The immune system is an integral part of human protection against disease, but the normally protective immune mechanisms

can sometimes cause detrimental reactions in the host. Such reactions are known as hypersensitivity reactions, and the study of these is termed immunopathology. The traditional classification for hypersensitivity reactions is that of Gell and Coombs and is currently the most commonly known classification system.[1] It divides the hypersensitivity reactions into the following 4 types: Type I reactions (ie, immediate hypersensitivity reactions) involve immunoglobulin E (IgE)mediated release of histamine and other mediators from mast cells and basophils. Type II reactions (ie, cytotoxic hypersensitivity reactions) involve immunoglobulin G or immunoglobulin M antibodies bound to cell surface antigens, with subsequent complement fixation. Type III reactions (ie, immune-complex reactions) involve circulating antigen-antibody immune complexes that deposit in postcapillary venules, with subsequent complement fixation. Type IV reactions (ie, delayed hypersensitivity reactions, cell-mediated immunity) are mediated by T cells rather than by antibodies. Some authors believe this classification system may be too general and favor a more recent classification system proposed by Sell et al.[2] This system divides immunopathologic responses into the following 7 categories: Pathophysiology: mmediate hypersensitivity reactions are mediated by IgE, but T and B cells play important roles in the development of these antibodies. T helper (TH) cells, which are CD4+, have been divided into 2 broad classes based on the cytokines they produce: TH1 and TH2.[5, 6] Regulatory T cells (Tregs) are CD4+CD25+ and may also play a role.[7] TH1 cells produce interferon gamma, interleukin (IL)2, and tumor necrosis factor-beta and promote a cell-mediated immune response (eg, delayed hypersensitivity reaction). TH2 cells, on the other hand, produce IL-4 and IL-13, which then act on B cells to promote the production of antigen-specific IgE. Therefore, TH2 cells play an important role in the development of immediate hypersensitivity reactions, and patients who are atopic are thought to have a higher TH2-to-TH1 cell ratio. Interestingly, the cytokines produced by TH1 cells (specifically interferon gamma) seem to diminish the production of TH2 cells.[8, 5, 6] Current evidence suggests that Tregs may also actively inhibit TH2 responses to allergens.[7] The allergic reaction first requires sensitization to a specific allergen and occurs in genetically predisposed individuals. The allergen is either inhaled or ingested and is then processed by the dendritic cell, an antigen-presenting cell.[9] The antigen-presenting cells then migrate to lymph nodes, where they prime naive TH cells (TH0 cells) that bear receptors for the specific antigen. TH0 cells are undifferentiated CD4 cells that release both TH1 and TH2 cytokines and can develop into either cell type. In the case of allergen sensitization, the TH0 cells are thought to be exposed to IL-4 (from as yet unidentified sources, but including germinal-center B cells) and possibly to histamineprimed dendritic cells, both of which cause them to develop into TH2 cells. These primed TH2 cells then release more IL-4 and IL-13. IL-4 and IL-13 then act on B cells to promote production of antigenspecific IgE antibodies.

For this to occur, B cells must also bind to the allergen via allergen-specific receptors. They then internalize and process the antigen and present peptides from it, bound to the major histocompatibility class II molecules found on B-cell surfaces, to the antigen receptors on TH2 cells. The B cell must also bind to the TH2 cell and does so by binding the CD40 expressed on its surface to the CD40 ligand on the surface of the TH2 cell. IL-4 and IL-13 released by the TH2 cells can then act on the B cell to promote class switching from immunoglobulin M production to antigen-specific IgE production (see image below). Immediate hypersensitivity reactions. Sensitization phase of an immunoglobulin Emediated allergic reaction. The antigen-specific IgE antibodies can then bind to high-affinity receptors located on the surfaces of mast cells and basophils. Reexposure to the antigen can then result in the antigen binding to and cross-linking the bound IgE antibodies on the mast cells and basophils. This causes the release and formation of chemical mediators from these cells. These mediators include preformed mediators, newly synthesized mediators, and cytokines. The major mediators and their functions are described as follows:[5, 6] Preformed mediators Histamine: This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause contraction of smooth muscles of the airway and GI tract, increased vasopermeability and vasodilation, enhanced mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion. Tryptase: Tryptase is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a as well as C5.[10] Tryptase is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation. Proteoglycans: Proteoglycans include heparin and chondroitin sulfate. The role of the latter is unknown; heparin seems to be important in storing the preformed proteases and may play a role in the production of alpha-tryptase. Chemotactic factors: An eosinophilic chemotactic factor of anaphylaxis causes eosinophil chemotaxis; an inflammatory factor of anaphylaxis results in neutrophil chemotaxis. Eosinophils release major basic protein and, together with the activity of neutrophils, can cause significant tissue damage in the later phases of allergic reactions. Newly formed mediators Arachidonic acid metabolites Leukotrienes - Produced via the lipoxygenase pathway Leukotriene B4 - Neutrophil chemotaxis and activation, augmentation of vascular permeability Leukotrienes C4 and D4 - Potent bronchoconstrictors, increase vascular permeability, and cause arteriolar constriction Leukotriene E4 - Enhances bronchial responsiveness and increases vascular permeability Leukotrienes C4, D4, and E4 - Comprise what was previously known as the slow-reacting substance of anaphylaxis Cyclooxygenase products Prostaglandin D2 - Produced mainly by mast cells; bronchoconstrictor, peripheral vasodilator, coronary and pulmonary artery vasoconstrictor, platelet aggregation inhibitor, neutrophil chemoattractant, and enhancer of histamine release from basophils Prostaglandin F2-alpha - Bronchoconstrictor, peripheral vasodilator, coronary vasoconstrictor, and platelet aggregation inhibitor Thromboxane A2 - Causes vasoconstriction, platelet aggregation, and bronchoconstriction

Platelet-activating factor (PAF): PAF is synthesized from membrane phospholipids via a different pathway from arachidonic acid. It aggregates platelets but is also a very potent mediator in allergic reactions. It increases vascular permeability, causes bronchoconstriction, and causes chemotaxis and degranulation of eosinophils and neutrophils. Adenosine: This is a bronchoconstrictor that also potentiates IgE-induced mast cell mediator release. Bradykinin: Kininogenase released from the mast cell can act on plasma kininogens to produce bradykinin. An additional (or alternative) route of kinin generation, involving activation of the contact system via factor XII by mast cell released heparin, has been described.[11, 12] Bradykinin increases vasopermeability, vasodilation, hypotension, smooth muscle contraction, pain, and activation of arachidonic acid metabolites. However, its role in IgE-mediated allergic reactions has not been clearly demonstrated.[3] Cytokines IL-4: IL-4 stimulates and maintains TH2 cell proliferation and switches B cells to IgE synthesis. IL-5: This cytokine is key in the maturation, chemotaxis, activation, and survival of eosinophils. IL-5 primes basophils for histamine and leukotriene release. IL-6: IL-6 promotes mucus production. IL-13: This cytokine has many of the same effects as IL-4. Tumor necrosis factor-alpha: This activates neutrophils, increases monocyte chemotaxis, and enhances production of other cytokines by T cells.[13] The actions of the above mediators can cause variable clinical responses depending on which organ systems are affected, as follows: Urticaria/angioedema: Release of the above mediators in the superficial layers of the skin can cause pruritic wheals with surrounding erythema. If deeper layers of the dermis and subcutaneous tissues are involved, angioedema results. Angioedema is swelling of the affected area; it tends to be painful rather than pruritic. Allergic rhinitis: Release of the above mediators in the upper respiratory tract can result in sneezing, itching, nasal congestion, rhinorrhea, and itchy or watery eyes. Allergic asthma: Release of the above mediators in the lower respiratory tract can cause bronchoconstriction, mucus production, and inflammation of the airways, resulting in chest tightness, shortness of breath, and wheezing. Anaphylaxis: Systemic release of the above mediators affects more than one system and is known as anaphylaxis. In addition to the foregoing symptoms, the GI system can also be affected with nausea, abdominal cramping, bloating, and diarrhea. Systemic vasodilation and vasopermeability can result in significant hypotension and is referred to as anaphylactic shock. Anaphylactic shock is one of the two most common causes for death in anaphylaxis; the other is throat swelling and asphyxiation.[3, 6] Allergic reactions can occur as immediate reactions, late-phase reactions, or chronic allergic inflammation. Immediate or acute-phase reactions occur within seconds to minutes after allergen exposure. Some of the mediators released by mast cells and basophils cause eosinophil and neutrophil chemotaxis. Attracted eosinophils and resident lymphocytes are activated by mast cell mediators.

These and other cells (eg, monocytes, T cells) are believed to cause the late-phase reactions that can occur hours after antigen exposure and after the signs or symptoms of the acute-phase reaction have resolved. The signs and symptoms of the late-phase reaction can include redness and swelling of the skin, nasal discharge, airway narrowing, sneezing, coughing, and wheezing. These effects can last a few hours and usually resolve within 24-48 hours. Finally, continuous or repeated exposure to an allergen (eg, a cat-owning patient who is allergic to cats) can result in chronic allergic inflammation. Tissue from sites of chronic allergic inflammation contains eosinophils and T cells (particularly TH2 cells). Eosinophils can release many mediators (eg, major basic protein), which can cause tissue damage and thus increase inflammation. This can result in structural and functional changes to the affected tissue. Furthermore, a repeated allergen challenge can result in increased levels of antigen-specific IgE, which ultimately can cause further release of IL-4 and IL-13, thus increasing the propensity for TH2 cell/IgEmediated responses.[

Inactivation/activation antibody reactions

Cytotoxic or cytolytic antibody reactions

Immune-complex reactions

Allergic reactions

T-cell cytotoxic reactions

Delayed hypersensitivity reactions

Granulomatous reactions

This system accounts for the fact that multiple components of the immune system can be involved in various types of hypersensitivity reactions. For example, T cells play an important role in the pathophysiology of allergic reactions (see Pathophysiology). In addition, the term immediate hypersensitivity is somewhat of a misnomer because it does not account for the late-phase reaction or for the chronic allergic inflammation that often occurs with these types of reactions.

Allergic reactions manifest clinically as anaphylaxis, allergic asthma, urticaria, angioedema, allergic rhinitis, some types of drug reactions, and atopic dermatitis. These reactions tend to be mediated by IgE, which differentiates them from pseudoallergic (formerly called anaphylactoid) reactions that involve IgEindependent mast cell and basophil degranulation. Such reactions can be caused by iodinated radiocontrast dye, opiates, or vancomycin and appear similar clinically by resulting in urticaria or anaphylaxis.[3]

Patients prone to IgE-mediated allergic reactions are said to be atopic. Atopy is the genetic predisposition to make IgE antibodies in response to allergen exposure.[4]

The focus of this article is allergic reactions in general. Although some of the clinical manifestations listed previously are briefly mentioned, refer to the articles on these topics for more detail. For example, see Allergic and Environmental Asthma; Anaphylaxis; Food Allergies; Rhinitis, Allergic; and Urticaria.