immune system disorder

Introduction

       Disorders of the immune systemany of various failures in the body's defense mechanisms against infectious organisms (see table (Disorders of the immune system)). Disorders of immunity include immune deficiency diseases, such as AIDS, that arise because of a diminution of some aspect of the immune response. Other types of immune disorders, such as allergies (allergy) and autoimmune disorders, are caused when the body develops an inappropriate response to a substance—either to a normally harmless foreign substance found in the environment, in the case of allergies, or to a component of the body, in the case of autoimmune diseases. Lymphocytes (lymphocyte) (white blood cells of the immune system) can become cancerous and give rise to tumours (tumour) called leukemias (leukemia), lymphomas (lymphoma), and myelomas (multiple myeloma).

      This article discusses various immune deficiencies, allergies, autoimmune disorders, and lymphocyte cancers. For additional information on leukemias, lymphomas, and myelomas, see the article cancer. A discussion of how the immune system works to prevent disease is found in the article immune system.

Immune deficiencies

      Immune deficiency disorders result from defects that occur in immune mechanisms. The defects arise in the components of the immune system, such as the white blood cells involved in immune responses (T and B lymphocytes and scavenger cells) and the complement proteins, for a number of reasons. Some deficiencies are hereditary and result from genetic mutations that are passed from parent to child. Others are caused by developmental defects that occur in the womb. In some cases immune deficiencies result from damage inflicted by infectious agents. In others drugs used to treat certain conditions, or even the diseases themselves, can depress the immune system. Poor nutrition also can undermine the immune system.

Hereditary (heredity) and congenital deficiencies

      Immune deficiencies resulting from hereditary and congenital (congenital disorder) defects are rare, but they can affect all major aspects of the immune system. Luckily many of those conditions can be treated. In the rare hereditary disorder called X-linked infantile agammaglobulinemia, which affects only males, B lymphocytes are unable to secrete all classes of immunoglobulins. (An immunoglobulin is a type of protein, also called an antibody, that is produced by B cells in response to the presence of a foreign substance called an antigen.) The disease can be treated by periodic injections of large amounts of immunoglobulin G (IgG). The congenital, but not hereditary, T-cell deficiency disease called DiGeorge syndrome arises from a developmental defect occurring in the fetus that results in the defective development of the thymus. Consequently the infant has either no mature T cells or very few. In the most severe cases—i.e., when no thymus has developed—treatment of DiGeorge syndrome consists of transplantation of a fetal thymus into the infant. The group of disorders called severe combined immunodeficiency diseases result from a failure of precursor cells to differentiate into T or B cells. bone marrow transplantation can successfully treat some of those diseases. The immune disorder called chronic granulomatous disease results from an inherited defect that prevents phagocytic cells from producing enzymes needed to break down ingested pathogens. Treatments include administration of a wide spectrum of antibiotics.

Deficiencies caused by infection

      Damage to lymphocytes that is inflicted by viruses is common but usually transient. During infectious mononucleosis, for example, the Epstein-Barr virus infects B cells, causing them to express viral antigens. T cells that react against these antigens then attack the B cells, and a temporary deficiency in the production of new antibodies lasts until the overt viral infection has been overcome. Because antibodies already present in the blood are slowly broken down, failure to make new ones is important only if the infection persists for a long time, as it does occasionally. A much more serious viral infection is that caused by the human immunodeficiency virus (HIV), which is responsible for the fatal immune deficiency disease AIDS. HIV selectively infects helper T cells and prevents them from producing cytokines and from functioning in cell-mediated immunity. Persons with AIDS may be unable to overcome infections by a variety of microbes that are easily disposed of by persons uninfected with HIV. Severe infections by certain parasites, such as trypanosomes, also cause immune deficiency, as do some forms of cancer, but it is uncertain how that comes about. For example, Hodgkin disease, which attacks the lymphatic system, makes the patient more susceptible to infection.

Deficiencies caused by drug therapy

      In countries with advanced medical services, immune deficiency often results from the use of powerful drugs to treat cancers (cancer). The drugs work by inhibiting the multiplication of rapidly dividing cells. Although the drugs act selectively on cancer cells, they also can interfere with the generation and multiplication of cells involved in immune responses. Prolonged or intensive treatment with such drugs impairs immune responses to some degree. Although the immune impairment is reversible, the physician must seek a balance between intentional damage to the cancer cells and unintentional damage to the immune system.

      Medically induced suppression of the immune system also occurs when powerful drugs, which are designed to interfere with the development of T and B cells, are used to prevent the rejection of organ or bone marrow transplants or to damp down serious autoimmune responses. Although use of such drugs has greatly improved the success of transplants (transplant), it also leaves patients highly susceptible to microbial infections. Fortunately, most of those infections can be treated with antibiotics, but the immunosuppressive drugs have to be used with great care and for as short a period as possible.

Deficiencies caused by malnutrition

      In countries where the diet, especially that of growing children, is grossly deficient in protein, severe malnutrition ranks as an important cause of immune deficiency. Antibody responses and cell-mediated immunity are seriously impaired, probably because of atrophy of the thymus and the consequent deficiency of helper T cells. The impairment renders children particularly susceptible to measles and diarrheal diseases. Fortunately, the thymus and the rest of the immune system can recover completely if adequate nutrition is restored.

Allergies (allergy)

      The immune system recognizes and responds to almost any foreign molecule; it cannot discern between molecules that are characteristic of potentially infective agents and those that are not. In other words, an immune response can be induced by materials that have nothing to do with infection. The mechanisms brought into play, though beneficial for eliminating microbes, are not necessarily beneficial when otherwise innocuous substances are targeted. Furthermore, even initially protective mechanisms can cause secondary disorders when they operate on too great a scale or for a longer period than necessary, thereby damaging tissues remote from the infection. The terms allergy and hypersensitivity are commonly used to describe inappropriate immune responses that occur when an individual becomes sensitized to harmless substances. Allergic reactions do not as a rule cause symptoms to arise on the first exposure to an antigen. At the initial exposure reactive lymphocytes are generated that go into action only when the individual is reexposed to the antigen.

      The manifestations of a particular allergic reaction depend on which of the immune mechanisms predominates in the response. Based on this criterion, immunologists use the Gell-Coombs classification system to recognize four types of hypersensitivity reactions. Types I, II, and III involve antibody-mediated mechanisms and are of rapid onset. The type IV reaction stems from cell-mediated mechanisms and has a delayed onset. It should be noted that the categorization, though useful, is an oversimplification and that many diseases involve a combination of hypersensitivity reactions.

Type I hypersensitivity (atopy)

      Type I, also known as atopic or anaphylactic hypersensitivity, involves IgE antibody, mast cells, and basophils.

Sensitization, activation, and effector phases

      Type I hypersensitivity can be divided into three phases. The first is called the sensitization phase and occurs when the individual is first exposed to antigen. Exposure stimulates the production of IgE antibodies, which bind to mast cells (mast cell) and circulating basophils. The mast cells are found in tissues, often near blood vessels. The second phase is the activation phase, and it occurs when the individual is reexposed to the antigen. Reintroduction of the antigen causes IgE molecules to become cross-linked, which triggers the mast cells and basophils to release the contents of their granules into the surrounding fluids, initiating the third phase, called the effector phase, of the type I reaction. The effector phase includes all the body's complex reactions to the potent chemicals from the granules. The chemicals include histamine, which causes small blood vessels to dilate and smooth muscle in the bronchial tubes of the lungs to constrict; heparin, which prevents blood coagulation; enzymes that break down proteins; signaling agents that attract eosinophils and neutrophils; and a chemical that stimulates platelets to adhere to blood vessel walls and to release serotonin, which constricts arteries. In addition the stimulated mast cells make chemicals (prostaglandins (prostaglandin) and leukotrienes) that have potent local effects; they cause capillary blood vessels to leak, smooth muscles to contract, granulocytes to move more actively, and platelets to become sticky.

Type I allergic reactions

 The overall result of the type I reaction is an acute inflammation marked by local seepage of fluid from and dilation of the blood vessels, followed by ingress of granulocytes into the tissues. This inflammatory reaction can be a useful local protective mechanism. If, however, it is triggered by an otherwise innocuous antigen entering the eyes and nose, it results in swelling and redness of the linings of the eyelids and nasal passages, secretion of tears and mucus, and sneezing—the typical symptoms of hay fever. If the antigen penetrates the lungs, not only do the linings of the bronchial tubes become swollen and secrete mucus, but the muscle in their walls contracts and the tubes are narrowed, making breathing particularly difficult. These are the symptoms of acute asthma. If the antigen is injected beneath the skin—for example, by the sting of an insect or in the course of some medical procedure—the local reaction may be extensive. Called a wheal-and-flare reaction, it includes swelling, produced by the release of serum into the tissues (wheal), and redness of the skin, resulting from the dilation of blood vessels (flare). If the injected antigen enters the bloodstream and interacts with basophils in the blood as well as with mast cells deep within the tissues, the release of active agents can cause hives, characterized by severe itching. If the antigen enters through the gut, the consequences can include painful intestinal spasms and vomiting. Local reaction with mast cells increases the permeability of the mucosa of the gut, and in many cases the antigen enters the bloodstream and also produces hives. Regardless of whether the allergen is injected or ingested, if it ends up in the bloodstream, it can induce anaphylaxis, a syndrome that in its most severe form is characterized by a profound and prolonged drop in blood pressure accompanied by difficulty in breathing. Death can occur within minutes unless an injection of epinephrine is administered immediately. This type of severe allergic reaction can occur in response to foods, drugs such as penicillin, and insect venom (see illustration—>).

      Another feature of type I hypersensitivity reactions is that, once the immediate local reaction to the allergen has taken its course, there may occur an influx of more granulocytes, lymphocytes, and macrophages at the site. If the allergen is still present, a more prolonged form of the same reaction—the so-called late-phase reaction, which lasts a day or two rather than minutes—may supervene. This is a feature of asthmatic attacks in some subjects, in whom repeated episodes also lead to increased sensitivity of the air passages to the constrictive action of histamine. If such persons can escape exposure to the allergen for several weeks, subsequent exposure causes much less severe attacks. A prolonged IgE-induced reaction also causes atopic dermatitis, a skin condition characterized by persistent itching and scaly red patches. These often develop at sites where the skin is bent, such as the elbows and knees. The persistence is due to the influx of mast cells stimulated by the continued presence of the allergen, which is often a harmless substance such as animal hair or dander.

Typical type I allergens (allergen)

      Most people are not unduly susceptible to hay fever or asthma. Those who are—about 10 percent of the population—are sometimes described as atopic (from the term atopy, meaning “uncommon”). Atopic individuals have an increased tendency to make IgE antibodies. This tendency runs in families, though there is no single gene responsible as there is in some hereditary diseases such as hemophilia. Although many innocuous antigens can stimulate a small amount of IgE antibody in the atopic individual, some antigens are much more likely to do so than others, especially if they are repeatedly absorbed in very small amounts through mucosal surfaces. Such antigens are often termed allergens (allergen). These substances are usually polypeptides that have carbohydrate groups attached to them. They are resistant to drying, but no special characteristic is known that clearly distinguishes allergens from other antigens. Allergens are present in many types of pollen (which accounts for the seasonal incidence of hay fever), in fungal spores, in animal dander and feathers, in plant seeds (especially when finely ground) and berries, and in what is called house dust. The main allergen in house dust has been identified as the excreta of mites (mite) that live on skin scales; other mites (those that live in flour, for example) also excrete potent allergens. This list is far from exhaustive. Sensitivities to chocolate, egg whites, oranges, or cow's milk are not uncommon.

      The amount of allergen needed to trigger an acute type I hypersensitivity reaction in a sensitive person is very small: less than one milligram can produce fatal anaphylaxis if it enters the bloodstream. Medical personnel should inquire about any history of hypersensitivity before administering drugs by injection, and if necessary they should inject a test dose into (rather than through) the skin to ensure that hypersensitivity is absent. In any case, a suitable remedy should be at hand.

Treatment of type I allergic responses

      Several drugs are available that mitigate the effects of IgE-induced allergic reactions. Some, such as the anti-inflammatory cromolyn, prevent mast-cell granules from being discharged if administered before reexposure to antigen. For treatment of asthma and severe hay fever, such drugs are best administered by inhalation. The effects of histamine can be blocked by antihistamine agents that compete with histamine for binding sites on the target cells. Antihistamines are used to control mild hay fever and such skin manifestations as hives, but they tend to make people sleepy. Epinephrine (epinephrine and norepinephrine) counteracts, rather than blocks as antihistamines do, the effects of histamine and it is most effective in treating anaphylaxis. Corticosteroid (corticoid) drugs can help control persistent asthma or dermatitis, probably by diminishing the inflammatory influx of granulocytes, but long-continued administration can produce dangerous side effects and should be avoided.

      Sensitivity to allergens often diminishes with time. One explanation is that increasing amounts of IgG antibodies are produced, which preferentially combine with the allergen and so prevent it from reacting with the cell-bound IgE. This is the rationale for desensitization treatment, in which small amounts of the allergen are injected beneath the skin in gradually increasing quantities over a period of several weeks, so as to stimulate IgG antibodies. The method is often successful in diminishing hypersensitivity to a tolerable level or even abolishing it. However, increased IgG production may not be the complete explanation. The capacity to make IgE antibodies depends on the cooperation of helper T cells, and they in turn are regulated by regulatory T cells. There is evidence suggesting that atopic individuals are deficient in regulatory T cells whose function is specifically to depress the B cells that produce IgE and that desensitization treatment may overcome this deficiency.

Type II hypersensitivity

      Allergic reactions of this type, also known as cytotoxic reactions, occur when cells within the body are destroyed by antibodies, with or without activation of the entire complement system. When antibody binds to an antigen on the surface of a target cell, it can cause damage through a number of mechanisms. When IgM or IgG molecules are involved, they activate the complete complement system, which leads to the formation of a membrane attack complex that destroys the cell (see immune system: Antibody-mediated immune mechanisms (immune system)). Another mechanism involves IgG molecules, which coat the target cell and attract macrophages and neutrophils to destroy it. Unlike type I reactions, in which antigens interact with cell-bound IgE immunoglobulins, type II reactions involve the interaction of circulating immunoglobulins with cell-bound antigens.

      Type II reactions only rarely result from the introduction of innocuous antigens. More commonly, they develop because antibodies have formed against body cells that have been infected by microbes (and thus present microbial antigenic determinants) or because antibodies have been produced that attack the body's own cells. This latter process underlies a number of autoimmune diseases, including autoimmune hemolytic anemia (immune system disorder), myasthenia gravis, and Goodpasture syndrome (immune system disorder).

 Type II reactions also occur after an incompatible blood transfusion, when red blood cells are transfused into a person who has antibodies against proteins on the surface of these foreign cells (either naturally or as a result of previous transfusions). Such transfusions are largely avoidable (see blood group: Uses of blood grouping (blood group)), but when they do occur the effects vary according to the class of antibodies involved. If these activate the complete complement system, the red cells are rapidly hemolyzed (made to burst), and the hemoglobin in them is released into the bloodstream. In small amounts it is mopped up by a special protein called hemopexin, but in large amounts it is excreted through the kidneys and can damage the kidney tubules. If activation of complement only goes part of the way (to the C3 stage; see illustration—>), the red cells are taken up and destroyed by granulocytes and macrophages, mainly in the liver and spleen. The heme pigment from the hemoglobin is converted to the pigment bilirubin, which accumulates in the blood and makes the person appear jaundiced (jaundice).

      Not all type II reactions cause cell death. Instead the antibody may cause physiological changes underlying disease. This occurs when the antigen to which the antibody binds is a cell-surface receptor, which normally interacts with a chemical messenger, such as a hormone. If the antibody binds to the receptor, it prevents the hormone from binding and carrying out its normal cellular function (see Autoimmune diseases of the thyroid gland (immune system disorder)).

Type III hypersensitivity

      Type III, or immune-complex, reactions are characterized by tissue damage caused by the activation of complement in response to antigen-antibody (immune) complexes that are deposited in tissues. The classes of antibody involved are the same ones that participate in type II reactions—IgG and IgM—but the mechanism by which tissue damage is brought about is different. The antigen to which the antibody binds is not attached to a cell. Once the antigen-antibody complexes form, they are deposited in various tissues of the body, especially the blood vessels, kidneys, lungs, skin, and joints. Deposition of the immune complexes causes an inflammatory response, which leads to the release of tissue-damaging substances, such as enzymes that destroy tissues locally, and interleukin-1, which, among its other effects, induces fever.

      Immune complexes underlie many autoimmune diseases (immune system disorder), such as systemic lupus erythematosus (lupus erythematosus) (an inflammatory disorder of connective tissue), most types of glomerulonephritis (inflammation of the capillaries of the kidney), and rheumatoid arthritis.

      Type III hypersensitivity reactions can be provoked by inhalation of antigens into the lungs. A number of conditions are attributed to this type of antigen exposure, including farmer's lung, caused by fungal spores from moldy hay; pigeon fancier's lung, resulting from proteins from powdery pigeon dung; and humidifier fever, caused by normally harmless protozoans that can grow in air-conditioning units and become dispersed in fine droplets in climate-controlled offices. In each case, the person will be sensitized to the antigen—i.e., will have IgG antibodies to the agent circulating in the blood. Inhalation of the antigen will stimulate the reaction and cause chest tightness, fever, and malaise, symptoms that usually pass in a day or two but recur when the individual is reexposed to the antigen. Permanent damage is rare unless individuals are exposed repeatedly. Some occupational diseases of workers who handle cotton, sugarcane, or coffee waste in warm countries have a similar cause, with the sensitizing antigen usually coming from fungi that grow on the waste rather than the waste itself. The effective treatment is, of course, to prevent further exposure.

      The type of allergy described in the preceding paragraph was first recognized as serum sickness, a condition that often occurred after animal antiserum had been injected into a patient to destroy diphtheria or tetanus toxins. While still circulating in the blood, the foreign proteins in the antiserum induced antibodies, and some or all of the symptoms described above developed in many subjects. Serum sickness is now rare, but similar symptoms can develop in people sensitive to penicillin or certain other drugs, such as sulfonamides (sulfonamide). In such cases the drug combines with the subject's blood proteins, forming a new antigenic determinant to which antibodies react.

      The consequences of antigen-and-antibody interaction within the bloodstream vary according to whether the complexes formed are large, in which case they are usually trapped and removed by macrophages in the liver, spleen, and bone marrow, or small, in which case they remain in the circulation. Large complexes occur when more than enough antibody is present to bind to all the antigen molecules, so that these form aggregates of many antigen molecules cross-linked together by the multiple binding sites of IgG and IgM antibodies. When the ratio of antibody to antigen is enough to form only small complexes, which can nevertheless activate complement, the complexes tend to settle in the narrow capillary vessels of the synovial tissue (the lining of joint cavities), the kidney, the skin, or, less commonly, the brain or the mesentery of the gut. The activation of complement—which leads to increased permeability of the blood vessels, release of histamine, stickiness of platelets (platelet), and attraction of granulocytes and macrophages—becomes more important when the antigen-antibody complexes are deposited in blood vessels than when they are deposited in the tissues outside the capillaries. The symptoms, depending on where the damage occurs, are swollen, painful joints, a raised skin rash, nephritis (kidney damage, causing blood proteins and even red blood cells to leak into the urine), diminished blood flow to the brain, or gut spasms.

      The formation of troublesome antigen-antibody complexes in the blood can also result from subacute bacterial endocarditis (endocarditis), a chronic infection of damaged heart valves. The infectious agent is often Streptococcus viridans, normally a harmless inhabitant of the mouth. The bacteria in the heart become covered with a layer of fibrin, which protects them from destruction by granulocytes, while they continue to release antigens into the circulation. These can combine with preformed antibodies to form immune complexes that can cause symptoms resembling those of serum sickness. Treatment involves eradication of the heart infection by a prolonged course of antibiotics.

Type IV hypersensitivity

      Type IV hypersensitivity is a cell-mediated immune reaction. In other words, it does not involve the participation of antibodies but is due primarily to the interaction of T cells with antigens. Reactions of this kind depend on the presence in the circulation of a sufficient number of T cells able to recognize the antigen. The specific T cells must migrate to the site where the antigen is present. Since this process takes more time than reactions involving antibodies, type IV reactions first were distinguished by their delayed onset and are still frequently referred to as delayed hypersensitivity reactions. Type IV reactions not only develop slowly—reactions appear about 18 to 24 hours after introduction of antigen to the system—but, depending on whether the antigen persists or is removed, they can be prolonged or relatively transient.

      The T cells involved in type IV reactions are memory cells derived from prior stimulation by the same antigen. These cells persist for many months or years, so that persons who have become hypersensitive to an antigen tend to remain so. When T cells are restimulated by this antigen presented on the surface of the macrophages (or on other cells that can express class II MHC molecules), the T cells secrete cytokines that recruit and activate lymphocytes and phagocytic cells, which carry out the cell-mediated immune response. Two common examples of delayed hypersensitivity that illustrate the various consequences of type IV reactions are tuberculin-type and contact hypersensitivity.

Tuberculin-type hypersensitivity

      The tuberculin test is based on a delayed hypersensitivity reaction. The test is used to determine whether an individual has been infected with the causative agent of tuberculosis, Mycobacterium tuberculosis. (A previously infected individual would harbour reactive T cells in the blood.) In this test, small amounts of protein extracted from the mycobacterium are injected into the skin. If reactive T cells are present—i.e., the test is positive—redness and swelling appear at the injection site the next day, increase through the following day, and then gradually fade away. If a tissue sample from the site of the positive reaction is examined, it will show infiltration by lymphocytes and monocytes, increased fluid between the fibrous structures of the skin, and some cell death. If the reaction is more severe and prolonged, some of the activated macrophages will have fused together to form large cells containing several nuclei. An accumulation of activated macrophages of this sort is termed a granuloma. Immunity to a number of other diseases (for example, leprosy, leishmaniasis, coccidiosis, and brucellosis) also can be gauged by the presence or absence of a delayed reaction to a test injection of the appropriate antigen. In all these cases, the test antigen provokes only a transitory response when the test is positive and, of course, no response at all when the test is negative.

      The same cell-mediated mechanisms are elicited by an actual infection with the living microbes, in which case the inflammatory response continues and the ensuing tissue damage and granuloma formation can cause serious damage. Moreover, in an actual infection, the microbes are often present inside the macrophages and are not necessarily localized in the skin. Large granulomas develop when the stimulus persists, especially if undegradable particulate materials are present and several macrophages, all attempting to ingest the same material, have fused their cell membranes to one another. The macrophages continue to secrete enzymes capable of breaking down proteins, and the normal structure of tissues in their neighbourhood becomes distorted. Although granuloma formation may be an effective method the immune system employs to sequester indigestible materials (whether or not of microbial origin) from the rest of the body, the harm inflicted by this immune mechanism may be much more serious than the damage caused by the infectious organisms. This is the case in such diseases as pulmonary tuberculosis and schistosomiasis and in certain fungal infections that become established within the body tissues rather than at their surface.

Contact hypersensitivity and dermatitis

      In contact hypersensitivity, inflammation occurs when the sensitizing chemical comes in contact with the skin surface. The chemical interacts with proteins of the body, altering them so that they appear foreign to the immune system. A variety of chemicals can cause this type of reaction. They include various drugs, excretions from certain plants, metals such as chromium, nickel, and mercury, and industrial products such as hair dyes, varnish, cosmetics, and resins. All these diverse substances are similar in that they can diffuse through the skin. One of the best-known examples of a plant that can provoke a contact hypersensitivity reaction is poison ivy (Toxicodendron radicans), found throughout North America. It secretes an oil called urushiol, which is also produced by poison oak (T. diversilobum), the poison primrose (Primula obconica), and the lacquer tree (T. vernicifluum). When urushiol comes in contact with the skin, it initiates the contact hypersensitivity reaction.

      As sensitizing chemicals diffuse into the skin, they react with some proteins of the body, changing the antigenic properties of the protein. The chemical can interact with proteins located in both the outer horny layer of the skin ( dermis) and the underlying tissue ( epidermis). Some of the epidermal protein complexes migrate to the draining lymph nodes (lymph node), where they stimulate T cells responsive to the newly formed antigen to multiply. When the T cells leave the nodes to enter the bloodstream, they can travel back to the site where the chemical entered the body. If some of the sensitizing substance remains there, it can reactivate the T cells, inducing a recurrence of inflammation. The clinical result is contact dermatitis, which can persist for many days or weeks. Treatment is by local application of corticosteroids, which greatly diminish lymphocyte infiltration, and by avoidance of further contact with the sensitizing agent.

      Although delayed hypersensitivity can be a nuisance when it produces skin allergies, it is an important part of the immune defense against intracellular parasites, and it may also play a role in the containment of some tumours.

Autoimmune disorders

      The mechanism by which the enormous diversity of B and T cells is generated is a random process that inevitably gives rise to some receptors that recognize the body's own constituents as foreign. Lymphocytes bearing such self-reactive receptors, however, are eliminated or rendered impotent by several different mechanisms, so that the immune system does not normally generate significant amounts of antibodies or T cells that are reactive with the body's components (self antigens (antigen)). Nevertheless, an immune response to self, called autoimmunity, can occur, and some of the ways that self-directed immune responses cause damage have been mentioned in the section Allergies (immune system disorder).

      Understanding and identifying autoimmune disorders is difficult given that all humans have many self-reactive antibodies in the blood but most show no sign of disease. Consequently the identification of autoantibodies is not a sufficient diagnostic tool for determining the presence of an autoimmune disorder. There is a difference between an autoimmune response and disease: in the former case the autoantibodies do not cause dysfunction, but in the latter case they do.

Basic processes underlying autoimmunity

      Immunologists cannot always explain why the mechanisms that normally prevent the development of autoimmunity have failed in a particular autoimmune disorder. They have, however, advanced a number of explanations for such failures.

Alteration of self antigens

      Various mechanisms can alter self components so that they seem foreign to the immune system. New antigenic determinants can be attached to self proteins, or the shape of a self antigen can shift—for a variety of reasons—so that previously unresponsive helper T cells are stimulated and can cooperate with preexisting B cells to secrete autoantibodies. Alteration of the shape of a self protein has been shown to occur in experimental animals and is the most probable explanation for the production of the rheumatoid factors that are characteristic of rheumatoid arthritis (immune system disorder). Infectious organisms also can alter self antigens, which may explain why viral infection of specialized cells—such as those in the pancreas that secrete insulin or those in the thyroid gland that make thyroid hormones—often precedes the development of autoantibodies against the cells themselves and against their hormonal products.

Release of sequestered self antigens

      Intracellular antigens and antigens found on tissues that are not in contact with the circulation normally are segregated effectively from the immune system. Thus, they may be regarded as foreign if they are released into the circulation as a result of tissue destruction caused by trauma or infection. After sudden damage to the heart, for example, antibodies against heart muscle membranes regularly appear in the blood.

Cross-reaction with foreign antigens

      This mechanism comes into play when an infectious agent produces antigens so similar to those on normal tissue cells that the antibodies stimulated to react against the foreign antigen also recognize the similar self antigen; hence, the two antigens are said to be cross-reactive. Autoantibodies stimulated by external antigens in this way can cause serious damage. For example, the streptococci that cause rheumatic fever make antigens that are cross-reactive with those on heart muscle membranes, and the antibodies that react with the bacteria also bind to the heart muscle membrane and cause damage to the heart. Another instance of an autoimmune disorder that arises from cross-reactivity is Chagas disease (Chagas' disease). The trypanosomes that cause the disease make antigens that are cross-reactive with antigens on the surface of the specialized nerve cells that regulate the orderly contraction of muscles in the bowel. Antibodies directed against the trypanosomes also interact with these nerve cells and disrupt normal bowel functioning.

Genetic (heredity) factors

      Several autoimmune diseases clearly run in families. Careful studies (for example, those comparing the incidence in identical twins with that in fraternal twins) have shown that the increased incidence of such autoimmune diseases cannot be explained by environmental factors. Rather, it stems from a genetic defect that is passed from one generation to the next. Such disorders include Graves disease, Hashimoto disease, autoimmune gastritis (including pernicious anemia), type I (insulin-dependent) diabetes mellitus, and Addison disease. These diseases are more common in persons who bear particular MHC antigens on their cells. The possession of these antigens does not imply that a person will contract such diseases, only that he or she is more likely to do so. Researchers generally agree that the interaction of many genes is needed before a person develops such autoimmune diseases. For example, type I diabetes is believed to result from at least 14 genes.

      Another interesting feature that appears to relate to the inheritance of autoimmune disorders is gender. Most human autoimmune diseases afflict far more women than men. Women are affected more often than men with most of the better-known disorders, including myasthenia gravis, systemic lupus erythematosis, Graves disease, rheumatoid arthritis, and Hashimoto disease. The reason for this is not fully understood, but researchers think it probably is related to hormonal effects on immune responses.

Examples of autoimmune disorders

      The spectrum of autoimmune disorders is wide, ranging from those that involve a single organ to others that affect several different organs as a secondary consequence of the presence of immune complexes in the circulation. It is not possible in this article to discuss them all. The following disorders have been chosen to illustrate some of the very different complications that can arise from autoimmunity.

Autoimmune diseases of the thyroid gland

       Hashimoto disease and Graves disease are two of the most common autoimmune disorders of the thyroid gland, the hormone-secreting organ (located in the throat near the larynx) that plays an important role in the development and maturation of all vertebrates. The thyroid (thyroid gland) is composed of closed sacs (follicles) lined with specialized thyroid cells. These cells secrete thyroglobulin, a large protein that acts as a storage molecule from which thyroid hormones are made and released into the blood. The rate at which this occurs is regulated by thyroid-stimulating hormone (TSH), which activates the thyroid cells by combining with TSH receptors found on the thyroid cell membrane. Hashimoto disease involves swelling of the gland (a condition called goiter) and a loss of thyroid hormone production ( hypothyroidism). The autoimmune process underlying this disorder is thought to be instigated by helper T cells that react with thyroid antigens, although the mechanism is not completely understood. Once activated, the self-reactive T cells stimulate B cells to secrete antibodies against several target antigens, including thyroglobulin.

       Graves disease is a type of overactive thyroid disease ( hyperthyroidism) involving excess production and secretion of thyroid hormones. The disease arises with the development of antibodies that are directed against the TSH receptor on the thyroid cells and that can mimic the action of TSH. When bound to the receptor, the antibodies stimulate excessive secretion of thyroid hormones.

      In both Hashimoto disease and Graves disease, the thyroid gland becomes infiltrated with lymphocytes and is partially destroyed. If the gland is completely destroyed, a condition called myxedema may ensue, involving a swelling of tissues, especially those around the face.

Autoimmune hemolytic anemia

      A number of autoimmune disorders are grouped under the rubric autoimmune hemolytic anemia. All result from the formation of autoantibodies against red blood cells (erythrocyte), an event that can lead to hemolysis (destruction of red blood cells). The autoantibodies sometimes appear after infection with the bacterium Mycoplasma pneumoniae, a rather uncommon cause of pneumonia. In that case the autoantibodies are directed against certain antigens that are present on red cells, and they are probably induced by a similar antigen in the microbes (an example of the cross-reaction of antigens). Autoantibodies directed against a different antigen of red blood cells are often produced in persons who have been taking the antihypertensive medication alpha methyldopa for several months; the reason for autoantibody development in such cases is unknown. Other drugs, such as quinine, sulfonamides (sulfonamide), or even penicillin, very occasionally cause hemolytic anemia. In such cases it is thought that the drug acts as a hapten—that is, it becomes bound to a protein on the surface of red blood cells, and the complex becomes immunogenic.

      The autoantibodies that form against red blood cells are categorized into two groups on the basis of their physical properties. Autoantibodies that bind optimally to red blood cells at 37 °C (98.6 °F) are categorized as warm-reacting. Warm-reacting autoantibodies belong primarily to the IgG class and cause about 80 percent of all cases of autoimmune hemolytic anemia. Autoantibodies that attach to red blood cells only when the temperature is below 37 °C are called cold-reacting. They belong primarily to the IgM class. Cold-reacting autoantibodies are efficient at activating the complement system and causing the cell to which they are bound to be destroyed. Nevertheless, as long as the body temperature remains at 37 °C, cold-reacting autoantibodies dissociate from the cell, and hemolysis is not severe. However, when limbs and skin are exposed to the cold for long periods of time, the temperature of circulating blood can be lowered, allowing cold-reacting autoantibodies to go to work. Infection with M. pneumoniae is met by cold-reacting antibodies.

Pernicious anemia and autoimmune gastritis

       pernicious anemia stems from a failure to absorb 12 (vitamin B12) (cobalamin), which is necessary for the proper maturation of red blood cells. It is characteristically accompanied by a failure to secrete hydrochloric acid in the stomach (achlorhydria) and is in fact a symptom of severe autoimmune gastritis. To be absorbed by the small intestine, dietary vitamin B₁₂ must form a complex with intrinsic factor, a protein secreted by the parietal cells in the stomach lining. Pernicious anemia results when autoantibodies against intrinsic factor bind to it, preventing it from binding to vitamin B₁₂ and thus preventing the vitamin from being absorbed into the body. The autoantibodies also destroy the acid-secreting parietal cells, which leads to autoimmune gastritis.

rheumatoid arthritis

       rheumatoid arthritis is a chronic inflammatory disease that affects connective tissues throughout the body, particularly the synovial membranes that line the peripheral joints. Rheumatoid arthritis is one of the most common autoimmune diseases. Its cause is not known, but a variety of altered immune mechanisms probably contribute to the disorder, especially in more severe cases.

      One theory suggests that the inflammatory process of the disease is initiated by autoimmune reactions that involve one or more autoantibodies, referred to collectively as rheumatoid factor. The autoantibodies react with the tail region of the Y-shaped IgG molecule—in other words, rheumatoid factor is anti-IgG antibodies. Immune complexes form between rheumatoid factor and IgG and apparently are deposited in the synovial membrane of joints. The deposition triggers a type III hypersensitivity reaction, activating complement and attracting granulocytes, which causes inflammation and pain in the joints. The granulocytes release enzymes that break down cartilage and collagen in the joints, and this eventually can destroy the smooth joint surface that is needed for ease of movement. If immune complexes in the blood are not effectively removed by the liver and spleen, they can produce systemic effects similar to those precipitated by serum sickness.

      The devastating effects of rheumatoid arthritis also have been seen in patients, especially younger ones, in whom no rheumatoid factor is detected, and thus other mechanisms of initiation of the disorder probably exist.

Systemic lupus erythematosus

      Systemic lupus erythematosus (lupus erythematosus) (SLE) is a syndrome characterized by organ damage that results from the deposition of immune complexes. The immune complexes form when autoantibodies are made against the nucleic acids and protein constituents of the nucleus of cells. Such autoantibodies, called antinuclear antibodies, do not attack healthy cells, since the nucleus lies within the cell and is not accessible to antibodies. Antigen-antibody complexes form only after the nuclear contents of a cell are released into the bloodstream during the normal course of cell death or as a result of inflammation. The resultant immune complexes are deposited in tissues, causing injury. Certain organs are more commonly involved than others, including the kidneys, joints, skin, heart, and serous membranes around the lungs.

multiple sclerosis

       multiple sclerosis is an autoimmune disease that results in the gradual destruction of the myelin sheath that surrounds nerve fibres. It is characterized by progressive degeneration of nerve function, interjected with periods of apparent remission. The cerebrospinal fluid of persons with multiple sclerosis contains large numbers of antibodies directed against myelin basic protein and perhaps other brain proteins. Infiltrating lymphocytes and macrophages may exacerbate the destructive response. The reason the immune system launches an attack against myelin is unknown, but several viruses have been suggested as initiators of the response. A genetic tendency toward the disease has been noted; susceptibility to the disorder is indicated by the presence of the major histocompatibility complex (MHC) genes, which produce proteins found on the surface of B cells and some T cells.

Type I (insulin-dependent) diabetes mellitus

      Type I diabetes mellitus is the autoimmune form of diabetes and often arises in childhood. It is caused by the destruction of cells of the pancreatic tissue called the islets of Langerhans. Those cells normally produce insulin, the hormone that helps regulate glucose levels in the blood. Individuals with type I diabetes have high blood glucose levels that result from a lack of insulin. Dysfunction of islet cells is caused by the production of cytotoxic T cells or autoantibodies that have formed against them. Although the initiating cause of this autoimmune response is unknown, there is a genetic tendency toward the disease, which also involves class II MHC genes. It can be treated with injections of insulin; however, even when treated, type I diabetes may eventually lead to kidney failure, blindness, or serious circulation difficulties within the extremities.

Other autoimmune disorders

      Mechanisms similar to those that produce autoimmune hemolytic anemia can result in the formation of antibodies against granulocytes and platelets, although autoimmune attacks against these blood cells occur less frequently. Antibodies against other types of cells occur in a number of autoimmune diseases, and those self-reactive responses may be primarily responsible for the damage incurred. In myasthenia gravis, a disease characterized by muscle weakness, autoantibodies react against receptors on muscle cells. Normally the receptors bind to acetylcholine, a neurotransmitter released from nerve endings. When acetylcholine binds to an acetylcholine receptor on the surface of muscle cells, it stimulates the muscle to contract. The autoantibodies in myasthenia gravis bind to the acetylcholine receptors without activating them. The antibodies prevent muscle contraction either by blocking acetylcholine from binding to its receptor or by destroying the receptors outright. This renders the muscle less responsive to acetylcholine and ultimately weakens muscle contraction.

      A different example is provided by Goodpasture syndrome, a disorder in which autoantibodies form against the basement membrane of the blood vessels in the kidney glomeruli and in the air sacs of the lung. The autoantibodies cause severe kidney damage and lung hemorrhage.

Cancers (cancer) of the lymphocytes

      Tumours (tumour) arising from lymphocytes are given various names: they are called leukemias if the cancer cells are present in large numbers in the blood, lymphomas (lymphoma) if they are mainly concentrated in lymphoid tissues, and myelomas if they are B-cell tumours that secrete large amounts of immunoglobulin. The following sections describe how cancers of the lymphocytes arise and how immunological techniques are being used to determine the prognosis and treatment of B- and T-cell tumours.

Genetic (genetic disease, human) causes of cancer

      Most cancers result from a series of random genetic accidents, or mutations, that occur to genes involved in controlling cell growth. One general group of genes implicated in cancer initiation and growth are called oncogenes (oncogene). The unaltered, healthy form of an oncogene is called a proto-oncogene. Proto-oncogenes stimulate cell growth in a controlled manner that involves the interplay of a number of other genes. However, should a proto-oncogene become mutated in some way, it may become hyperactive, leading to uncontrolled cellular proliferation and the exaggeration of some normal cellular activities. A proto-oncogene can become mutated in a number of ways. According to one mechanism, called chromosomal translocation, part of one chromosome is severed from its normal position and reattached (translocated) onto another chromosome. If a proto-oncogene appears on the piece of the chromosome that is moved, it may be separated from the region that normally regulates it. In this manner the proto-oncogene becomes unregulated and turns into an oncogene. Chromosomal translocation of proto-oncogenes is involved in a number of B-cell tumours, including Burkitt lymphoma and chronic myelogenous leukemia. T-cell leukemia also results from a chromosomal translocation.

Malignant transformation of lymphocytes

      At any stage in its development, from stem cell to mature form, a lymphocyte may undergo malignant (cancerous) transformation. The transformed cell is no longer constrained by the processes that regulate normal development, and it proliferates to produce a large number of identical cells that make up the tumour. These cells retain the characteristics of the transformed cell's particular developmental stage, and because of this cancers can be distinguished according to the stage at which transformation took place. For example, B cells that become cancerous in the early stages of development give rise to such conditions as chronic myelogenous leukemia and acute lymphocytic leukemia, whereas malignant transformation of late-stage B cells—i.e., plasma cells—can result in multiple myeloma. Regardless of what stage of the cell becomes cancerous, malignant cells outgrow and displace other cells that continue to develop normally.

Treatment of cancers through identification of antigens

      Both T and B cells have surface antigens (antigen) that are characteristic of different stages in their life cycle, and antibodies have been prepared that identify the antigens. Knowledge of the specific type and stage of maturation of the tumour cells helps physicians determine the prognosis and course of treatment for the patient. This is important because different types of tumours respond to different therapies and because the chances of effecting a cure vary from type to type. Advances made in drug treatments have dramatically improved the outlook for children with acute lymphoblastic leukemia, the most prevalent of the childhood leukemias. Similarly, most cases of Hodgkin disease, a common type of lymphoma that mainly strikes adults, can be cured by drugs, radiation, or a combination of both. Myelomas (multiple myeloma) primarily arise in older individuals. These tumours grow fairly slowly and are usually diagnosed by virtue of the characteristic immunoglobulin they secrete, which may be produced in such large amounts that they cause secondary damage such as kidney failure.

Samuel Scott Perdue John H. Humphrey

Additional Reading

Lloyd J. Old, “Immunotherapy for Cancer,” Scientific American, 275(9):136–143 (September 1996), explores the use of the human immune system in combating cancer. Clinical aspects are covered by G.L. Asherson and A.D.B. Webster, Diagnosis and Treatment of Immunodeficiency Diseases (1980); Max Samter (ed.), Immunological Diseases, 4th ed., 2 vol. (1988); and P.J. Lachmann et al. (eds.), Clinical Aspects of Immunology, 5th ed., 3 vol. (1993).

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