Mediator of hypersensitivity

Histamine A chemical produced by various cells in the body that is involved in the modulation of certain physiologic responses (e.g., secretion of gastric acid), as well as in the mediation of hypersensitivity (allergic) responses. 

Must histamine is synthesized and stored in mast cells and basophilic granultKytes. Protein-complexed histamine is then stored in secretory granules and released by exocytosis in le.sponse to a wide variety of immune (antigen and antibody) and nonimmunc (bacterial products, xenobiotics, physical effects, and cholinergic effects) stimuli. The release of histamine as one of the mediators of hypersensitivity reactions is initiated by the interaction of an antigen-IgE com-... 

Beta-agonists, indirectly via c-AMP, act on mast cell p2-receptors inhibiting the release of bronchoconstrictor mediators such as histamine. Slow-reacting substance of anaphylaxis (SRS-A), now known to be leukotriene D3 and D4 (Fig. 5-5), and eosinophil chemo-tactic factor of anaphylaxis (ECF-A) may also have their release inhibited by c-AMP. Leukotriene D, which is a mediator of hypersensitivity reactions, may still have an important role in causing asthmatic symptoms. In fact, it is 100 times more effective than histamine in producing vascular permeability. 

Goetzl EJ. Lipid mediators of hypersensitivity and inflammation. In Adkinson NF, Yunginer JW, Busse WW, et al., eds. Middleton s Allergy Principles and Practice. 6th Ed. Philadelphia Mosby, 2003 213-230. 

Allergic Release of Mediators of Hypersensitivity from Mast Cells... 

Goetzl, E. J., 1981 Oxygenation products of arachidonic acid as mediators of hypersensitivity and inflammation. Med. Clin. North Am. 65, 809-828. 

The rate of non-lgE-mediated immediate hypersensitivity reactions usually varies between 20 and 50% [1-7, 9], They are assumed to result from direct non-specific mast cell and basophil activation, which causes direct histamine release [19], Histamine release is predominantly found with the use of the benzylisoquinoUnes d-tubocurarine, atracurium and mivacurium, and the aminosteroid rapacuronium. Severe bronchospasm related to rapacuronium administration has been reported in children and adults. It might be related to the higher affinity of rapacuronium for M2 versus M3 muscarinic receptors [20]. Rapacuronium has been withdrawn from the market in the USA. 

Hypnotics. Common hypnotics are thiopental, propofol, midazolam, etomidate, ketamine and inhaled anesthetics. The incidence of hypersensitivity reactions with thiopental is rare. Recently, thiopental was involved in less than 1% of allergic reactions in France [9]. Ever since Cremophor EL, used as a solvent for some non-barbiturate hypnotics, has been avoided, many previously reported hypersensitivity reactions have disappeared. In the last French surveys, reactions to propofol accounted for less than 2.5% of allergic reactions, and reactions to midazolam, etomidate or ketamine appear to be really rare [9]. Finally, no immune-mediated immediate hypersensitivity reaction involving isoflurane, desflurane or sevoflurane has been reported despite their wide use. 

IgE Mediates immediate hypersensitivity by causing release of mediators from mast cells and basophils upon exposure to antigen (allergen). Defends against worm infections by causing release of enzymes from eosinophils. Does not fix complement. Main host defense against helminthic infections. 

An immediate reaction occurs within seconds to minutes, resulting in the rapid release of preformed mediators and newly generated mediators from the arachidonic acid cascade. Mediators of immediate hypersensitivity include histamine, leukotrienes, prostaglandin, tryptase, and kinins. These mediators cause vasodilation, increased vascular permeability, and production of nasal secretions. Histamine produces rhinorrhea, itching, sneezing, and nasal obstruction. 

The other major arachidonic acid (AA) converting enzyme is an integral binding protein, 5-lipoxygenase, which is responsible for the initial transformation in a cascade of events towards the biosynthesis of leukotrienes. Leukotrienes are major mediators of numerous biological processes, including chemotaxis, and are implicated in hypersensitivity disorders like asthma. It was discovered in the early 1990s that another protein is necessary for the cellular synthesis of... 

In sensitized asthmatic individuals, antigen challenge generally causes a Type I (IgE-mediated) immediate hypersensitivity response by release of preformed mediators, including histamine, and prostaglandins, which are responsible for bronchoconstric-tion and increased vascular permeability. Between 2 and 8 hours after the immediate response, asthmatics experience a more severe and prolonged (late phase) reaction that is characterized by mucus hyper-secretion, bronchoconstriction, airway hyperresponsiveness to a variety of nonspecific stimuli (e.g., histamine, methacholine), and airway inflammation characterized by eosinophils. This later response is driven by leukotrienes, chemokines and cytokines synthesized by activated mast cells and Th2 cells. Both proteins and haptens have been associated with these types of reactions. 

Jackson, A. and Hammerberg, B., Evaluation of a spontaneous canine model of immunoglobulin E-mediated food hypersensitivity dynamic ranges in serum and fecal allergen-specific immunoglobulin E values relative to dietary change. Comp. Med., 52, 316, 2002. 

Adkinson, Jr., N.F. et al., Task force report future research needs for the prevention and management of immune-mediated drug hypersensitivity reactions, J. Allergy Clin. Immunol., 109, S461, 2002. 

Types II and III Hypersensitivity. No simple animal models are currently available to assess Type II (antibody-mediated cytotoxicity) hypersensitivity reactions. IgE antibodies and immune complexes in the sera of exposed animals can be assayed using ELISA or RIA techniques that require the use of specific antibodies to the drug. 

Individualistic adverse reactions to foods can occur through several different types of mechanisms (Taylor and Hefle, 2001). True allergic reactions can include both IgE-mediated immediate hypersensitivity reactions and cell-mediated delayed h)q5ersensitivity reactions (Taylor and Hefle, 2001). However, only IgE-mediafed reactions have been documented to occur with ingestion of molluscan shellfish in sensifive individuals. 

These are adverse reactions resembling the effects of histamine liberation Chistaminoid ) and unrelated to the mode of action of the drug itself. Histamine release appears to be the main factor involved in all types of hypersensitivity reactions and its release explains most of the manifestations. The term anaphylactoid may equally be used to describe these reactions, meaning simply that they resemble anaphylactic reactions, while the term anaphylactic is used specifically for immune-mediated phenomena involving previous sensitisation of the patient. It is often difficult to determine the true nature and cause of the reaction. 

Hypersensitivity can be classified as antibody-mediated or cell-mediated. Three types of hypersensitivity are antibody-mediated (types I—III), while the fourth is cell-mediated (type IV). Hypersensitivity occurs in two phases the sensitization phase and the effector phase. Sensitization occurs upon initial encounter with an antigen the effector phase involves immunologic memory and results in tissue pathology upon a subsequent encounter with that antigen. 

Drug reactions mediated by immune responses can have several different mechanisms. Thus, any of the four major types of hypersensitivity discussed earlier in this chapter (page 967) can be associated with allergic drug reactions ... 

The newer derivatives seem less likely to cause hypersensitivity reactions, perhaps because the protein adducts generated are shorter lived. All four types of hypersensitivity reaction have been observed with penicillin. Thus, high doses may cause hemolytic anemia and immune complex disease and cell-mediated immunity may give rise to skin rashes and eruptions, and the most common reactions are urticaria, skin eruptions, and arthralgia. Antipenicillin IgE antibodies have been detected consistently with an anaphylactic reaction. The anaphylactic reactions (type 1 see above), which occur in 0.004% to 0.015% of patients, may be life threatening. 

Serafin WE, Austen KF. 1987. Mediators of immediate hypersensitivity reactions. NEJM. 317 30-34. 

---