Sunday, July 27, 2008

Basic Immunology

Current Medical Diagnosis & Treatment 2008

Allergy is an immunologically mediated reaction to a foreign antigen manifested by tissue inflammation and organ dysfunction. These responses have a genetic basis, but the clinical expression of disease depends on both immunologic responsiveness and antigen exposure. Allergic disorders may be local or systemic. Because the allergen is foreign (ie, environmental), the skin and respiratory tract are the organs most frequently involved in allergic disease. Allergic reactions may also localize to the vasculature, gastrointestinal tract, or other visceral organs. Anaphylaxis is the most extreme form of systemic allergy.

Immunologic Classification

Hypersensitivity diseases can be classified according to (1) the immunologic mechanism involved in pathogenesis, (2) the organ system affected, and (3) the nature and source of the allergen. An immunologic classification is preferred because it serves as a rational basis for diagnosis and treatment. The classification follows.

Type I—IgE-Mediated (Immediate) Hypersensitivity

IgE antibodies occupy receptor sites on mast cells. Within minutes after exposure to the allergen, a multivalent antigen links adjacent IgE molecules, activating and degranulating mast cells. Clinical manifestations depend on the effects of released mediators on target end organs. Both preformed and newly generated mediators cause vasodilation, visceral smooth muscle contraction, mucus secretory gland stimulation, vascular permeability, and tissue inflammation. Arachidonic acid metabolites, cytokines, and other mediators induce a late-phase inflammatory response that appears several hours later. There are two clinical subgroups of IgE-mediated allergy: atopy and anaphylaxis.


The term "atopy" is applied to a group of diseases (allergic rhinitis, allergic asthma, atopic dermatitis, and allergic gastroenteropathy) occurring in persons with an inherited tendency to develop antigen-specific IgE to environmental allergens or food antigens. Aeroallergens such as pollens, mold spores, animal danders, and house dust mite antigen are common triggers for allergic conjunctivitis, allergic rhinitis, and allergic asthma. The allergic origin of atopic dermatitis is less well understood, but some patients' symptoms can be triggered by exposure to dust mite antigen and ingestion of certain foods.

The allergic reaction is localized to a susceptible target organ, but more than one of these diseases may occur in an allergic individual. There is a strong familial tendency toward the development of atopy.


Certain allergens—especially drugs, insect venoms, latex, and foods—may induce an IgE antibody response, causing a generalized release of mediators from mast cells and resulting in systemic anaphylaxis. This is characterized by (1) hypotension or shock from widespread vasodilation, (2) bronchospasm, (3) gastrointestinal and uterine muscle contraction, and (4) urticaria or angioedema. The condition is potentially fatal and can affect both nonatopic and atopic persons. Isolated urticaria and angioedema are cutaneous forms of anaphylaxis, are much more common, and have a better prognosis.

Type II—Antibody-Mediated (Cytotoxic) Hypersensitivity

Cytotoxic reactions involve the specific reaction of either IgG or IgM antibody to cell-bound antigens. This results in activation of the complement cascade and the destruction of the cell to which the antigen is bound. Examples include immune hemolytic anemia and Rh hemolytic disease in the newborn.

Type III—Immune Complex-Mediated Hypersensitivity

Immune complex-mediated reactions occur when similar concentrations of antigen and IgG or IgM antibodies form circulating immune complexes. Complexes are usually cleared from the circulation by the phagocytic system. However, deposition of these complexes in tissues or in vascular endothelium can produce immune complex-mediated tissue injury through activation of the complement cascade, anaphylatoxin generation, chemotaxis of polymorphonuclear leukocytes, phagocytosis, and tissue injury. The Arthus reaction is an example of a localized cutaneous and subcutaneous inflammatory response to injected allergen. Serum sickness is characterized by fever, arthralgias, nephritis, and dermatitis. It can be a response to a drug, a foreign serum, or certain infections such as infective endocarditis and hepatitis B.

Type IV—T Cell–Mediated Hypersensitivity (Delayed Hypersensitivity, Cell-Mediated Hypersensitivity)

Type IV delayed hypersensitivity is mediated by activated T cells, which accumulate in areas of antigen deposition. The most common expression of delayed hypersensitivity is allergic contact dermatitis, which develops when a low-molecular-weight sensitizing substance haptenates with dermal proteins, becoming a complete antigen. Sensitized T cells release cytokines, activating macrophages and promoting the subsequent dermal inflammation; this occurs 1–2 days after the time of contact. Common topical agents associated with allergic contact dermatitis include nickel, formaldehyde, potassium dichromate, thiurams, mercaptos, parabens, quaternium-15, and ethylenediamine. Rhus (poison oak and ivy) contact dermatitis is caused by cutaneous exposure to oils from the toxicodendron plants. Acutely, contact dermatitis is characterized by erythema and induration with vesicle formation, often with pruritus, with exudation and crusting in more severe cases. Chronic allergic contact dermatitis may be associated with fissuring, lichenification, or dyspigmentation and may be mistaken for other forms of dermatitis. To diagnose allergic contact dermatitis, patch testing can be performed. Panels of common sensitizing agents are applied to the skin, and cutaneous responses are observed 48 and 96 hours later for evidence of induration and vesiculation. Hypersensitivity pneumonitis (extrinsic allergic alveolitis) is a pulmonary hypersensitivity disease that appears to be due in part to T cell–mediated inflammation. Although identification of serum precipitins indicates the presence of antigen-specific IgG antibodies in the circulation, specific T cell populations may be found during bronchoalveolar lavage or during histopathologic examination of involved tissue, supporting a role of type IV reactions in the pathophysiology of this disease.


Atopic disorders are associated with tissue inflammation, characterized immunohistologically by infiltration with certain subsets of CD4 lymphocytes. This has generated interest in the T helper 1 (TH1)/T helper 2 (TH2) paradigm of allergic immunopathology. In this model, antigen-specific CD4 (T helper) cells develop into one of two lymphocyte subsets—TH1 or TH2—which comprise the functional phenotype of the T helper cell. TH1 cells produce gamma interferon (IFN-γ). TH2 cells synthesize interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13). Since both IL-4 and IL-13 stimulate isotype switching with IgE synthesis and since IL-5 promotes eosinophil survival and function, these cytokines have been implicated in the generation of allergic inflammation. TH1 and TH2 phenotypes appear to be mutually exclusive. The development of a dominant TH2 response to an environmental allergen may be the cause of IgE-mediated hypersensitivity disease. The association between early childhood exposure to viral infections and a reduced risk of development of atopy disease may be explained by this paradigm.

Upper & Lower Airway Connections

Up to 80% of asthmatic patients suffer from rhinitis and, conversely, 15% of patients with allergic rhinitis have asthma. Furthermore, the immunopathophysiology of inflammation is similar in the upper and lower airways. Both airways are lined by pseudostratified columnar epithelium. In atopic states, these airways are characterized by edematous mucosa, hyperplasia of mucus-secreting goblet cells, numerous mast cells, infiltration with mononuclear cells, including TH2-type lymphocytes and eosinophils, and airway hyperresponsiveness. Only the lower airways contain bronchial smooth muscle, but the similarities in immunohistology otherwise suggest an overlap in the causes of and possible treatments for disease. There is a measurable reduction in bronchial hyperreactivity after treatment of upper airway inflammation with topical nasal corticosteroids alone. Concomitant sinusitis can lead to a worsening of asthma in some patients, and sinobronchial reflexes have been identified. These observations suggest a coordinated approach to airways disease to optimize patient care of atopic individuals.

The Late-Phase Allergic Response

The immediate allergic response occurs after reexposure to allergen in previously sensitized individuals. Six to 12 hours following allergen exposure, a late-phase allergic response can cause a recrudescence of symptoms in anaphylaxis or allergic airways disease. Histologically, the late-phase allergic responses are characterized by infiltration with inflammatory cells, including mononuclear cells, basophils, and eosinophils. These cells release mediators that cause symptoms but also set the stage for chronic inflammation, persistence of disease, and the phenomenon of "priming" or heightened sensitivity to antigen. Increased nonspecific hyperresponsiveness to respiratory irritants can also be secondary to mediators released during the late phase. A rationale for topical corticosteroids or allergen immunotherapy in the treatment of allergic rhinitis or allergic asthma is based on the observation that suppression of the late-phase reaction will decrease eosinophil activity, and inhibit allergen-induced cytokine production and mediator release, inhibiting proinflammatory responses and chronic symptoms.

Atopic Disease

Clinical manifestations resembling allergic hypersensitivity can also occur in the absence of an immunologic mechanism. Specific examples include nonallergic (intrinsic) asthma, which is triggered by the effect of inhaled dusts and fumes, weather changes, viral respiratory infections, and stress rather than by aeroallergen-induced IgE-mediated mast cell degranulation; irritant dermatitis, the result of physical or chemical damage to skin rather than development of sensitized lymphocytes; and "anaphylactoid reactions" from nonimmunologic release of mast cell mediators. Therefore, the diagnosis of allergy requires answers to the following questions: (1) What is the nature of the disease? (2) Is the disease caused by an IgE-mediated mechanism? (3) What specific allergens are responsible?

The relevant history includes a survey of allergen exposure associated with home, work, hobbies, and habits as well as medications. Physical examination is most useful if performed during exposure. Demonstration of allergic hypersensitivity by in vivo or in vitro testing confirms clinical suspicions of allergic disease.

Specific IgE Antibody Tests

To maximize the positive predictive value of allergy testing, a positive test result must be correlated with the history. Patients selected for testing include those with moderate to severe disease, those who are potential candidates for allergen immunotherapy, and those with strong predisposing factors for atopic diatheses, eg, a strong family history of atopy or ongoing exposure to potential sources of allergen. Since the development of rhinitis precedes the presentation of asthma in over half of cases, early intervention may decrease the risk of more severe clinical allergic disease. The type of immune response must be consistent with the nature of the disease. IgE antibody causes allergic rhinitis but not allergic contact dermatitis. IgE antibodies are detected by in vivo (skin tests) or in vitro methods.

Skin Tests

Epicutaneous or cutaneous allergen testing produces a localized pruritic wheal (induration) and flare (erythema) that is maximal at 15–20 minutes. It is used most commonly in the diagnosis of allergic respiratory disease (rhinitis and asthma) but also in suspected cases of food or drug allergy and hymenoptera (bee, wasp, hornet or yellow jacket) venom hypersensitivity. Allergen extracts are available for pollens, fungi, animal danders, and dust mites and are selected appropriately for the patient's geographic area.

Skin testing is preferred to in vitro methods (discussed below) because it detects the presence of IgE antibody in tissue and shows biologic activity. In vivo skin testing is generally more sensitive, more specific, more rapid, and less expensive than in vitro radioallergosorbent (RAST) testing. Any drug with antihistamine effects (H1-antagonists, tricyclic antidepressants, phenothiazines) must be withdrawn prior to testing. Appropriate controls with a negative diluent and a positive histamine response are mandatory for valid results and accurate interpretation. There is a remote risk of inducing a systemic reaction. To avoid this, most allergists perform epicutaneous (prick) testing first, followed by selected intradermal tests to allergens negative by prick testing. Intradermal skin testing techniques are often used for diagnostic confirmation of hymenoptera (insect venom) or penicillin hypersensitivity, as this method increases sensitivity of the assay for detection of IgE-mediated anaphylaxis. Skin testing with hymenoptera venom or a drug is performed by serial titration, starting with diluted solutions. Special allergenic extracts can be prepared for other allergens (food or latex).

Skin testing for allergy to drugs is reliable for high-molecular-weight proteins (eg, heterologous serum) but not for low-molecular-weight compounds (most drugs), which must bind to larger proteins (haptens) to become immunogenic. With the exception of penicillin, in vivo skin testing for low-molecular-weight drugs is limited in sensitivity and availability. Penicillin testing is available because the immunochemistry has been delineated, identifying all haptenated molecules including the native drug and all immunogenic metabolites. The combination of skin testing with the major and minor metabolic determinants of penicillin is highly predictive of anaphylaxis. (The minor determinants are not available commercially, though they may be synthesized and are often available at specialized centers.) The negative predictive value of skin tests for IgE-mediated reactions to subsequently administered penicillin is good.

In Vitro Tests of IgE Antibody

IgE antibodies can be detected in serum by RAST or enzyme-linked immunosorbent assay (ELISA). Many of the usual atopic allergens are available commercially for RAST or ELISA testing. In vitro tests detect allergen-specific antibody in serum. Since IgE-mediated allergy is caused by IgE antibodies bound to mast cells (not by circulating IgE), in vitro tests generally are less sensitive than skin tests for diagnostic use. They are not affected by antihistamine therapy but can give false-positive results in patients with high total serum IgE levels and false-negative results in patients treated with immunotherapy who have significant allergen-specific IgG antibodies. The test is significantly more expensive than skin testing, and results are not immediately available. The RAST or ELISA method is particularly useful for detecting IgE antibodies to certain occupational chemicals or potentially toxic allergens. The total IgE level in serum is higher in atopic patients but because of overlap, it is not a satisfactory diagnostic test for atopy.

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