Anaphylaxis mechanisms

There are also other immimological mechanisms, especially via IgG or IgM antibodies with immune complex formation, which can lead to similar clinical conditions [20, 34, 42] as has been shown in dextran anaphylaxis (table 1). Triggering of mast cells and basophils leads to release of various vasoactive mediators, among which histamine was the first recognized in 1908 (fig. 3,4) [6]. 

This chapter highlights the mechanisms responsible for mast cell activation during anaphylactic responses to environmental substances. In addition to discussing in detail the activation of mast cells and basophils by IgE and antigen, we also will describe how mouse models have been used to analyze the importance of various proteins, cells, mediators and activation mechanisms in the expression of anaphylaxis in that species. 

Although human anaphylaxis is a systemic reaction, the mouse model of passive cutaneous anaphylaxis (PGA) has been used extensively to enhance our understanding of mechanisms which also may contribute to systemic anaphylaxis. Unlike systemic anaphylaxis in the mouse, PGA appears to be entirely dependent on mast cells [4,6]. While IgE appears to be the primary antibody isotype that mediates PCA reactions in actively immunized mice, activation of FcyRIII by a fraction of IgGl antibodies (called anaphylactic IgGl) can also mediate PCA reactions in mice [4]. 

Few prospective studies of induced anaphylaxis have been performed in human subjects to imderstand the molecular basis of systemic anaphylaxis, because of the potentially rapid, Ufe-threatening outcome. Accordingly, various models of anaphylaxis have been estabUshed in laboratory animals, particularly mice, and extensively studied to clarify the underlying mechanisms. Such studies revealed that the classical pathway utilizing mast cells, IgE and histamine cannot explain all cases of anaphylaxis. 

Kemp SF, Lockey RF Anaphylaxis a review of causes and mechanisms. J Allergy Clin Immunol 2002 110 341-348. 

Studies have now started to clarify the role of histamine Hi and H2 receptors in the cardiovascular manifestations of anaphylaxis. However, histamine can activate H3 and H4 receptors [56, 57]. Levi and coworkers [58-60] identified H3 receptors as inhibitory heteroreceptors in cardiac adrenergic nerve endings. This suggests a mechanism by which endogenous histamine can activate norepinephrine release in normal and ischemic conditions [61,62]. The functional identification ofH3 receptors in the human heart [59] means that these receptors might be directly and/or indirectly involved in the cardiovascular manifestations of anaphylactic reactions. 

Mast cells express high-affinity IgE Fc receptors (FceRI) on their surface, contain cytoplasmic granules which are major sources of histamine and other inflammatory mediators, and are activated to release and generate these mediators by IgE-dependent and non-IgE-dependent mechanisms [1]. Disturbances either in the release of mast cell mediators or in mast cell proliferation are associated with clonal mast cell disorders including monoclonal mast cell activation syndrome (MMAS) and mastocytosis respectively, which are in turn associated with some cases of anaphylaxis [2], Molecular mechanisms have been identified which may link increased releasability of mast cell mediators and conditions leading to increased mast cell numbers [3]. Patients with mastocytosis have an increased risk to develop anaphylaxis [4, 5] and those with anaphylaxis may suffer from unrecognized mastocytosis or may display incomplete features of the disease [6-8]. 

Physical factors, such as heat, mechanical stimulation and exercise, may sometimes lead to mast cell degranulation and whealing in the skin, but rarely provoke systemic anaphylaxis [4, 26]. Patients do report that these and other factors in combination (such as exercise, heat and alcohol) may elicit anaphylaxis in summation. 

The mechanisms of the allergy-like reactions to RCM are still a matter of speculation (table 2). Anaphylaxis to RCM has been discussed to be due to a direct membrane effect possibly related to the osmolality of the RCM solution or the chemical structure of the RCM molecule (pseudo-allergy) [2], an activation of the complement system [27], a direct bradykinin formation [28], or an IgE-mediated mechanism [3]. 

A non-allergic mechanism imderlying precipitation of asthmatic attacks by aspirin in hypersensitive patients was proposed over 30 years ago [4]. It was founded on pharmacological inhibition of COX of arachidonic acid and explained a cross-reactivity between different NSAIDs varying in chemical structure. This COX theory was confirmed by several studies [11] and was further refined following discovery of the second COX isoenzyme - COX-2. At least two COX isoenzymes, COX-1 and COX-2, are coded by separate genes. Their role in inflammation, asthma and anaphylaxis has been reviewed previously [12]. 

With regard to epinephrines potential adverse cardiac effects, it is important to remember that in anaphylaxis, the heart is a target organ. Mast cells located between myocardial fibers, in perivascular tissue, and in the arterial intima are activated through IgE and other mechanisms to release chemical mediators of inflammation, including histamine, leukotriene C4, and prostaglandin D2. Coronary artery spasm, myocardial injury, and cardiac dysrhythmias have been documented in some patients before epinephrine has been injected for treatment of anaphylaxis, as well as in patients with anaphylaxis who have not been treated with epinephrine [11, 12]. 

---