Immune System

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The Human Immune System

The system of internal defence mechanisms which enables the body to resist disease. The body's first line of defence is the skin and lining of the cavities (especially the gut and lungs). They act as a barrier to the entry of unwanted substances and foreign cells. If foreign bodies penetrate through these defences, the immune system is activated. Cells and proteins within the blood and lymph attack, disarm, destroy, and remove the foreign bodies. Special white blood cells (B-cell lymphocytes) are able to recognize the chemicals (called antigens) associated with foreign bodies and produce antibodies, proteins which attack them. The immune system seems to be able to remember previous encounters with a specific foreign substance, so that if confronted again with the same substance it can mount a prompt and effective defence. This is the basis of immunity.

People with allergies may have an overzealous immune system that attacks harmless substances or fails to attack harmful ones. Sometimes the immune system breaks down and starts to attack the body's own cells. This condition is called autoimmunity and is implicated in the development of a number of diseases, including rheumatoid arthritis.

The immune system can function efficiently only if it is supplied with adequate nutrients. Energy from carbohydrates and fat is needed to mobilize the army of white cells that fight off attacks. Vitamins and minerals are essential components of many chemicals produced to defend the body (see antioxidant). A deficiency or an overdose of any nutrient is likely to harm the immune system.

The immune system is also affected by the physiological and psychological stress of exercise. Although the results of scientific investigations are not clear, it appears that low to moderate levels of exercise are generally beneficial, activating the immune system and improving its ability to defend the body against disease. Exercise may boost the production of natural killer cells. One of their main duties is to destroy cancer cells before they can develop into full-blown tumours. However, there seems to be a critical level of exercise, specific to each individual, above which the immune system becomes increasingly compromised (see also general adaptation syndrome). Many athletes preparing for a major competition push themselves to their mental and physical limits, exceed their critical level, and succumb to illness. Elite athletes walk a tightrope between supreme physical condition and a breakdown of health. A new test that uses saliva samples is being devised for monitoring the competence of the immune system. This should help athletes and others know when they should take particular care to avoid overtraining.

Have you ever wondered why you are resistant to the colds that plague your friends, even though you have been exposed to the same environment? This is because you have an efficient immune system which is working overtime to identify and mount a reaction to ‘invaders’, including microorganisms capable of causing disease and foreign macromolecules like polysaccharides and proteins — a phenomenon known as immunity.

Historically, immunity referred to protection from infectious diseases, and the term was derived from the Latin word immunitas, meaning the exemption from civic duties and prosecution extended to Roman senators. However the concept of immunity existed long before, especially in the Chinese custom of making children inhale powders of crust of skin lesions of patients recovering from small pox. The first scientifically documented evidence of inducing immunity was the landmark work of Dr Edward Jenner, an English physician. He noticed that milkmaids who had recovered from cowpox were resistant to contracting small pox. When he injected the material from a cowpox pustule into a young boy, the boy did not develop small pox even when intentionally inoculated. Jenner published his findings in 1798 and laid the foundation for the future development of ‘vaccination’ (the Latin word vacinus means of or from cows) and other forms of immunization.

Two basic levels of immunity exist in healthy individuals to confer protection against microbes and other foreign bodies; the less perfect natural immunity and the more specific acquired immunity.

Natural immunity

Those defence mechanisms that exist prior to exposure to foreign substances, that are not enhanced by subsequent exposures, and that cannot discriminate between most foreign molecules, are categorized as natural or innate immunity. This includes the first line of defence — the protective barriers like the skin and the mucous membranes lining the body tracts, which secrete acids and enzymes capable of digesting bacterial cell walls. Often a failure at this level may lead to fatal complications (such as in cystic fibrosis, where the mucus formed is not protective).

If this protective barrier is breached, the next lines of defence involve two components of natural immunity — the humoral (mediated by substances free in the body fluids) and the cellular (mediated by cells). A number of humoral agents are rapidly produced or activated to exert non-specific effects: that is, they are equally effective against multiple microbes. They include acute phase proteins, serum complements, and interferons. Interferons are vital mainly in controlling viral infections. At this time the cellular component also comes into play. Two types of phagocytic cells ‘eat up’ and destroy the foreign molecules. The first of these are the polymorphonuclear neutrophil leucocytes (white blood cells), which circulate in blood and migrate to sites of microbial invasion; the second are called monocytes in the blood and macrophages in the tissues (they migrate between the two) — collectively, the macrophage-monocyte system. Humoral and cellular mechanisms interact: serum complements bind to the surface of the foreign molecule and increase the efficiency of phagocytosis by the cells.

Acquired immunity

By the time the components of natural immunity perform their act, more specific defence mechanisms are also mounted. These mechanisms are induced by exposure to the foreign molecules which are known as antigens. Besides amplifying the protective mechanisms of innate immunity, the specific immune system also ‘memorizes’ each encounter with a particular antigen such that subsequent exposure to that antigen leads to the development of ‘active immunity’. Specific immunity can also be induced in an individual by transferring cells or serum (depending on the type of immune response, see later) from a specifically immunized individual, so that the recipient becomes immune to the particular antigen without getting an actual exposure to it. This form of immunity is called ‘passive immunity’, and often is a useful method for rapid conferring of immunity. This technique has helped in saving lives following potentially lethal snake bites, by the administration of antibodies from immunized individuals. Much more commonly, anti-tetanus serum has been widely used to confer passive immunity after potentially contaminated minor injuries.

Lymphocytes are the primary players in specific immunity. These are cells that are present throughout the body, circulating in the blood and lymph and organized in lymphoid tissues. They are produced in primary lymphoid organs — the liver in the fetus, the thymus, and the bone marrow. Some lymphocytes pass through the thymus after release from the bone marrow, re-enter the circulation and then settle in secondary lymphoid organs like the spleen and the lymph nodes. During passage through the thymus these lymphocytes acquire antigen specificity, properties which equip them to act against a particular invader, and are thereafter known as T-cells. Other lymphocytes do not pass through the thymus, but settle directly in the secondary lymphoid organs where they mature and develop antigen specificity. These cells are called B-lymphocytes or B-cells; they carry on their surface a ‘recognition molecule’ or antibody, which acts as a receptor for an antigen.

Antibodies belong to a group of proteins called immunoglobulins. They are similar in their overall Y-shaped structure. The 2 arms form the part known as ‘Fab’, which binds with the antigen. Here the amino acid sequence varies widely; these regions determine the specificity of the antibody and also account for the diversity of immunity. In fact there are between 10 and 1000 million structurally different antibodies in an individual, each with unique amino acid sequences in the Fab region. The stem of the antibody determines its biological function, and its properties are used in classifying the immunoglobulins (IgG, IgM, IgA, IgD, and IgE.)

Humoral immunity is mediated by antibodies that are released into the circulation from B-lymphocytes, and can therefore be transferred to non-immunized individuals by cell-free components of blood. It is the principal defence mechanism against extra-cellular foreign molecules or their toxins because the antibodies bind to these and lead to their destruction. Intracellular antigens are handled by cell-mediated immunity, of which the main component is T-lymphocytes. This form of immunity can be transferred only through the cells of the blood. Humoral and cellular immunity are thus the two types of acquired or specific immunity.

Following exposure to an antigen, the specific immune response is brought about in a sequential manner, which can be divided into three phases: ‘cognitive’, ‘activation’ and ‘effector’. During the cognitive phase, the antigen binds to specific receptors on mature lymphocytes of both types. The antibody on B-lymphocytes recognizes and binds foreign proteins, polysaccharides, or lipids in soluble form. Receptors on T-lymphocytes, on the other hand, can recognize only short peptide sequences in protein antigens present on the surface of other cells. In the technical jargon of immunology, the portion of an antigen that is specifically recognized by the antibody is called an ‘epitope’.

Next, in the activation phase, the antigen-specific lymphocytes of both types proliferate by cloning, thus amplifying the immune response. Lymphocytes develop into cells whose primary function is to eliminate the antigen. All clonal B-cells secrete the same antibody, which combines with the antigen and initiates a sequence of events leading to destruction of that antigen. Subsets of the antigen-specific T-cell clones develop different functions; some activate phagocytes; others, called T-cytotoxic cells, directly break down cells that produce viral antigens; some regulate the production of antibody by B-cells. Those T-cells, which promote the immune response, are called T-helper cells, while others that inhibit it as part of the self-limiting capability of the immune response, are called T-suppressor cells. Another subset, the Tdth cells (delayed type hypersensitivity) produce factors that modulate the functions of lymphocytes and macrophages.

A set of membrane proteins that are products of genes determining (in) compatibility of tissues between individuals are known as HLA (called human lymphocyte antigens, because they were first recognized on these cells, but they occur on other cells also). They regulate the T-cell activity in such a way that T-cells recognize other antigens only when they are associated with the HLA molecules. This system is highly variable in the human population and it is rare for two individuals to have the same HLA products. This is often the reason for transplant rejection due to an immune response, when the donor's proteins serve as antigens in the recipient. HLA typing and matching is thus an essential step before any transplant surgery to minimize the chances of an immune response.

Once the lymphocytes have been activated and the antigen has been presented to them, the immune response enters the effector phase. Few antigens bind directly to antigen-reactive T- or B-cells but are presented to the lymphocytes bound to other ‘antigen presenting cells’ such as macrophages. The effector phase requires the participation also of other non-lymphoid ‘effector cells’ such as mast cells, eosinophils, or natural killer (NK) cells, which act also as components of natural immunity. Antibodies bind to the antigen, and this promotes phagocytosis by neutrophils or other phagocytes. Antibodies can also activate the ‘complement system’, generating proteins that cause inflammation, cell breakdown, and phagocytosis of the antigen. Some antibodies, like IgA released from mucous membranes, coat the antigen and prevent its docking on the epithelial lining of body tracts. T-cells also secrete chemicals called cytokines, which stimulate an inflammatory response and enhance the function of natural immunity. The antigen thus faces a barrage of defence mechanisms' which leads to its destruction.

Once the antigenic stimulation is removed, lymphocytes become quiescent and only some remain viable as memory cells. On a subsequent exposure to the same antigen these become rapidly activated and can mount a faster response than the first time, called the secondary immune response. A series of feedback controls also come into play, which makes the immune response self limiting.

One of the distinguishing and essential features of the immune system is its ability to discriminate between foreign and ‘self-antigens’. Immunity is unresponsive to molecules present in the individual that would be antigenic in another. This arises due to an acquired process called self-tolerance. Thus during the early stages of development, functionally immature ‘self-recognizing’ lymphocytes come in contact with self-antigens and are prevented from developing to a stage where they can respond to self-antigens. However, in certain unfortunate conditions, abnormalities in induction or maintenance of self-tolerance may occur, which leads to the immune system acting against a normal component of the same body. This leads to the development of autoimmune diseases.

— Shiladitya Sengupta, Tai-Ping Fan

Food and Nutrition: immune system

Series of defence mechanisms of the body. There are two major parts: humoral, mediated through antibodies secreted into the circulation (immunoglobulins); and cell-mediated. Lymphocytes produce antibodies against, and bind to, the antigens of foreign cells, leading to death of the invading organisms; other white blood cells are phagocytic and engulf the invading organisms.

The Immune System, Part II

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.

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