Testing the 'toxin hypothesis of allergy': mast cells, IgE, and innate and acquired immune responses to venoms

Abstract

Work in mice indicates that innate functions of mast cells, particularly degradation of venom toxins by mast cell-derived proteases, can enhance resistance to certain arthropod or reptile venoms. Recent reports indicate that acquired Th2 immune responses associated with the production of IgE antibodies, induced by Russell's viper venom or honeybee venom, or by a component of honeybee venom, bee venom phospholipase 2 (bvPLA2), can increase the resistance of mice to challenge with potentially lethal doses of either of the venoms or bvPLA2. These findings support the conclusion that, in contrast to the detrimental effects associated with allergic type 2 (Th2) immune responses, mast cells and IgE-dependent immune responses to venoms can contribute to innate and adaptive resistance to venom-induced pathology and mortality.

Figure 1. Mast cells can enhance resistance to both high levels of endogenous peptides (helping to restore homeostasis) and structurally similar peptides in reptile venoms

Mouse MC cytoplasmic granules contain proteases such as carboxypeptidase A3 (mCPA3) and mast cell protease 4 (mMCPT4) that, upon secretion by activated mast cells, can degrade certain endogenous peptides, such as endothelin-1 (ET-1) and vasoactive intestinal polypeptide (VIP), respectively, as well as structurally similar peptides contained in the venoms of poisonous reptiles, such as sarafotoxin 6b in the venom of the Israeli mole viper (Atractaspis engaddensis) and helodermin in the venom of the Gila monster (Heloderma suspectum). The ability of mast cells to be activated to degranulate by components of venoms such as these, which can act at the same receptors which recognize the corresponding structurally similar endogenous peptides, permits mast cells to release proteases that can reduce the toxicity of these peptides and which thereby help to enhance the survival of mice injected with the whole venoms of these reptiles, that contain many toxins in addition to sarafotoxin 6b and helodermin. This mechanism may also permit mast cells to restore homeostasis in settings associated with markedly increase levels of the endogenous peptides. This is a modified version of Fig. 4 in the review: Rouse-Whipple Award Lecture: The mast cell-IgE paradox: From homeostasis to anaphylaxis, by Stephen J. Galli, reproduced with the permission of the publisher.

Figure 2. Innate and IgE/ FcεRI-dependent activation of mast cells by venom components can enhance resistance to a potentially lethal dose of whole venoms

(A) MCs can enhance innate resistance of mice to the morbidity and mortality induced by the whole venoms of the honeybee, three species of snakes (Israeli Mole Viper, Western diamondback rattlesnake, and Southern copperhead), the Gila monster lizard, and two species of scorpions through mechanisms that depend on the release of mediators that can neutralize toxic components of venoms. (B) Injection of a sub-lethal dose of honeybee (BV) or Russell's viper venom (RVV) induces an adaptive type 2 immune response in mice that is associated with development of IgE antibodies that can increase the resistance of mice to a potentially lethal dose of the same venom. (C) The protective effect of the type 2 immune response against BV is mediated by IgE antibodies, FcεRI and mast cells.