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The Immunologic Basis of Allergic Diseases

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I. The Immune System - Protecting the Host

The human immune system has been designed to protect the integrity of the host by maintaining the healthy "status quo" called homeostasis. When this homeostatic mechanism is disturbed through challenge by foreign invaders or altered self tissue (e.g. neoplasms, aged, worn out cells, etc), the immune system is activated to protect the host. The innate immune system, consisting of barriers such as skin and mucus membranes, enzymes and cells such as neutrophils (granulocytic white blood cells) protects against many invaders. If the innate immune system is unsuccessful, the adaptive immune system takes over.
This system consists of cells such as lymphocytes and monocytes and their products, such as antibodies, cytokines and antigen-specific cytotoxic (killer) cells. It functions to protect the host by containing and destroying the foreign invader and/or altered self that evoked the response. Adaptive immunity has two major characteristics - (1) It can discriminate self from nonself, leaving host tissues undamaged and selectively destroying the pathogenic material; and (2) it remembers the encounters with specific pathogenic agents such that subsequent encounters by the host with the same agents activates the immune response more quickly and vigorously, preventing reoccurrence of the disease caused by the specific pathogen. The self-nonself discrimination begins in utero, where everything the developing immune system sees is self. The immunologic memory mechanism is the theoretical basis behind the effectiveness of vaccines (and probably, at least in part, allergen immunotherapy. More on that later).

II. Immunologic Diseases - Defect or Deception?

When an individual develops a disease involving the immune system, it is either because an element or component is missing (deficiency) or because the normal control mechanisms of the adaptive response have "misfired", resulting in the lack of an appropriate immune response or even too vigorous a response (dysregulation). Remember, the immune response is supposed to protect the host. As those of us who care for patients with profound immunodeficiencies can attest, these folks typically die of overwhelming infections, often by infections that are harmless to those us with intact immune systems. In contrast, a normal immune response against a specific antigenic entity can produce reactions designed to be protective but actually producing disease in the host.

III. Hypersensitivity Disease

When an immune response to an antigen is in itself harmful to the host, it is referred to as a hypersensitivity disease. Gel and Coombs recognized that many such diseases had common mechanisms and classified them accordingly.

Type I reactions occur as a result of production of IgE. This immediate hypersensitivity accounts for the classic allergic diseases that we treat (much more about this in future articles).

Type II reactions occur as a result of specific antibodies that bind to host cells and kill the cell (cytolysis). Such reactions involve either a series of plasma proteins collectively termed complement that bind to the cell-bound antibodies or a specific lymphocyte that binds to the back of the cell-bound antibodies to cause antibody dependent cellular cytotoxicity (ADCC). Type II reactions commonly occur in certain drug reactions, particularly those causing a hemolytic anemia. This mechanism is also responsible for the once common hemolytic disease of newborns occurring in Rh+ infants born to Rh- mothers.

Type III reactions occur as a result of soluble antigen-antibody complexes that deposit on various organ surfaces (such as the kidney, lung, synovium, etc) where they activate complfs€nt. Theses activated complement components, among other things, attract inflammatory cells to the site of the immune complex depositions. The inflammatory cells attempt to "swallow" the tissue and release proteolytic enzymes that damage the tissues. Diseases such as rheumatoid arthritis and systemic lupus erythematosus occur as a result of this mechanism.

Type IV reactions are the only ones not involving antibodies. Rather, sensitized T cells secrete small peptides called cytokines that activate macrophages to form granulomas, apparently to contain the infectious agent. Diseases such as tuberculosis, leprosy and sarcoidosis all occur as a result of this mechanism.

IV. IgE- The Allergy Antibody

IgE is one of five classes of antibodies (immunoglobulins) made by humans (the others being IgM, IgG, IgA and IgD) and apparently is made as a primary defense against certain parasites. While parasitic disease may not be a major clinical issue in most industrialized nations, it is a major public health problem in third world countries. The antigen specific IgE acts with mast cells and eosinophils to protect the host against the invading parasite. However, the same antibody-cell combination is also responsible for the signs and symptoms of allergic diseases.

V. Mast Cells- The Central Cell of Allergic Reactions

When IgE is produced, it seeks cells containing receptors for the back of the antibody molecule (called the Fc portion). There are two major types of receptors for IgE on cells. One, called a low affinity receptor, is found on a variety of cells including lymphocytes and eosinophils. The other, a high affinity receptor, is found primarily on mast cells. Mast cells are found in or near a variety of organs and tissues including nose, lungs, gut, skin and even blood vessels. They contain large granules which house molecules such as histamine ,serotonin and tryptase. They normally function as part of the host defense system.

Once the mast cells are "armed" by the allergen-specific IgE molecules binding to the high affinity receptors, the "immune gun is cocked". Subsequent exposure to the specific allergen (i.e. pollen, dander, etc.) causes pairs of IgE molecules to become crosslinked. This "pulls the trigger" on the mast cell, causing its granules to release their contents as well as activating to form new molecules. The histamine causes itching, increase in vascular permeability, smooth muscle constriction and reflexes such as sneezing, coughing and gastrointestinal motility increases.
Crosslinking also activates mast cells to begin to synthesize and secrete molecules that can attract inflammatory cells (such as eosinophils) and further the allergic reaction itself. One such mechanism is activation of biochemical pathways that metabolize a component of cell membranes called arachadonic acid. Arachadonic acid can be metabolized down two major pathways by two different enzyme systems - cyclooxygenase and lipooxygenase. The end products of these pathways are called prostaglandins and leukotrienes. Both prostaglandins and leukotrienes are capable of enhancing the inflammation characteristic of this part of the allergic reaction. While the immediate hypersensitivity of histamine release typically occurs in minutes, the inflammatory response take several hours (3-24) and is referred to as a late phase allergic response. The affected organs define the specific signs and symptoms of allergic disease in a particular patient. Why all allergic patients do not have rhinitis, asthma, atopic dermatitis and anaphylaxis together is not understood but is the subject of great interest and research.

VI. Establishing Clinical Allergic Disease

The major target organs affected by IgE-mediated reactions define the clinical syndrome in a particular patient. Diagnosis of allergic disease is a combination of history, physical findings and judicious use of laboratory testing, including allergy testing. The history is fundamental to any diagnosis of allergic disease. What are the symptoms? Do they occur in a certain place (i.e home, workplace), time of year, time of day, after ingesting certain things (i.e. food, drugs, etc), after exercise, when stressed, etc. are all vitally important questions to be explored with every patient. Past medical history of previous allergic (and/or other immunologic) conditions can be associated with current illness. Family history of similar reactions as well as atopy in general is significant. The incidence of allergic diseases is estimated at about 10-15 % of the population (1 in 8 to 10). If one parent is truly atopic, the incidence is up to 1 in 4 and if both parents are atopic, the incidence rises to 1 in 2.

Physical examination is important because there are characteristic findings of allergic vs nonallergic conditions in a variety of organ systems including nose, eyes, lung and skin. Ruling out other causes for symptoms (i.e. mechanical obstruction for nasal congestion, pneumonia for shortness of breath, infection for irritated eyes and nonatopic inflammation for a skin rash) typically occur at this point.

Laboratory evaluation must be directed and cost effective. There are relatively few indications for obtaining a total serum IgE in the evaluation of routine allergic disease. However, directed assessment of allergen-specific IgE is very helpful in differentiating atopic from nonatopic individuals who have characteristic symptoms. Indeed, it is estimated that up to 50% of individuals who have nasal symptoms compatible with allergic rhinitis are nonatopic. Management strategies are dependent upon this distinction.

Allergy testing is commonly done by two methods - skin testing and in vitro determination of allergen specific IgE in the blood (RAST). Skin testing takes advantage of the allergen-specific IgE bound to mast cells in the skin. For safety, testing usually begins with percutaneous ("prick") testing. The allergen is applied and a needle passed through the drop to prick the skin. In highly sensitive individuals, this will result in the formation of a white, raised area (wheal) surrounded by a red, erythematous zone (flair) within 15-20 minutes indicative of a positive reaction. When indicated, negative prick tests may be confirmed by injecting a minute amount of more dilute allergen into the skin (intradermal) and observing an add itional 15-20 minutes for the appearance of a wheal and flair.

Controls are typically placed in conjunction with the skin tests. Positive control is usually limited to histamine which is the major mediator responsible for the wheal and flair. This is to be certain that the skin reaction can occur in a particular patient when histamine is released from a degranulated mast cell. Such reactions are most commonly suppressed by the recent use of antihistamines. The negative control (most commonly saline) is used to confirm that the skin mast cells do not nonspecifically degranulate from the mechanical manipulation of the skin (i.e. pricking or injecting). This is called dermatographism and is a contraindication to allergy skin testing, at least at that particular time.

In vitro testing is indicated when the histamine controls are negative (i.e. recent use of long acting antihistamines) or if the individual has a chronic skin condition that would make proper reading of skin tests impossible (i.e. dermatitis, dermatographism, etc). The principle is the use of a method that can detect allergen-specific IgE molecules in patient blood samples.

This method, while useful, has certain drawbacks. First, IgE is a very minor component of the circulating plasma. Allergen-specific IgE, even in highly atopic individuals, is only a small portion of the total IgE. Thus, very sensitive methods must be employed to detect allerfs€ specific IgE in plasma. In contrast, it is estimated that as little as 50 crosslinked IgE pairs may be sufficient to activate a mast cell. This results in the sensitivity of RAST being only about 70% of skin testing. In addition, the half life of IgE in the blood is only 2-3 days , making determination of pollen-specific IgE by RAST more difficult out of season since the plasma level goes down during that time. In contrast, mast cell bound IgE is apparently stable for a more prolonged time (up to months). Finally, RAST testing is, on a per allergen basis, considerably more expensive that skin testing.

Interpretation of positive allergy testing results must be incorporated with historical and physical findings. It is only in this context that the diagnosis of allergic disease can be made and specific therapies initiated.

VII. Specific Allergic Diseases

In discussing allergic diseases, there are selected differences between organ systems that makes diagnosis and management distinctive.

Allergic rhinitis is the most common of all atopic diseases in the United States, affecting up to 10% of the adult population. While no one dies directly as a result of allergic rhinitis, the economic impact is substantial. Over $600 million is spent in the USA annually in the management of this disease. This does not include the costs of the 2 million lost workdays , 3 million lost school days and 28 million days of decreased productivity from the symptoms of the disease and/or side effects of the medications used to treat them.

Clinically, information is gained from a nasal examination which may reveal pale, boggy turbinate as well as clear to greenish rhinorrhea. When colored nasal secretions are stained and examined, they typically reveal large numbers of eosinophils as the main inflammatory cell. In many instances (particularly in children) complications such as chronic otitis media, rhinosinusitis and conjunctivitis can be traced to chronic obstruction from allergic rhinitis.

Asthma is a disease whose incidence and mortality rate continue to increase. It is commonly considered a bronchospastic disease. However, we now know that this is in fact a chronic disease of the airways characterized by mucus hypersecretion as well as bronchial inflammation, edema, and hyperresponsiveness resulting in increased bronchoconstriction. The end result may be frequent exacerbations and need for multiple medications.

The contribution of IgE to this disease process has long been implicated and more recently estimated. It is suggested that up to 95% of children less than 15 are "allergic" (or extrinsic) asthmatics. This number is still 70% in young adults between 15 and 30. Finally, 50% of asthmatics over the age of 40 have demonstrable asthma triggers that are IgE-mediated.

Thus history that emphasizes exacerbating factors, physical examinations that correlated degree of breathlessness with wheezing and peak flow measurement and laboratory that at time quantitates the number of peripheral blood eosinophils are all important in management.

Allergic skin diseases including urticaria and angioedema as well as atopic dermatitis are less clearly defined as a true allergic disease. Urticaria and angioedema are both due to excessive mast cell activity in the skin. Chronic urticaria and angioedema is seldom due to a definable IgE mechanism but , when determined, is due to a drug, food or food additive.

Atopic dermatitis is associated with high serum IgE levels as well as a history of atopic disease (rhinitis, asthma, etc). Unfortunately, management is most difficult since the medications classically associated with treatment of allergic diseases (i.e. antihistamines) have little effect in these patients.

VIII. The Reasons We Use Specific Drugs for Treating Allergic Diseases

Antihistamines

When mast cell-bound IgE is crosslinked, the mast cell membrane becomes activated. This "destabilizes" the membrane, resulting in the release of mediators from the large basophilic granules in the mast cell (a process called degranulation). The major constituent of the large granules is histamine. Histamine has many effects including itching, sneezing, bronchospasm and increased vascular permeability that can result in loss of intravascular volume (anaphylaxis) and/or extravasation of plasma into skin (wheal), fat layers (angioedema), nose or lung. Most histamine-induced effects occur when histamine binds to target tissue via histamine receptors. There are three distinct type of histamine receptors (H1,H2 and H3). Most allergic reactions are via H1 receptor binding.

The major therapy for most allergic diseases is the use of antihistamines which are H1 receptor blockers. They do NOT stop histamine release from mast cells, rather they compete with histamine for the H1 receptor on target cells. It then follows that antihistamines are less effective after histamine has been released than if they block the receptor prior to mast cell degranulation.

Mast Cell Stabilizers (Cromolyn, Nedocromil)

It would be even more desirable to stop histamine from being released at all. One way would be to stop crosslinking of IgE by allergen (discussed below). Another way would be to stop mast cells from degranulating even if IgE was crosslinked. Several drugs have this property. Cromolyn is the first drug licensed as a mast cell stabilizer, that is inhibit degranulation and activation. It is available for use in the nose, lungs and GI tract. Its major limitation is a short duration of action (approx. 6 hours) and lack of available systemic preparation. Recently, a related compound called nedocromil has been released in the U.S for use in asthmatics. It appears to have a longer duration of action and may have more antiinflammatory properties than cromolyn.

After histamine is released, other mediators are also released, the importance of which is not fully understood. Such mediators include TAME esterase, tryptase, serotonin and various cytokines. Research is underway to evaluate the clinical potential for drugs that antagonize the release and/or activity of many of these agents.

As the mast cell is activated, several other events occur that contribute to the pathophysiology of allergic diseases. One such event is the activation of a membrane enzyme called phospholipase A2 , which breaks down membrane components to arachidonic acid, a 20 carbon fatty acid. Arachidonic acid is further metabolized by one of two enzyme pathways into various prostaglandins ( by cyclooxygenase) or leucotrienes (by lipooxygenase). Both prostaglandins and leucotrienes are highly proinflammatory, bronchospastic and vasodilatory.

In addition, other mediators are synthesized that act as chemotaxins to attract inflammatory cells to the activated mast cell environment. The major inflammatory cell in allergic reactions is the eosinophil. Other inflammatory cells found in allergic reactions include basophils, lymphocytes, monocytes/macrophages and neutrophils. But it is the eosinophil that appears to have the most harmful potential.

As the eosinophil is drawn to the increasingly inflammatory milieu, it becomes activated by a variety of the mediators present. Its large granules release their contents (such as major basic protein, eosinophilic cationic protein, various cytokines, etc.) which can further promote inflammation and direct tissue toxicity. Research is currently underway to evaluate drugs that antagonize the activity of these eosinophil-derived mediators.

Since the process of mast cell activation, mediator production and chemotaxis takes longer than mast cell degranulation, allergic reactions often have two distinct phases - the first or early phase occurs in minutes and is primarily from the preforfs€ granular contents. The second or late phase occurs some 3-12 hours later and is an inflammatory reaction from the above mentioned mast cell and eosinophil products. Antihistamines have no effect on late phase reactions while corticosteroids have little direct effect on early phase reactions. Cromolyn and nedocromil appear to be active against both.

Corticosteroids

The discussion of the pharmacotherapy of allergic diseases would be incomplete without mentioning the most commonly used class of medications - corticosteroids. These agents are antiinflammatories - that is, they inhibit late phase allergic reactions.

This occurs via a variety of mechanisms including decreasing the density of mast cells along mucosal surfaces, decreasing chemotaxis and activation of eosinophils, decreasing cytokine production by lymphocytes, monocytes, mast cells and eosinophils, inhibiting the metabolism of arachidonic acid and other mechanisms.

But for the side effects, corticosteroids would likely be the only drug needed for treating allergic reactions. Much effort is underway to develop safer corticosteroids including topical application and modifying the molecules to preserve the antiinflammatory properties while minimizing the undesirable side effects.

IX. Allergen Immunotherapy

Finally, a word should be said about allergen immunotherapy or allergy shots. They are still the only attempt at definitive therapy for IgE-mediated diseases. Through the parenteral administration of these allergens, clinical sensitivity to allergen-mediated reactions gradually diminishes.

Multiple theories have been advanced to explain the mechanism of action of allergen immunotherapy. Most researchers agree that three major events commonly occur in patients who receive a course of allergen immunotherapy - first, the production and release of many of the proinflammatory mediators (particularly cytokines) are diminished. This may be via a direct effect on mast cells and eosinophils or an immunoregulatory effect mediated by specific populations of lymphocytes.

Second, it is common to find increasing amounts of allergen-specific IgG circulating in the plasma of patients receiving allergen immunotherapy. Such IgG could also bind to the specific allergen and prevents its interaction with mast cell-bound IgE.

Finally, it can be demonstrated that, after an initial rise, allergen-specific IgE levels in the plasma fall with allergen immunotherapy. This is thought to be due to active immunoregulatory mechanisms that alter how a specific individual responds to a particular allergen.

Not all mechanisms are likely to be active in every treated patient. Many researchers are trying to determine exactly which mechanism(s) is(are) active in a specific patient so allergen immunotherapy can be better tailored to the individual. Also work is ongoing to better chemically define the treating allergens, make allergen immunotherapy safer and even safely increase the interval between injections.