Allergy

An allergy is an abnormally high or misguided reaction by the immune system to various foreign substances that are normally harmless, such as pollen, molds, animal proteins, dust mites, insect poisons, and foods. Symptoms may include sneezing, skin rashes, difficulty breathing, itching, watery eyes, and so forth. An allergen is a substance that triggers an allergic reaction.

The immune system is the system of specialized cells and organs that protects an organism from outside biological influences. When the immune system is functioning properly, it protects the body against foreign bacteria and viral infections and destroys cancer cells and foreign substances. When someone is experiencing an allergy, the complex coordination of the immune system overreacts to the outside substances.

Allergies are very common disorders and more than 50 million people in the United States suffer from allergic diseases. Allergies are the sixth leading cause of chronic disease in the United States, costing the health care system $18 billion annually.

Allergies are a variety of hypersensitivity, a term that refers to an immune response that damages the body's own tissues. Hypersensitivities can be classified into several types, based on the parts of the immune system involved and the length of time it takes for the reaction to occur. Allergies are generally considered to be the type of hypersensitivity involving an immediate (or atopic, or anaphylactic) reaction provoked by exposure to a specific antigen. This hypersensitivity involves the interaction of the antigen (i.e. foreign substance, or allergen when a person is hypersensitized to it) with immunoglobulin E (IgE, a subclass of antibodies). This hypersensitivity is characterized by immediate reaction, in which mast cells and basophils (a type of white blood cell) are excessively activated by immunoglobulin E. The mast cells and basophils release histamine, which results in a systemic inflammatory response that can cause symptoms ranging from a benign runny nose to life-threatening anaphylactic shock and death.

Allergies also may be considered to be another type of hypersensitivity, the cell-mediated (or delayed) reaction, as the reaction takes two to three days to develop. Unlike the other type, it is not antibody mediated, but rather is a type of cell-mediated response. The allergens in this hypersensitivity interact with T lymphocytes (white blood cells of the immune system) rather than antibodies, as in the case of the first type of hypersensitivity.

The majority of this article deals with the first type of hypersensitivity, which is the general application for the word allergy.

Allergens

An allergen is any foreign substance (antigen), most often eaten or inhaled, that is recognized by the immune system and causes an allergic reaction.

No comprehensive list of allergens is currently possible. Sensitivities vary from one person to another and it is possible to be allergic to an extraordinary range of substances.

Dust, pollen, and pet dander are all common allergens, but it is possible to be allergic to anything from chlorine to perfume. Food allergies are not as common as food sensitivity, but some foods such as peanuts (really a legume), nuts, seafood, and shellfish are the cause of serious allergies in many people. A few people have even been recorded to be allergic to certain chemicals found in almost all water. Poison ivy (and other plants, like poison sumac or poison oak) is a plant that will cause an allergic reaction for anyone, given enough repeated contact—like any allergy, the human body must learn to fight the allergen, some bodies learn slower and will appear to be "immune" to poison ivy.

An allergic reaction can be caused by any form of direct contact with the allergen—eating or drinking a food you are sensitive to (ingestion), breathing in pollen, perfume or pet dander (inhalation), or brushing your body against an allergy-causing plant (direct contact, generally resulting in hives). Other common causes of serious allergy are wasp, fire ant, and bee stings, penicillin, and latex. An extremely serious form of an allergic reaction, which can kill in mere minutes, is called anaphylaxis.

Types of Common allergens

In addition to foreign proteins found in foreign serum (from blood transfusions) and vaccines, common allergens include:

• Plant pollens (Hay fever):
  • rye grass
  • ragweed
  • timothy grass
  • birch trees
• Mold spores
• Drugs:
  • penicillins
  • sulfonamides
  • salicylates (also found naturally in numerous fruits)
  • local anaesthetics
• Foods (food allergy):
  • nuts (2 separate cases)
    • peanuts
    • nuts
  • sesame
  • seafood
  • egg (typically albumen, the white)
  • peas, beans, peanuts, soybeans and other legumes
  • soy
  • milk
  • wheat
  • corn or maize
• Insect stings:
  • bee sting venom
  • wasp sting venom
• Animal products (animal allergy):
  • Animal hair and dander
  • cockroach calyx
  • dust mite excretion
• Other
  • Latex

History

The word allergy is derived from the Greek words allos, meaning "other," and ergon, meaning "work." The term and concept of "allergy" was coined by a Viennese pediatrician named Clemens von Pirquet in 1906. He observed that the symptoms of some of his patients might have been a response to outside allergens such as dust, pollen, or certain foods.

For a long time, all hypersensitivities were thought to stem from the improper action of inflammatory immunoglobulin class IgE. However, it soon became clear that several different mechanisms, utilizing different effector molecules, were responsible for the myriad hypersensitivity disorders previously classified as "allergies." A new four-class classification scheme was designed by P. G. H. Gell and R. R. A. Coombs. Allergy has since been kept as the name generally applied to the first type of hypersensitivity ("immediate, atopic, or anaphylactic reaction to a specific antigen") characterized by classical IgE mediation of effects.

Basis of allergic response

Genetic basis

There is much evidence to support the genetic basis of allergy, as allergic parents are more likely to have allergic children. However some allergies are not consistent along genealogies. For example, some parents may be allergic to peanuts, but their children may be allergic to ragweed. Additionally, siblings may not share allergens.

Ethnicity has also been shown to play a role in some allergies. Interestingly, in regard to asthma, it has been suggested that different genetic loci (specific positions of genes on chromosomes) are responsible for asthma in people of Caucasian, Hispanic, Asian, and African origins. It has also been suggested that there are both general atopy (allergy-sensitive) genes and tissue-specific allergy genes that target the allergic response to specific mucosal tissues. Potential disease-associated alleles (the individual DNA coding of a gene) include both variation in the coding region (section of the DNA coding for the eventual protein) and SNPs (Single Nucleotide Polymorphism) found in gene regulatory elements (non-coding sections of the gene).

Relationship with parasites

Some research has indicated that certain kinds of common parasites, such as intestinal worms (e.g. hookworms), secrete immunosuppressant chemicals into the gut wall and bloodstream that prevent the body from attacking the parasite. The relationship of these parasites to allergies gives rise to a new slant on the "hygiene hypothesis" (see below)—the speculation that co-evolution of man and parasites has resulted in an immune system that only functions correctly in the presence of the parasites, that without these parasites, the immune system becomes unbalanced and oversensitive. The fact that allergies are more prevalent in people living in developed countries than in underdeveloped countries supports this hypothesis. Gutworms and similar parasites are present in untreated drinking water in underdeveloped countries, and in developed countries until the routine chlorination and purification of drinking water supplies. The development of this routine cleansing and expunging of parasites from drinking water coincides with the time period in which a significant rise in allergies has been observed. So far, there is only sporadic evidence to support this hypothesis and full clinical trials have yet to be performed.

Basis of increasing prevalence

There has been a notable increase in the commonness of allergies in the past decades, and there are multiple hypotheses explaining this phenomenon.

Hygiene Hypothesis

One theory that has been gaining strength is the "hygiene hypothesis." This theory maintains that since children in more affluent countries are leading a cleaner and cleaner life (less exposure to dirt, extra use of disinfectants, etc.), their immune systems have less exposure to parasites and other pathogens than children in other countries or in decades past. Their immune systems may, therefore, have many "loaded guns," cells that might have targeted, say, the intestinal worms that no longer cause trouble in affluent neighborhoods. Having no reasonable target, these cells inadvertently become activated by environmental antigens that might only cause minor reactions in others. The symptoms of this exaggerated response are seen as the allergic reaction.

Many common allergies such as asthma have seen huge increases in the years since the Second World War, and many studies appear to show a correlation between this and the increasingly affluent and clean lifestyles in the West. This is supported by studies in less developed countries that do not enjoy Western levels of cleanliness, and similarly do not show Western levels of incidences of asthma and other allergies. During this same period, air quality, at one time considered the "obvious" cause of asthma, showed a considerable improvement. This has led some researchers to conclude that it is our "too clean" upbringing that is to blame for the lack of immune system stimulation in early childhood and the resulting allergies later in life.

So far the evidence to support this theory is limited. One supporting fact is that many Chinese will develop hay fever after moving into USA for three or more years. However, contradictory examples also exist.

Increasing use of chemicals

Another theory is the exponential use and abuse of chemicals in affluent nations since the Second World War. Vast numbers of chemicals are introduced into our indoor and outdoor environments with little or no testing regarding their toxicity to living beings. Many believe that air quality is getting worse rather than better, particularly if one considers indoor air quality as well as outdoor. (Indoor air quality is considered to have become significantly worse since building codes changed in the 1970s to make buildings more air-tight to conserve energy. This affects buildings built since that time.) Adverse reactions to toxins vary considerably from one person to another, and can involve extremes in symptoms, including the urological and endocrine systems, as well as the more commonly recognized allergy symptoms listed above.

In 2004, a joint Swedish-Danish research team found a very strong link between allergies in children and the phthalates (chemicals often added to plastics to increase flexibility) DEHP and BBzP, commonly used in polyvinyl chloride (PVC) (Bornehag 2004).

Allergies are also viewed by some medical practitioners as a negative consequence of the use and abuse of antibiotics and vaccinations. This mainstream Western approach to treatment and prevention of infectious disease has been used in the more affluent world for a longer period of time than in the rest of the world, providing an explanation for the much greater commonality of allergies there. It is hypothesized that use of antibiotics and vaccination affect the immune system, and that allergies are a dysfunctional immune response.

Diagnosis

There are several methods for the diagnosis and assessment of allergies.

Skin test

The typical and most simple method of diagnosis and monitoring of the first type of hypersensitivity (immediate, atopic, or anaphylactic reaction) is the skin test, also known as the prick test due to the series of pricks made into the patient's skin. Small amounts of suspected allergens and/or their extracts (pollen, grass, mite proteins, peanut extract, etc.) are introduced to sites on the skin marked with pen or dye (the ink/dye should be carefully selected, lest it cause an allergic response itself). The allergens are either injected intradermally or into small scratchings made into the patient's skin, often with a lancet. Common areas for testing include the inside forearm and back. If the patient is allergic to the substance, then a visible inflammatory reaction will usually occur within 30 minutes. This response will range from slight reddening of the skin to hives in extremely sensitive patients.

After performing the skin test and receiving results, the doctor may apply a steroid cream to the test area to reduce discomfort (caused by possible itching and inflammation).

Skin test problems

While the skin test is probably the most preferred means of testing because of its simplicity and economics, it is not without complications. Some people may display a delayed-type hypersensitivity (DTH) reaction, which can occur as far as six hours after application of the allergen and last up to 24 hours. This can also cause serious long-lasting tissue damage to the affected area. These types of serious reactions are quite rare.

Additionally, the application of previously unencountered allergens can actually sensitize certain individuals to the allergen, causing the inception of a new allergy in susceptible individuals.

Skins tests also are not always able to pinpoint a patient's specific allergies, as a patient may respond to various substances even if only one is the culprit.

Total IgE count

Another method used to qualify type I hypersensitivity is measuring the amount of IgE contained within the patient's serum. This can be determined through the use of radiometric and colorimetric immunoassays. The amount of serum IgE specific to certain allergens can be measured through use of the radioallergosorbent test (RAST).

Pathophysiology

All hypersensitivities result from an aberration in the normal immune process. The exact cause of such malfunctions is not always apparent, however, and several arguments from genetic-basis, environmental-basis, and intermediate proponents exist with varying validity and acceptance. (See also pathophysiology section in asthma.)

Acute response

The difference between the first type of hypersensitivity reaction against an allergen (allergy) to the normal humoral response against a foreign body is that plasma cells secrete IgE as opposed to either IgM (against novel antigens) or IgG (against immunized antigens). IgE binds to Fc receptors on the surface of mast cells and basophils, both involved in the acute inflammatory response.

When IgE is first secreted it binds to the Fc receptors on a mast cell or basophil, and such an IgE-coated cell is said to be sensitized to the allergen in question. A later exposure by the same allergen causes reactivation of these IgE, which then signals for the degranulation (process of losing granules) of the sensitized mast cell or basophil.

There is now strong evidence that mast cells and basophils require costimulatory signals for degranulation in vivo, derived from GPCRs (G-protein coupled receptors) such as chemokine receptors. These granules release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) into the surrounding tissue causing several systemic effects, such as vasodilation, mucus secretion, nerve stimulation, and smooth muscle contraction. This results in the previously described symptoms of rhinorrhea (runny nose), itchiness, dyspnea (shortness of breath), and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be system-wide (calliscal anaphylaxis), or localized to particular body systems (for example, asthma to the respiratory system, or eczema to the dermis).

Late-phase response

After the chemical mediators of the acute response subside, late phase responses can often occur. This is due to the migration of other leukocytes (white blood cells) such as neutrophils, lymphocytes, eosinophils, and macrophages to the initial site. The reaction is usually seen four to six hours after the original reaction and can last from one to two days. Cytokines from mast cells may also play a role in the persistence of long-term effects. Late phase responses seen in asthma are slightly different to those seen in other allergic responses.

Signs and symptoms

Allergies are characterized by a local or systemic inflammatory response to allergens. Local symptoms include:

• Nose: swelling of the nasal mucosa (allergic rhinitis)
• Eyes: redness and itching of the conjunctiva (allergic conjunctivitis)
• Airways: bronchoconstriction, wheezing and dyspnea, sometimes outright attacks of asthma
• Ears: feeling of fullness, possibly pain, and impaired hearing due to the lack of eustachian tube (auditory tube) drainage.
• Skin: various rashes, such as eczema, hives (urticaria) and contact dermatitis.
• Head: while not as common, headaches are seen in some with environmental or chemical allergies.

Systemic allergic response is also called anaphylaxis. Depending of the rate of severity, it can cause cutaneous (skin-related) reactions, bronchoconstriction, edema, hypotension, coma, and even death.

Hay fever is one example of an exceedingly common minor allergy—large percentages of the population suffer from hayfever symptoms in response to airborne pollen. Asthmatics are often allergic to dust mites. Apart from ambient allergens, allergic reactions can be due to medications.

Treatment

There are limited mainstream medical treatments for allergies. Probably the most important factor in rehabilitation is the removal of sources of allergens from the home environment and the avoidance of environments in which contact with allergens is likely.

Alternative therapies

In alternative medicine, a number of treatment modalities are considered effective by its practitioners in the treatment of allergies, particularly naturopathic, herbal medicine, homeopathy (a treatment that involves treating the sick with extremely diluted agents that, in undiluted doses, produce similar symptoms in the healthy), traditional Chinese medicine, and kinesiology (study of movement of the body). These modalities are frequently offered as treatment for those seeking additional help when mainstream medicine has failed to provide adequate relief from allergy symptoms. However, mainstream physicians maintain that these claims lack a scientific basis and warn that the efficacy of such treatments is only supported by anecdotal evidence.

Chemotherapy

Several antagonistic drugs are used to block the action of allergic mediators, preventing activation of basophils and mast cells and degranulation processes. They include antihistamines, cortisone, epinephrine (adrenalin), theophylline, and Cromolyn sodium. These drugs help alleviate the symptoms of allergy, but play little role in chronic alleviation of the disorder. They can play an imperative role in the acute recovery of someone suffering from anaphylaxis, which is why those allergic to bee stings, peanuts, nuts, and shellfish often carry an adrenalin needle with them at all times.

Immunotherapy

Hyposensitization is a form of immunotherapy where the patient is gradually vaccinated against progressively larger doses of the allergen in question. This can either reduce the severity or eliminate hypersensitivity altogether. It relies on the progressive skewing of IgG ("the blocking antibody") production, as opposed to the excessive IgE production seen in the first type of hypersensitivity. Delivery can occur via allergy injection, or sublingual immunotherapy (allergy drops taken under the tongue). Though not commonly offered in the United States, sublingual immunotherapy is gaining attention internationally and is very common in Europe.

A second form of immunotherapy involves the intravenous injection of monoclonal anti-IgE antibodies. These bind to free IgE in the blood, preventing IgE from binding to the receptors on the mast cells and basophils, thus preventing the inflammatory response. They do not bind to IgE already bound to the Fc receptor on basophils and mast cells as this would stimulate the allergic inflammatory response. The first agent in this class is omalizumab.

An experimental treatment form, enzyme potentiated desensitization, has been tried with some success but is not in widespread use. EPD uses dilutions of allergen and an enzyme, beta-glucuronidase, to which T-regulatory lymphocytes respond by favoring desensitization, or down-regulation, rather than sensitization. EPD is also under development for the treatment of autoimmune diseases.

References

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• Goldsby, R. A., T. K. Kindt, B. A. Osborne, and J. Kuby. 2003. Immunology, 5th edition. New York, NY: W. H. Freeman and Company. ISBN 071674947-5
• Bornehag, C. G., J. Sundell, C. J. Weschler, T. Sigsgaard, B. Lundgren, M. Hasselgren, and L. Hagerhed-Engman. 2004. The association between asthma and allergic symptoms in children and phthalates in house dust: a nested case-control study. Environ Health Perspect. 112(14):1393-7. PMID 15471731.
• Ono, S. J. 2000. Molecular genetics of allergic diseases. Annu Rev Immunol. 18: 347-66. Review. PMID: 10837062