barriers

Several barriers protect organisms from infection, including mechanical, chemical and biological barriers. The waxy cuticle of many leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin are examples of the mechanical barriers that are the first line of defense against infection.^[5] However, as organisms cannot be completely sealed against their environments, other systems act to protect body openings such as the lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms.^[6]

Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins.^[7] Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antibacterials.^[8]^[9] Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens.^[10]^[11] In the stomach, gastric acid and proteases serve as powerful chemical defenses against ingested pathogens.

Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, by changing the conditions in their environment, such as pH or available iron.^[12] This reduces the probability that pathogens will be able to reach sufficient numbers to cause illness. However, since most antibiotics non-specifically target bacteria and do not affect fungi, oral antibiotics can lead to an “overgrowth” of fungi and cause conditions such as a vaginal candidiasis (a yeast infection).^[13] There is good evidence that re-introduction of probiotic flora, such as pure cultures of the lactobacilli normally found in unpasteurized yoghurt, helps restore a healthy balance of microbial populations in intestinal infections in children and encouraging preliminary data in studies on bacterial gastroenteritis, inflammatory bowel diseases, urinary tract infection and post-surgical infections.^[14]^[15]^[16]

Innate

For more details on this topic, see Innate immune system.

Microorganisms or toxins that successfully enter an organism will encounter the cells and mechanisms of the innate immune system. The innate response is usually triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms,^[17] or when damaged, injured or stressed cells send out alarm signals, many of which (but not all) are recognized by the same receptors as those that recognize pathogens.^[18] Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way.^[5] This system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms.^[2]

Humoral and chemical barriers

Inflammation

For more details on this topic, see Inflammation.

Inflammation is one of the first responses of the immune system to infection.^[19] The symptoms of inflammation are redness and swelling, which are caused by increased blood flow into a tissue. Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes).^[20]^[21] Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell.^[22] Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens.^[23]

Complement system

For more details on this topic, see Complement system.

The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to “complement” the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response.^[24]^[25] Many species have complement systems, including non-mammals like plants, fish, and some invertebrates.^[26]

In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response.^[27] The speed of the response is a result of signal amplification that occurs following sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback.^[28] The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane.^[24]

Cellular barriers

A scanning electron microscope 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.

Leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system.^[5] The innate leukocytes include the phagocytes (macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms.^[26] Innate cells are also important mediators in the activation of the adaptive immune system.^[3]

Phagocytosis is an important feature of cellular innate immunity performed by cells called 'phagocytes' that engulf, or eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines.^[5] Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome.^[29]^[30] Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism.^[31] Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.^[32]

Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens.^[33] Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, normally representing 50% to 60% of the total circulating leukocytes.^[34] During the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils migrate toward the site of inflammation in a process called chemotaxis, and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce a wide array of chemicals including enzymes, complement proteins, and regulatory factors such as interleukin 1.^[35] Macrophages also act as scavengers, ridding the body of worn-out cells and other debris, and as antigen-presenting cells that activate the adaptive immune system.^[3]

Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines.^[36] They are named for their resemblance to neuronal dendrites, as both have many spine-like projections, but dendritic cells are in no way connected to the nervous system. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigen to T cells, one of the key cell types of the adaptive immune system.^[36]

Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response.^[37] They are most often associated with allergy and anaphylaxis.^[34] Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma.^[38] Natural killer (NK cells) cells are leukocytes that attack and destroy tumor cells, or cells that have been infected by viruses.^[39]

Adaptive

For more details on this topic, see Adaptive immune system.

The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen.^[40] The adaptive immune response is antigen-specific and requires the recognition of specific “non-self” antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.

Lymphocytes

The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow.^[26] B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response.

Association of a T cell with MHC class I or MHC class II, and antigen (in red)

Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a “non-self” target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a “self” receptor called a major histocompatibility complex (MHC) molecule. There are two major subtypes of T cells: the killer T cell and the helper T cell. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors.^[41]

In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes whole pathogens without any need for antigen processing. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture.^[26]

Killer T cells

Killer T cells directly attack other cells carrying foreign or abnormal antigens on their surfaces.^[42]

Killer T cell are a sub-group of T cells that kill cells infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional.^[43] As with B cells, each type of T cell recognises a different antigen. Killer T cells are activated when their T cell receptor (TCR) binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T cell contacts such cells, it releases cytotoxins, such as perforin, which form pores in the target cell's plasma membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis.^[44] T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T cells (see below).^[44]

Helper T cells

Function of T helper cells: Antigen presenting cells (APCs) present antigen on their Class II MHC molecules (MHC2). Helper T cells recognize these, with the help of their expression of CD4 co-receptor (CD4+). The activation of a resting helper T cell causes it to release cytokines and other stimulatory signals (green arrows) that stimulate the activity of macrophages, killer T cells and B cells, the latter producing antibodies. The stimulation of B cells and macrophages succeeds a proliferation of T helper cells.

Helper T cells regulate both the innate and adaptive immune responses and help determine which types of immune responses the body will make to a particular pathogen.^[45]^[46] These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks.

Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex is also recognized by the helper cell's CD4 co-receptor, which recruits molecules inside the T cell (e.g. Lck) that are responsible for the T cell's activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T cell must be bound by an MHC:antigen in order to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell.^[47] The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells.^[5] In addition, helper T cell activation causes an upregulation of molecules expressed on the T cell's surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B cells.^[48]

γδ T cells

γδ T cells possess an alternative T cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells are not fully understood. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T cells, γδ T cells straddle the border between innate and adaptive immunity.^[49] On one hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells in epithelia will respond to stressed epithelial cells.^[50]

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.^[42]

B lymphocytes and antibodies

A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen.^[51] This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell.^[52] As the activated B cell then begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.^[53]

Alternative adaptive immune system

Although the classical molecules of the adaptive immune system (e.g. antibodies and T cell receptors) exist only in jawed vertebrates, a distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals possess a large array of molecules called variable lymphocyte receptors (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity.^[54]

Immunological memory

For more details on this topic, see Immunity (medical).

When B cells and T cells are activated and begin to replicate, some of their offspring will become long-lived memory cells. Throughout the lifetime of an animal, these memory cells will remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can either be in the form of passive short-term memory or active long-term memory.

Passive memory

Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly across the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother.^[55] Breast milk or colostrum also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies.^[56] This is passive immunity because the fetus does not actually make any memory cells or antibodies—it only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In medicine, protective passive immunity can also be transferred artificially from one individual to another via antibody-rich serum.^[57]

The time-course of an immune response begins with the initial pathogen encounter, (or initial vaccination) and leads to the formation and maintenance of active immunological memory.

Active memory and immunization

Long-term active memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through vaccination. The principle behind vaccination (also called immunization) is to introduce an antigen from a pathogen in order to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism.^[5] This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed.^[26]^[58]

Most viral vaccines are based on live attenuated viruses, while many bacterial vaccines are based on acellular components of micro-organisms, including harmless toxin components.^[5] Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional adjuvants that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity.^[59]

Disorders of human immunity

The immune system is a remarkably effective structure that incorporates specificity, inducibility and adaptation. Failures of host defense do occur, however, and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities.

Immunodeficiencies

For more details on this topic, see Immunodeficiency.

Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence.^[60]^[61] In developed countries, obesity, alcoholism, and drug use are common causes of poor immune function.^[61] However, malnutrition is the most common cause of immunodeficiency in developing countries.^[61] Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Deficiency of single nutrients such as iron; copper; zinc; selenium; vitamins A, C, E, and B₆; and folic acid (vitamin B₉) also reduces immune responses.^[61] Additionally, the loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection.^[62]

Immunodeficiencies can also be inherited or 'acquired'.^[5] Chronic granulomatous disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. AIDS and some types of cancer cause acquired immunodeficiency.^[63]^[64]

Autoimmunity

For more details on this topic, see Autoimmunity.

Overactive immune responses comprise the other end of immune dysfunction, particularly the autoimmune disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with “self” peptides.^[65] One of the functions of specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity.^[51]

Hypersensitivity

For more details on this topic, see Hypersensitivity.

Hypersensitivity is an immune response that damages the body's own tissues. They are divided into four classes (Type I – IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by IgE released from mast cells and basophils.^[66] Type II hypersensitivity occurs when antibodies bind to antigens on the patient's own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies.^[66] Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions.^[66] Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis (poison ivy). These reactions are mediated by T cells, monocytes, and macrophages.^[66]

Other mechanisms

For more details on this topic, see Innate immune system#Other forms of innate immunity.

It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not generate lymphocytes or an antibody-based humoral response.^[1] Many species, however, utilize mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the structurally most simple forms of life, with bacteria using a unique defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages.^[67] Prokaryotes also possess acquired immunity, through a system that uses CRISPR sequences to retain fragments of the genomes of phage that they have come into contact with in the past, which allows them to block virus replication through a form of RNA interference.^[68]^[69]

Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with pathogens. Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune response found in all animals and plants, and represent the main form of invertebrate systemic immunity.^[1] The complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to viruses.^[70]

Unlike animals, plants lack phagocytic cells, and most plant immune responses involve systemic chemical signals that are sent through a plant.^[71] When a part of a plant becomes infected, the plant produces a localized hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the disease to other parts of the plant. Systemic acquired resistance (SAR) is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent.^[71] RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication.^[72]

Tumor immunology

Further information: Cancer immunology

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. Immunotherapy for the treatment of cancer is an active area of medical research.^[73]

Another important role of the immune system is to identify and eliminate tumors. The transformed cells of tumors express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources;^[74] some are derived from oncogenic viruses like human papillomavirus, which causes cervical cancer,^[75] while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor cells. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (e.g. melanocytes) into tumors called melanomas.^[76]^[77] A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes.^[74]^[78]^[79]

The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells.^[77]^[80] Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal.^[81] NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors.^[82] Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system.^[78]

Clearly, some tumors evade the immune system and go on to become cancers.^[83] Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells.^[81] Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes.^[84] In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells.^[83]

Paradoxically, macrophages can promote tumor growth ^[85] when tumor cells send out cytokines that attract macrophages which then generate cytokines and growth factors that nurture tumor development. In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks metastasis and thereby assists spread of cancer cells.

Physiological regulation

Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive^[86] and innate immune responses.^[87] Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By contrast, male sex hormones such as testosterone seem to be immunosuppressive.^[88] Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D.^[89]^[90] It is conjectured that a progressive decline in hormone levels with age is partially responsible for weakened immune responses in aging individuals.^[91] Conversely, some hormones are regulated by the immune system, notably thyroid hormone activity.^[92]

Sleep

The immune system is enhanced by sleep and rest,^[93] and is impaired by stress.^[94] Sleep deprivation is detrimental to immune function, and sleep can be considered a vital part of the immune system. Viewed in this light, decreases in the length and quality of sleep in the population have far-reaching public health implications.^[95] Complex feedback loops exist between the sleep cycle and immune response: acute infection causes changes in the sleep cycle, including an increase in slow-wave sleep relative to REM sleep.^[96] Cytokines, a class of peptides, appear to be one of the main mechanisms through which the immune system and sleep cycle interact, as cytokines are produced by the immune system in response to infection, and also play a role in the normal sleep cycle.^[97]

Nutrition and diet

The functioning of the immune system, like most systems in the body, is dependent on proper nutrition. It has been long known that severe malnutrition leads to immunodeficiency. Overnutrition is also associated with diseases such as diabetes and obesity which are known to affect immune function. More moderate malnutrition, as well as certain specific trace mineral and nutrient deficiencies, can also compromise the immune response.^[98]

Specific foods may also affect the immune system; for example, fresh fruits, vegetables, and foods rich in certain fatty acids may foster a healthy immune system.^[99] Likewise, fetal undernourishment can cause a lifelong impairment of the immune system.^[100] In traditional medicine, some herbs are believed to stimulate the immune system, such as echinacea, licorice, ginseng, astragalus, sage, garlic, elderberry, and hyssop, as well as honey.

Medicinal mushrooms like Shiitake,^[101] Lingzhi mushrooms,^[102]^[103], the Turkey tail mushroom,^[104] Agaricus blazei,^[105] and Maitake^[106] have shown evidence of immune system up-regulation both in vitro and in vivo. An isolated compound from Shiitake, known as Active Hexose Correlated Compound^[107]^[108]^[109] has also shown evidence of being able to up-regulate certain aspects of the immune system. Research suggests the compounds in medicinal mushrooms most responsible for up-regulating the immune system, are a diverse collection of polysaccharides, particularly beta-glucans, and to a lesser extent, alpha-glucans. Beta-glucans are currently known as "biological response modifiers", and their ability to activate the immune system is well documented. Specifically, beta-glucans stimulate the innate branch of the immune system. Research has shown beta-glucans have the ability to stimulate macrophage,^[110] NK cells,^[111] T cells,^[112] and immune system cytokines. Research has also shown polysaccharides present in medicinal mushrooms may enhance dendritic cell function.^[113] The mechanisms in which beta-glucans stimulate the immune system is only partially understood. One mechanism in which beta-glucans are able to activate the immune system, is by interacting with the Macrophage-1 antigen (CD18) receptor on immune cells.^[114] Other human receptors have been identified as being able to receive signals from beta-glucans such as Toll-like receptor 2,^[115] Dectin-1, lactosylceramide, and scavenger receptors.^[116]

Studies have suggested that such herbs can indeed stimulate the immune system,^[117] although their mode of action is complex and difficult to characterize.

Manipulation in medicine

The immunosuppressive drug dexamethasone

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 (see immunization). Immunosuppressive drugs are used to control autoimmune disorders or inflammation when excessive tissue damage occurs, and to prevent transplant rejection after an organ transplant.^[26]^[118]

Anti-inflammatory drugs are often used to control the effects of inflammation. The glucocorticoids are the most powerful of these drugs; however, these drugs can have many undesirable side effects (e.g., central obesity, hyperglycemia, osteoporosis) and their use must be tightly controlled.^[119] Therefore, lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine. Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. However, the killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects.^[118] Immunosuppressive drugs such as ciclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways.^[120]

Larger drugs (>500 Da) can provoke a neutralizing immune response, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 Da). In some cases, the drug itself is not immunogenic, but may be co-administered with an immunogenic compound, as is sometimes the case for Taxol. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids;^[121] however, more recent developments rely on machine learning techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set.^[122] A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells.^[123] The emerging field of bioinformatics-based studies of immunogenicity is referred to as immunoinformatics.^[124]

Manipulation by pathogens

The success of any pathogen is dependent on its ability to elude host immune responses. Therefore, pathogens have developed several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system.^[125] Bacteria often overcome physical barriers by secreting enzymes that digest the barrier — for example, by using a type II secretion system.^[126] Alternatively, using a type III secretion system, they may insert a hollow tube into the host cell, providing a direct route for proteins to move from the pathogen to the host. These proteins are often used to shut down host defenses.^[127]

An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their host (also called intracellular pathogenesis). Here, a pathogen spends most of its life-cycle inside host cells, where it is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium falciparum) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement.^[128] Many pathogens secrete compounds that diminish or misdirect the host's immune response.^[125] Some bacteria form biofilms to protect themselves from the cells and proteins of the immune system. Such biofilms are present in many successful infections, e.g., the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis.^[129] Other bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus magnus (protein L).^[130]

The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is to rapidly change non-essential epitopes (amino acids and/or sugars) on the surface of the pathogen, while keeping essential epitopes concealed. This is called antigenic variation. An example is HIV, which mutates rapidly, so the proteins on its viral envelope that are essential for entry into its host target cell are constantly changing. These frequent changes in antigens may explain the failures of vaccines directed at this virus.^[131] The parasite Trypanosoma brucei uses a similar strategy, constantly switching one type of surface protein for another, allowing it to stay one step ahead of the antibody response.^[132] Masking antigens with host molecules is another common strategy for avoiding detection by the immune system. In HIV, the envelope that covers the viron is formed from the outermost membrane of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify them as "non-self" structures.^[133]

History of immunology

For more details on this topic, see History of immunology.

Paul Ehrlich

Immunology is a science that examines the structure and function of the immune system. It originates from medicine and early studies on the causes of immunity to disease. The earliest known mention of immunity was during the plague of Athens in 430 BC. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time.^[134] This observation of acquired immunity was later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease.^[135] Pasteur's theory was in direct opposition to contemporary theories of disease, such as the miasma theory. It was not until Robert Koch's 1891 proofs, for which he was awarded a Nobel Prize in 1905, that microorganisms were confirmed as the cause of infectious disease.^[136] Viruses were confirmed as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed.^[137]

Immunology made a great advance towards the end of the 19th century, through rapid developments, in the study of humoral immunity and cellular immunity.^[138] Particularly important was the work of Paul Ehrlich, who proposed the side-chain theory to explain the specificity of the antigen-antibody reaction; his contributions to the understanding of humoral immunity were recognized by the award of a Nobel Prize in 1908, which was jointly awarded to the founder of cellular immunology, Elie Metchnikoff.^[139]

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External links

Vaccine Research Center Information regarding preventative vaccine research studies
Immune System - from the University of Hartford
Immunobiology; Fifth Edition – Online version of the textbook by Charles Janeway (Advanced undergraduate/graduate level)
Immunology - BioMed Central (free content) scientific journal
The Inner Life of a Cell - Rendering of the inner functions of the human body
The Microbial World - Animal defenses against microbes - Chapter in on-line microbiology textbook
Microbiology and Immunology On-Line Textbook - from the University of South Carolina School of Medicine
Cell Biology of the Immune Response on-line lecture by Ira Mellman

Immune system / Immunology

Systems

Adaptive vs. Innate · Humoral vs. Cellular · Complement (Anaphylatoxins) · Intrinsic

Lymphoid

Antigens	Antigen (Superantigen, Allergen) · Hapten Epitope (Linear, Conformational)

Antibodies	Antibody (Monoclonal antibodies, Polyclonal antibodies, Autoantibody) · Polyclonal B cell response · Allotype · Isotype · Idiotype Immune complex

Immunity vs. tolerance	action: Immunity · Autoimmunity · Alloimmunity · Allergy · Inflammation · Cross-reactivity inaction: Tolerance (Central, Peripheral, Clonal anergy, Clonal deletion, Tolerance in pregnancy) · Immunodeficiency

Immunogenetics	Somatic hypermutation · V(D)J recombination · Junctional diversity · Immunoglobulin class switching · MHC/HLA

Immune cells/
White blood cells

Lymphoid: T cell · B cell · NK cell

Myeloid: Mast cell · Basophil · Eosinophil · Phagocytes (Neutrophil, Macrophage/Reticuloendothelial system)

Professional APCs: Dendritic cell · Macrophage · B cell

Substances

Cytokines · Opsonin · Cytolysin

Lymphopoiesis

Lymphoblast · Prolymphocyte

Other

Diagnostic immunology · Plant disease resistance

lymphocyte navs: cells/physio, immunodeficiency/immunoproliferative immunoglobulin/neoplasia, proc

Immune system: Lymphatic system (Lymph, Lymphocytes, Lymph vessels) (TA A13.1-2, GA 8)

Primary

Bone marrow · Thymus (Hassall's corpuscles)

Secondary

Spleen (process blood)	structural: Hilum · Trabeculae Red pulp (Cords of Billroth, Marginal zone) White pulp (Periarteriolar lymphoid sheaths, Germinal center) blood flow: Trabecular arteries · Trabecular veins

Lymph nodes (process extracellular fluid)	lymph flow: Afferent lymph vessels · Cortical sinuses · Medullary sinuses · Efferent lymph vessels T cells: High endothelial venules B cells: Primary follicle/Germinal center · Mantle zone · Marginal zone layers: Capsule/Trabeculae · Subcapsular sinus · Cortex · Paracortex · Medulla (Medullary cord) · Hilum

MALT (process mucosa)	GALT · Peyer's patches · Germinal center

lymphatic organ navs: anat, physio, lymphatic disease/splenic disease/thymus disorders/thymus neoplasia/vascular tumors, proc

v • d • e Human organ systems

Cardiovascular system · Endocrine system · Gastrointestinal tract (Digestion) · Immune system · Integumentary system · Lymphatic system · Muscular system · Musculoskeletal system · Nervous system · Reproductive system · Respiratory system · Skeletal system · Urinary system

Transmembrane receptors: immune receptors

Cytokine receptor

Type I	Interleukins (2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 21, 23, 27) CSF receptors (EPO, GM-CSF, G-CSF) GH · prolactin · Oncostatin M · Leukemia inhibitory factor common subunits (Common gamma chain, common beta chain, gp130)

Type II	Interleukins (10, 20, 22, 28) · interferon (-α/β, -γ)

Ig superfamily	CSF1 · C-kit · IL-1 · IL-18

TNF	CD27 · CD30 · CD40 · CD120 · Lymphotoxin β

Chemokines	IL-8 (α, β), CCR1,CXCR4

Other	IL-17 · TGF-beta (1, 2) · Thrombopoietin

Other endogenous

Fc receptor

Epsilon (ε)	FcεRI · FcεRII

Gamma (γ)	FcγRI · FcγRII · FcγRIII · Neonatal

Alpha (α)/mu (μ)	FcαRI · Fcα/μR

Lymphocyte homing receptor

CD44 · L-selectin · integrin (VLA-4, LFA-1)