Mechanisms of anaphylaxis

A complement-independent mechanism of anaphylaxis would be classical allergy employing IgE antibodies. We found these antibodies to be elevated in only a few cases—possibly atopic individuals [142]. The serum of one of these children was used for passive sensitization of basophils of a healthy blood donor. The cells released histamine upon incubation of the cells with 1-ASP (Fig. 10). indicating that in some children IgE-mediated allergy may also play a role for clinical symptoms,... 

Finkelman, F.D., Rothenberg, M.E., Brandt, E.B., Morris, S.C., and Strait, R.T. 2005. Molecular mechanisms of anaphylaxis Lessons from studies with murine models. J Allergy Clin Immunol 115 449 157. 

Dejarnatt AC, Grant JA. Basic mechanisms of anaphylaxis and anaphylactoid reactions. Immunol Allergy Clin North Am 1992 12 33-46. 

Gardner RC, Ovary Z (1960) Immunologic mechanism of anaphylaxis. III. Inhibition phenomenon in passive cutaneous anaphylaxis in the mouse. Proc Soc Exp Biol Med 105 342... 

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Otz U, Schneider CH, de Week AL, Gruden E, Gill TG (1978) Induction of immunological tolerance to the penicilloyl antigenic determinant I. Evaluation of BPO-amino acid polymers and copolymers in mice. Eur J Immunol 8 406 Ovary Z, Karush F (1960) Studies on the immunologic mechanism of anaphylaxis I. Anti-body-hapten interactions studied by passive cutaneous anaphylaxis in the guinea pig. J Immunol 84 409... 

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. 

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. 

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]. 

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]. 

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]. 

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