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Allergies
Definition
A collection of symptoms caused by an immune response to substances that do not trigger an immune response in most people. See also food allergies; hay fever; allergy to mold, dander, dust; drug allergies; allergy testing; allergic reactions.
Causes, incidence, and risk factors
Allergy is caused by hypersensitivity of the immune system leading to a misdirected immune response. The immune system normally protects the body against harmful substances such as bacteria, viruses, and toxins. Allergy occurs when the immune system reacts to substances (allergens) that are generally harmless and in most people do not cause an immune response.

The first exposure to the allergen causes a mild immune response that sensitizes the immune system to the substance (triggers the immune system to recognize the substance). The second and subsequent exposure to the allergen results in symptoms. The type of symptom that develops depends on the specific allergen, the part of the body where exposure occurs, and the way the immune system reacts to the allergen.

When an allergen enters the body of a person with a sensitized immune system, it triggers antibody production. Histamine and other chemicals are released by body tissues as part of the immune response. This causes itching, swelling of affected tissues, mucus production, muscle spasms, hives and rashes, and other symptoms. Symptoms vary in severity from person to person.

The part of the body contacted by the allergen will, in part, also affect symptoms. For example, allergens that are inhaled often cause nasal congestion, itchy nose/throat, mucus production, coughing, wheezing, or similar symptoms. Food allergies often include abdominal pain, cramping, or similar symptoms, although the whole body may be affected when the food is absorbed. Allergies to plants often cause skin rash. Drug allergies usually involve the whole body.

Many disorders are associated with, triggered, or worsened by allergies. These include hay fever, eczema, asthma, and many others.

Common allergens include environmental agents that contact the skin, breathing passages, or the surface of the eye (such as pollen; see also allergy to mold, dander, dust). Food allergies and drug allergies are common. Allergic reactions can be caused by insect bites, jewelry, cosmetics, and almost any substance that contacts the body.

Some people have allergic-type reactions to hot or cold temperatures, sunlight, or other physical stimuli. In some persons, friction (such as rubbing or vigorously stroking the skin) will cause symptoms. The mechanism that causes this is not well understood, but it is possible that minute changes in the chemistry of the skin may occur in response to physical stimuli and some component of this chemical change triggers the allergy. (See also atopic dermatitis and contact dermatitis.).

Allergies are common. Heredity, environmental conditions, number and type of exposures, emotional factors (stress and emotional upset can increase the sensitivity of the immune system), and many other factors can indicate a predisposition to allergies.
Prevention
There is no known way to prevent allergies. Symptoms may be prevented by avoiding known allergens.
Symptoms
  • runny nose (rhinitis)
  • tearing, increased
  • itching of the nose, mouth, eyes, throat, skin, or any area
  • wheezing
  • coughing
  • difficulty breathing
  • skin redness
  • hives
  • skin rashes
  • stomach cramps
  • vomiting
  • diarrhea
  • bloated feeling of the stomach
  • headache
  • hearing loss
  • ear discharges/bleeding
  • chemosis

Note: Allergies vary according to the type of antigen and the part of the body in which the allergic reaction occurs.
Signs and tests
History is important in diagnosing allergies, including whether the symptoms vary according to time of day or the season and possible exposures that involve pets, diet changes, or other sources of allergens.

Testing may be required to determine if symptoms are an actual allergy or caused by other problems. For example, contaminated food ("food poisoning") may resemble food allergies. Some medications (such as aspirin, ampicillin, and others) can produce non-allergic reactions, including rashes, that resemble drug allergies but are not true allergies.
  • Antibody/immunoglobulin (particularly IgE) levels that are elevated indicate allergic reaction.
  • Complement levels may be abnormal.
  • Testing may reveal the specific allergen(s).
    • Skin testing is the most common method of allergy testing. This may include intradermal, scratch, patch, or other tests.
    • Occasionally, the suspected allergen is dissolved and dropped onto the lining of the lower eyelid (conjunctiva) as a means of testing for allergies.
    • Other testing to determine the specific allergen may include various types of "use" or "elimination" tests where suspected items are eliminated and/or introduced while the person is observed for response to the substance.
    • Tests for reaction to physical stimuli may include application of the stimuli (heat, cold, and so on) and observation for an allergic response.

This disease may also alter the results of the following tests:

  • WBC count
  • CBC
  • immunoelectrophoresis - serum

An allergy is a harmful immune response elicited by an antigen that is not itself intrinsically harmful.

Examples:
  • The windblown pollen released by orchard grass has no effect on me but produces a violent attack of hay fever (known to physicians as allergic rhinitis) in my wife.
  • She, on the other hand, can safely handle the leaves of poison ivy while if I do so, I break out in a massive skin rash a day or two later.
Antigens that trigger allergies are often called allergens.

Four different immune mechanisms can result in allergic responses.

1. Immediate Hypersensitivities.

These occur quickly after exposure to the allergen. They are usually mediated by antibodies of the IgE class.

Examples:
  • hay fever
  • hives
  • asthma

2. Antibody-Mediated Cytotoxicity

Cell damage caused by antibodies directed against cell surface antigens. Hence a form of autoimmunity.

Examples:
  • Hemolytic disease of the newborn (Rh disease).
  • Myasthenia gravis (MG)

3. Immune Complex Disorders

Damage caused by the deposit in the tissues of complexes of antigen and their antibodies. Examples:
  • Serum sickness
  • Systemic lupus erythematosus (SLE)

4. Cell-Mediated Hypersensitivities

These reactions are mediated by CD4+ T cells. Examples:
  • The rash produced following exposure to poison ivy. Because it takes a day or two for the T cells to mobilize following exposure to the antigen, these responses are called delayed-type hypersensitivities (DTH). Those, like poison ivy, that are caused by skin contact with the antigen are also known as contact sensitivities or contact dermatitis.
  • certain autoimmune diseases, including
    • Insulin-dependent diabetes mellitus (IDDM)
    • Multiple sclerosis (MS)

Immediate Hypersensitivities

Local Anaphylaxis

The constant region of IgE antibodies (shown in blue) has a binding site for a receptor present on the surface of basophils and their tissue-equivalent the mast cell. These cell-bound antibodies have no effect until and unless they encounter allergens (shown in red) with epitopes that can bind to their antigen-binding sites.

When this occurs, the mast cells to which they are attached explosively discharge their granules by exocytosis. The granules contain a variety of active agents including histamine and leukotrienes. Release of these substances into the surrounding tissue causes local anaphylaxis: swelling, redness, and itching. In effect, each IgE-sensitized mast cell is a tiny bomb that can be exploded by a particular antigen. The most common types of local anaphylaxis are:
  • allergic rhinitis (hay fever) in which airborne allergens react with IgE-sensitized mast cells in the nasal mucosa and the tissues around the eyes;
  • bronchial asthma in which the allergen reaches the lungs either by inhalation or in the blood;
  • hives (physicians call it urticaria) where the allergen usually enters the body in food.

Leukotrienes are far more potent than histamine in mediating these reactions.

Leukotrienes and prostaglandins are derivatives of arachidonic acid (AA) an unsaturated fatty acid produced from membrane phospholipids. The principal pathways of arachidonic acid metabolism are
  • the 5-lipoxygenase pathway, which produces a collection of leukotrienes (LT) and
  • the cyclooxygenase pathway, which yields a number of prostaglandins (PG) and thromboxanes (Tx).
All three are synthesized by monocytes and macrophages. Mast cells and basophils generate a mixture of leukotrienes. The products of both pathways act in concert to cause inflammation with prostaglandins producing fever and pain. Aspirin, ibuprofen, and certain other nonsteroidal anti-inflammatory drugs (NSAIDs) achieve their effects (fever and pain reduction) by blocking the activity of cyclooxygenase.

Some people respond to environmental antigens (e.g., pollen grains, mold spores) with an unusually vigorous production of IgE antibodies. Why this is so is unclear; heredity certainly plays a role. In any case, the immune system of these people is tilted toward the production of T helper cells of the Th2 subtype. These release interleukin 4 (IL-4) and interleukin 13 (IL-13) on the B cells that they "help". These lymphokines promote class switching in the B cell causing it to synthesize IgE antibodies.

An inherited predisposition to making IgE antibodies is called atopy. Atopic people are apt to have higher levels of circulating IgE (up to 12 µg/ml) than is found usually (about 0.3 µg/ml). Whereas only 20-50% of the receptors on mast cells are normally occupied by IgE, all the receptors may be occupied in atopic individuals.

Skin Testing

When the problem allergen is not obvious, it can often be identified by skin testing. A panel of suspected allergens is injected into separate sites in the skin and each site is observed for the development of a "wheal and flare" reaction. The
  • wheal is a sharply delineated soft swelling surrounded by the
  • flare - a reddened area.
Both are caused by the release of leukotrienes at the site, which increase the flow of blood to the site making it swollen and red. A positive skin test occurs within minutes or even seconds (in contrast to patch testing for DTH responses described below). In some patients, a response can be elicited by as little as 0.1 ng of allergen.

Systemic Anaphylaxis

Some allergens can precipitate such a massive IgE-mediated response that a life-threatening collapse of the circulatory and respiratory systems may occur.

Frequent causes:

  • insect (e.g., bee) stings
  • many drugs (e.g., penicillin)
  • a wide variety of foods (shellfish and nuts are common offenders; in fact, some school systems in the U. S. now ban peanuts and peanut-butter sandwiches when they have a student at risk of systemic anaphylaxis from exposure to peanuts.)
Treatment of systemic anaphylaxis centers on the quick administration of adrenaline, antihistamines, and - if shock has occurred - intravenous fluid replacement.

An example of systemic anaphylaxis

The three graphs show the physiological responses of a physician (Dr. Vick) stung by a single bee while on a picnic with coworkers (fortunately some with medical training!). Dr. Vick required cardiac massage and intravenous injections of adrenaline at the times shown. He and his colleagues worked in a laboratory studying bee venom, but prior to this episode he had no idea that he had developed such extreme susceptibility. 

Desensitization

So far, the most effective preventive for IgE-mediated allergies is to inject the patient with gradually-increasing doses of the allergen itself. The goal is to shift the response of the immune system away from Th2 cells in favor of Th1 cells.

Unfortunately, this therapy takes a long time and the results are too often disappointing.

Anti-IgE Antibodies

IgE molecules bind to mast cells and basophils through their constant region. If you could block this region, you could interfere with binding - hence sensitization of - these cells.

Humanized monoclonal antibodies specific for the constant region of IgE are in clinical trials. They have shown some promise against asthma and peanut allergy, but such treatment will probably have to be continued indefinitely (and will be very expensive).

Antibody-Mediated Cytotoxicity

In these disorders, the person produces antibodies directed against antigens present on the surface of his or her own cells. Thus these qualify as autoimmune disorders. Some examples: Binding of antibodies to the surface of the cell can result in:
  • phagocytosis of the cell
  • lysis of the cell
  • damage to molecules on the cell surface (e.g., myasthenia gravis)
  • activation of cell-surface receptors (e.g., thyrotoxicosis)

Hemolytic Disease of the Newborn (Rh Disease)

Rh antigens are expressed at the surface of red blood cells. During pregnancy, there is often a tiny leakage of the baby's red blood cells into the mother's circulation. If the baby is Rh-positive (having inherited the trait from its father) and the mother Rh-negative, these red cells will cause her to develop antibodies against the Rh antigen. The antibodies, usually of the IgG class, may not develop fast enough to cause problems for that child, but can cross the placenta and attack the red cells of a subsequent Rh+ fetus. This destroys the red cells producing anemia and jaundice. The disease may be so severe as to kill the fetus or even the newborn infant.

Although certain other red cell antigens (in addition to Rh) sometimes cause problems for a fetus, an ABO incompatibility does not. Why is an Rh incompatibility so dangerous when ABO incompatibility is not?

It turns out that most anti-A or anti-B antibodies are of the IgM class and these do not cross the placenta. In fact, an Rh-/type O mother carrying an Rh+/type A, B, or AB fetus is resistant to sensitization to the Rh antigen. Presumably her anti-A and anti-B antibodies destroy any fetal cells that enter her blood before they can elicit anti-Rh antibodies in her.

This phenomenon has led to an extremely effective preventive measure to avoid Rh sensitization. Shortly after each birth of an Rh+ baby, the mother is given an injection of anti-Rh antibodies. The preparation is called Rh immune globulin (RhIG) or Rhogam. These passively acquired antibodies destroy any fetal cells that got into her circulation before they can elicit an active immune response in her.

Rh immune globulin came into common use in the United States in 1968, and within a decade the incidence of Rh hemolytic disease became very low.

Immune Hemolytic Anemia

Some people synthesize antibodies against their own red blood cells, and these may lyze the cells producing anemia. Infections, cancer, or an autoimmune disease like systemic lupus erythematosus (SLE) are often involved. Many drugs (e.g. penicillin, quinidine) can also trigger the disorder. In these cases, stopping the drug usually brings about a quick cure.

Immune Thrombocytopenic Purpura

This is an autoimmune disorder in which the patient develops antibodies against his or her own platelets (thrombocytes). The life span of the platelets may be reduced from the normal of 8 days to as little as 1 hour, and platelet counts may drop from a normal of 250,000/µl to 20,000/µl. This greatly interferes with normal clotting, causing

  • external bleeding (e.g., from the nose) and
  • internal bleeding into the skin causing purple patches (called purpura).
Often no cause of the disorder can be found (the physicians call it "idiopathic"). Some cases are triggered by prescription drugs like aspirin, digitoxin, and sulfa drugs. These cases can be cured by stopping the drug. The idiopathic cases can sometimes be helped by giving corticosteroids and/or removing the patient's spleen.

Myasthenia gravis (MG)

The hallmark of this autoimmune disorder is weakness of the skeletal muscles, especially those in the upper part of the body. It is caused by antibodies that attack the acetylcholine (ACh) receptors at the subsynaptic membrane of neuromuscular junctions. As the number of receptors declines, the ACh released with the arrival of a volley of nerve impulses is inadequate to generate end-plate potentials (EPPs) of the normal size. After repeated stimulation, the EPPs fail to reach the threshold needed to generate an action potential and the muscle stops responding.

The signs and symptoms of myasthenia gravis can be quickly - but only temporarily - relieved by injecting a drug that inhibits the action of cholinesterase. This prolongs the action of ACh at the neuromuscular junction. The immunosuppressant action of corticosteroids, like prednisone, can provide longterm improvement for patients.

The exclusive role of antibodies (of the IgG class) in this disorder is demonstrated by the presence of the disease in the newborn babies of mothers with the disorder. As these antibodies, which the fetus had received from the mother's circulation, disappear (in 1 -2 weeks), so do all signs of the disease.

Thyrotoxicosis (Graves' disease)

In this disorder, the patient has antibodies that bind to the TSH receptors on the thyroxine-secreting cells of the thyroid. These antibodies mimic the action of TSH itself (thus they behave as a TSH agonist) and trigger secretion of thyroxine (T4) and T3 by the thyroid gland.

The role of antibodies (of the IgG class) in this disorder is demonstrated by the presence of the disease in the newborn babies of mothers with the disorder. As these antibodies, which the fetus had received from the mother's circulation, disappear (in 1 -2 weeks), so do all signs of the disease.

Immune Complex Disorders

While binding of antibody to antigen is often a helpful - even life-saving - response, in some circumstances it causes pathological changes.

Serum sickness

In passive immunization, an antiserum containing needed antibodies is injected into the patient. At one time, these antisera were prepared by immunizing horses or sheep. While they did their intended work, (usually to provide immediate protection to a person exposed to
  • diphtheria or
  • tetanus
they also often later lead to a syndrome called serum sickness. The patient developed
  • fever
  • hives
  • arthritis and
  • protein in the urine.
After a week or two, the symptoms would disappear spontaneously.

Serum sickness is caused by the many extraneous proteins present in the antiserum. Being foreign to the recipient, an active immunity develops against these proteins. The resulting antibodies bind to them forming immune complexes. These are carried by the blood and deposited in the walls of blood vessels as well as in the glomeruli of the kidneys.

Antigen-antibody complexes bind to a system of serum proteins collectively known as complement. The complex of antigen-antibody-complement attracts basophils and mast cells and causes them to release their histamine and leukotrienes producing inflammation.

Thanks to nearly universal active immunization against both tetanus and diphtheria, serum sickness is now quite rare. However, kidney damage (called glomerulonephritis) produced by deposits of immune complexes is found in other ailments.

Persistent infections

Some infectious agents live in the body for long periods
Examples:
  • the protozoans that cause malaria
  • the worms that cause schistosomiasis and filariasis
  • the virus that causes hepatitis B.
In these cases, the continued presence of the pathogen provides a renewable source of antigen to combine with antibodies synthesized by the host resulting in deposits of immune complexes.

Systemic lupus erythematosus (SLE)

Humans with SLE develop (for unknown reasons) antibodies against a wide variety of self components:
  • their own DNA and RNA
  • red blood cells
  • platelets
  • ribosomes
  • even their own IgG molecules. (These "anti-antibodies" are called rheumatoid factors. They are also found in people with rheumatoid arthritis (hence the name) and, for a time, in people with mononucleosis.)
In all these cases of autoimmunity, immune complexes form and are deposited in the skin, joints, and kidneys where they initiate inflammation.

"Farmer's Lung"

Repeated exposure to airborne organic particles, like mold spores, can elicit formation of antibodies. When these interact with inhaled antigen, inflammation of the alveoli occurs. The sufferer develops a cough, fever, and difficulty in breathing. Once removed from the source of antigen, the attack subsides within a few days.

Farmers exposed to moldy hay often develop this problem (technically known as extrinsic allergic alveolitis). Sugarcane workers, cheese makers, mushroom growers, pigeon fanciers, and a number of other occupational or hobby groups are apt to develop allergic alveolitis from exposure to the spores and dusts associated with their activities.

Cell-Mediated Hypersensitivities

Cell-mediated hypersensitivities can occur with extrinsic antigens or with internal ("self") antigens.

Extrinsic antigens

The most common example of cell-mediated hypersensitivity to external antigens is the contact dermatitis caused in some people when their skin is exposed to a chemical to which they are allergic. Some examples:
  • the catechols found in poison ivy, poison oak, and poison sumac
  • nickel (often used in jewelry)
  • some dyes
  • certain organic chemicals used in industry
In every case, these simple chemicals probably form covalent bonds with proteins in the skin, forming the antigen that initiates the immune response. Phagocytic cells in the skin take up the complex, process it, and "present" it to CD4+ T cells.

Because it takes a day or two for the CD4+ T cells to mobilize to the affected area of skin, these cases are examples of delayed-type hypersensitivity (DTH).

When a patient is unsure of what chemical is causing the dermatitis, the physician can try a patch test. Pieces of gauze impregnated with suspected allergens are placed on the skin. After 48 hours, they are removed and each site is examined for a positive response (a reddened, itching, swollen area).

Intrinsic ("self") antigens

Cell-mediated hypersensitivities to "self" cause autoimmune diseases. Examples:
  • Insulin-dependent diabetes mellitus (IDDM or Type I diabetes)
  • Multiple sclerosis (MS)
  • Rheumatoid arthritis.

Insulin-dependent diabetes mellitus

In this disease, T cells attack and destroy the insulin-producing beta cells of the islets of Langerhans in the pancreas. Discussion. The chief culprits are CD4+ T cells of the inflammation-producing Th1 subset.

Multiple Sclerosis

In this case, T cells - again mostly Th1 cells - attack and destroy the myelin sheath of neurons.

Rheumatoid arthritis (RA)

In this disorder, Th1 cells attack antigens (as yet unidentified) in the joints producing tumor necrosis factor (TNF) with resulting inflammation and damage to the joints.

A genetically engineered fusion protein consisting of has shown promise as a treatment for RA. Given by injection, the fusion protein binds TNF and interferes with its action.

Autoimmune disorders are more common in females than in males.

Graves' disease, systemic lupus erythematosus (SLE), multiple sclerosis, and rheumatoid arthritis are all more common in women than in men. The sex bias ranges from 9:1 for SLE to >2:1 for multiple sclerosis and rheumatoid arthritis.

Why?

The answer is unclear, but hormones are probably involved.

A few clues: high levels of estrogen and progesterone
  • suppress Th1 responses (cell-mediated immunity). This may account for the improvement that often occurs in multiple sclerosis and rheumatoid arthritis during pregnancy (an improvement that ends after birth).
  • promote Th2 responses (antibody-mediated immunity). SLE results from antigen-antibody complexes and so it is not surprising that pregnancy does not help - and in some women actually exacerbates - this autoimmune disorder.
 

All information contained within this website is meant for educational purposes only.  All medical treatments">

All information contained within this website is meant for educational purposes only.  All medical treatments, or uses of vitamins, herbs or any other substances should be discussed with your doctor first.  If you decide to use any of  the information for personal use, you do so of your own accord and with no responsibility to the the authors of this web site. 

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