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Review
. 2015 Oct:36:80-7.
doi: 10.1016/j.coi.2015.07.001. Epub 2015 Jul 23.

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

Mindy Tsai  1 , Philipp Starkl  1 , Thomas Marichal  2 , Stephen J Galli  3
Affiliations
Review

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

Mindy Tsai et al. Curr Opin Immunol. 2015 Oct.

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.

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Conflict of interest statement

An annotated bibliography with comments about some of the same articles which are cited and commented on in this review is scheduled to appear in the October, 2015 issue of Experimental Dermatology, to accompany a lecture that will be given by Stephen J. Galli at a meeting organized by the Fondation René Touraine, on "Mast cells and urticaria", that will be held in Paris, France, on December 4, 2015.

Figures

Figure 1
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
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.
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References

    1. Akahoshi M, Song CH, Piliponsky AM, Metz M, Guzzetta A, Abrink M, Schlenner SM, Feyerabend TB, Rodewald HR, Pejler G, et al. Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice. J Clin Invest. 2011;121:4180–4191. ** Studies employing MC-engrafted genetically MC-deficient WBB6F1-KitW/W-v and C57BL/6-KitW-sh/W-sh mice, as well as mice lacking either the MC chymase, MC protease-4 (MCPT4) or CPA3 enzymatic activity, showed that MCs and MCPT4 (which can degrade helodermin, a peptide in Gila monster [Heloderma suspectum] venom that is structurally similar to mammalian VIP), but not CPA3, can enhance host resistance to the toxicity of Gila monster venom. MCs and MCPT4 also limited the toxicity associated with high concentrations of VIP, and reduced the morbidity and mortality induced by the venoms of the Deathstalker (Yellow) scorpion (Leiurus quinquestriatus hebraeus) and the Arizona bark scorpion (Centruroides exilicauda).

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