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

doi:10.1016/j.coi.2015.07.001

Current Opinion in Immunology

Volume 36, October 2015, Pages 80-87

https://doi.org/10.1016/j.coi.2015.07.001 Get rights and content

Highlights

•
Mast cell activation can contribute to innate immunity to multiple animal venoms.
•
Mast cell granule-associated proteases can degrade toxic components of venoms.
•
Th2 immune responses can enhance survival in mice injected with certain venoms.
•
IgE and FcɛRI can be key elements of acquired Th2 immune resistance to venom.
•
IgE-dependent mast cell activation can contribute to acquired resistance to venoms.

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.

Introduction

Venoms from diverse animal species, including honeybees, wasps, scorpions, ants, Portuguese man-of-war, snakes, a lizard, and the platypus can induce mast cell (MC) activation and degranulation [1••, 2, 3, 4••]. Venom-induced release of granule-associated mediators by MCs has been thought to contribute to the symptoms associated with envenomation because some of these MC-derived mediators can increase vascular permeability (enhancing systemic dissemination of venom toxins), promote local recruitment and activation of inflammatory cells, influence complement activation, clotting and fibrinolysis, and induce shock [5]. Moreover, many components of venoms also are ‘allergens’ that can induce host sensitization via induction of type 2 immune responses (hereafter, Th2 immune responses) and production of venom-specific Immunoglobulin E (IgE). Indeed, humans that have been sensitized with venoms, upon subsequent venom exposure, can develop allergic reactions, including fatal anaphylaxis, which reflect the rapid secretion of mediators by MCs activated by venom antigens which induce cross-linking of venom-specific IgE bound to high affinity receptors for IgE on the MCs’ surface [6, 7, 8, 9, 10, 11, 12].

Such findings have supported the conclusion that venomous animals exploit to their own advantage the biological activities of the host's MCs and IgE, recruiting these components of innate and adaptive immunity to increase the toxicity of the venom. In 1991, Margie Profet suggested an alternative interpretation of the evidence indicating that MCs and IgE participate in immune responses to venoms, proposing that these components of innate and adaptive immunity may function to enhance rather than impair host resistance to venoms and, potentially, other toxins [13^••]. We review herein recent lines of evidence from studies in mice supporting the conclusion that both the innate functions of MCs and IgE-dependent Th2 immunity can be beneficial rather than detrimental in host responses to the venoms of some arthropods or reptiles.

Section snippets

Mast cells in innate resistance to envenomation

Higginbotham suggested in 1965 and 1971 that MCs, which are numerous in the skin, might enhance resistance to environmental noxious insults, such as bee stings [2] or snake bites [14^•]. He reported evidence that heparin, a highly anionic proteoglycan stored in MC granules, can neutralize venom toxicity by binding highly cationic components of the venoms, such as melittin in bee venom. This work was done before knock-out or MC-deficient mice had been described, and even now it is difficult to

Mechanisms of mast cell activation in innate responses to envenomation

Multiple mechanisms can contribute to MC activation during envenomation. Some venoms contain peptides that are structurally similar to endogenous peptides (e.g., kallikrein, atrial natriuretic peptide, or vascular endothelial growth factor [20]) and that are recognized by innate receptors on the MC surface. For example, ET_A and ET_B recognize ET-1 and sarafatoxins [4••, 19] while VPAC₁ and VPAC₂ recognize VIP and helodermin [21]. Venoms also can contain cytolytic peptides, enzymes (particularly

IgE, FcɛRI, and mast cells in adaptive immune resistance to envenomation

Allergies, characterized by acquired Th2 immune responses and the production of allergen-specific IgE antibodies [27, 28, 29], are widely considered misdirected and maladaptive immune responses, often against otherwise innocuous environmental agents [30, 31]. The immediate hypersensitivity reactions which occur in sensitized individuals within moments of allergen exposure range from localized areas of swelling, erythema and itching (in response to cutaneous encounters with the allergen) to

Conclusions

Work done independently by two groups now supports the conclusion that Th2 and IgE-associated immune responses can enhance resistance to whole BV [17^••] and bvPLA₂ [39^••]. We think that this likely reflects, at least in part, the ability of MCs bearing on their surface venom-specific IgE antibodies to respond more rapidly and perhaps more extensively to encounters with venom than do MCs which can respond to these venoms solely by innate mechanisms. Such venom-IgE-sensitized MCs also can be

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We thank all members of the Galli laboratory for discussions. T.M. was supported by a Marie Curie International Outgoing Fellowship for Career Development: European Union's Seventh Framework Programme (FP7-PEOPLE-2011-IOF), 299954, and a ‘Charge de recherches’ fellowship of the Belgian National Fund for Scientific Research (F.R.S-FNRS). P.S. was supported by a Max Kade Fellowship of the Max Kade Foundation and the Austrian Academy of Sciences and a Schroedinger Fellowship of the Austrian

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Mast cells likely evolved to promote health and survival of their hosts, but these pathways and mechanisms have facilitated the development of immediate hypersensitivity reactions in humans. Holistically, mast cell activation is best conceived of as summative event having multiple inputs, with antigen-dependent immunoglobulin E (IgE)-mediated hypersensitivity being an important component. Patients with inappropriate mast cell activation, frequently independent of classical IgE-mediated allergic disease(s), are said to have mast cell–associated disorders (MCADs), that in some individuals result from clonal expansion of mast cells. A number of biomarkers and genetic tests have been developed that aid in confirmation of these clinical diagnoses. However, significant limitations remain in diagnostic modalities and management options for patients with suspected MCADs. Here we discuss human mast cells in an historical and evolutionary context and provide a clinical and genetic background for MCADs, as well as a practical approach for their evaluation and diagnosis.
Mast cells in kidney regeneration
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Mast cells are key effectors of inflammation in tissues. In progressive kidney disease, they constitute an essential feature of the observed interstitial infiltrate of inflammatory cells. Their presence was largely interpreted as being contributory to pathology. Recent experimental evidences, however, have highlighted that mast cells participate in multiple features of chronic inflammatory responses in kidneys through diverse effects that besides promoting inflammation can also suppress aspects of these responses and exert beneficial actions. The appropriate and timely controlled secretion of a wide range of inflammatory products by these cells, besides inducing an initial inflammatory response, was shown to take part in antiinflammatory mechanisms and repair activities that contribute to healing. Their action is dictated by the pathophysiologic context. In this chapter, we review the beneficial actions mast cells might have in kidneys and postulate that, when appropriately controlled, their prime action is to contribute to the restoration of tissue homeostasis.
Mast Cells, Basophils, and Mastocytosis
2019, Clinical Immunology: Principles and Practice
Mast cells and basophils are functionally related effector cells of hematopoietic origin that are implicated in allergy, type 2 immune responses to parasites, and innate immunity. Both cell types derive from bone marrow progenitors and express high-affinity IgE Fc receptors (FcεRI) on their surface. Both release histamine and generate a variety of other inflammatory mediators in response to both IgE- and non-IgE-mediated activation. However, there are important differences between mast cells and basophils in terms of their developmental origins, morphology, distribution, and mechanisms and responses to stimulation. Whereas mast cells are normal residents of all vascularized tissues, basophils are recruited to mucosal sites in response to inflammation. Both cells are important effectors of hypersensitivity responses, and both play roles in host defense as well as the pathophysiology of a variety of disease processes. Unchecked mast cell growth underlies mastocytosis, a group of disorders defined by a constellation of symptoms resulting from excessive mast cell products and infiltration into tissues.
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Citation Excerpt :
Furthermore, venom-specific IgE antibodies and IgE-mediated mast cell responses after re-exposure to venoms contribute to protection against lethal doses of these toxic venoms.88,89 An interpretation of these observations in mouse models is that anaphylaxis, when appropriately regulated, is beneficial rather than detrimental in the pathology associated with envenomation.87 The TPSAB1 and TPSB2 mast cell tryptase loci in human subjects encode α- and β-tryptases.
FcεRI is the primary receptor in mast cells that mediates allergic reactions by inducing rapid release of mediators, an adaptive immune response that might have evolved as a host defense against parasites and venoms. Yet it is apparent that mast cells are also activated through non-IgE receptors, the significance of which is just beginning to be understood. This includes the Mas-related G protein–coupled receptor X2, which might contribute to reactions to diverse antimicrobials and polybasic compounds, and the adhesion G protein–coupled receptor E2, variants of which are associated with familial vibratory urticaria and are activated by mechanical vibration. Similarly, mast cells have long been recognized as the main repository for histamine, heparin, and proteases. Recent evidence also points to new functions, modes of delivery, and mechanisms of action of mast cell proteases that add new dimensions to the roles of mast cells in human biology. In addition, exposure of mast cells to environmental cues can quantitatively and qualitatively modulate their responses and thus their effect on allergic inflammation. Illustrating this paradigm, we summarize a number of recent studies implicating the injury/tissue damage cytokine IL-33 as a modulator of allergen-induced mast cell responses. We also discuss the discovery of markers associated with transformed mast cells and new potential directions in suppressing mast cell activity.
In vitro antihistamine-releasing activity of a peptide derived from wasp venom of Vespa orientalis
2016, Asian Pacific Journal of Tropical Biomedicine
Citation Excerpt :
Thus, researchers concerning mast cells should focus on their detrimental pathologic effects. However, mast cells play important roles in homeostasis and may have a significant function in defense against parasitic and bacterial infections, the healing of wounds, and participating in innate and adaptive immunity [2]. Mast cells are the initial storage location of histamine in mammalian tissues and placed in secretory granules [3].
To investigate the antihistamine-releasing effect of a peptide isolated from wasp venom of Vespa orientalis.
This peptide was separated from crude venom by chromatography methods and mass spectrometry. Then various concentrations (2, 4, 8, 16, 32, 64, 128 and 256 μmol/L) of the peptide were incubated with mast cells and lactate dehydrogenase assay was performed.
No significant effect was observed in lactate dehydrogenase absorbance under 128 μmol/L concentration. This implied that the peptide did not cause cell death in mast cells and consequently, histamine release did not happen. Moreover, the results showed the IC₅₀ of mast cells degranulation at 126 μmol/L, which was approximately high implying that this peptide had high selectivity for normal cells and did not cause histamine release from these cells.
This would be a great aim in new drug development, in which an agent acts potentially on its target tissue without activating the immune system.
SnapShot: Integrated Type 2 Immune Responses
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View all citing articles on Scopus

^☆: 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.

View full text

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

Highlights

Introduction

Section snippets

Mast cells in innate resistance to envenomation

Mechanisms of mast cell activation in innate responses to envenomation

IgE, FcɛRI, and mast cells in adaptive immune resistance to envenomation

Conclusions

References and recommended reading

Acknowledgements

Clin Exp Allergy

Annu Rev Genomics Hum Genet

Proc Natl Acad Sci U S A

J Allergy Clin Immunol

Science

Annu Rev Immunol

J Clin Invest

J Exp Med

Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice

J Clin Invest

The significance of the mast cell response to bee venom

J Immunol

Mast cells in the promotion and limitation of chronic inflammation

Immunol Rev

Mast cells can enhance resistance to snake and honeybee venoms

Science

Mast cells

Physiol Rev

Hypersensitivity responses to bee venom and the mellitin

Int Arch Allergy Appl Immunol

Reactions of anti-bee venom mouse reagins and other antibodies with related antigens

Int Arch Allergy Appl Immunol

IgE antibodies to bee venom, phospholipase A, melittin and wasp venom

Clin Allergy

Development of specific IgE antibodies after repeated exposure to snake venom

J Allergy Clin Immunol

Bee venom allergy

Clin Exp Allergy

Diagnosis of Hymenoptera venom allergy

Allergy

The function of allergy: immunological defense against toxins

Q Rev Biol

Mast cells and local resistance to Russell's viper venom

J Immunol

Mast cell secretory granules: armed for battle

Nat Rev Immunol

Molecular mechanism of mast cell mediated innate defense against endothelin and snake venom sarafotoxin

J Exp Med

A beneficial role for immunoglobulin E in host defense against honeybee venom

Immunity