| 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. Atopy 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. Anaphylaxis 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. Immunopathophysiology 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. |