Mast cells and the immune response against venoms

Allergic reactions are defined as hypersensitivity reactions of the immune system against exogenous proteins known as allergens. They are initiated by activation of effector cells (mast cells in tissue, basophils in circulation) by allergen cross-linking of surface bound specific IgE antibodies resulting in rapid release of preformed, granule stored, as well as newly synthesized bioactive mediators which cause the immediate symptoms of allergic reactions. The "physiologic" role of the allergy module of the immune system which justifies its evolutionary conservation for the price of allergic reactions is still unclear. The "toxin hypothesis", proposed almost 20 years ago, suggests a role for allergic reactions in the defense against toxic compounds (for example plant toxins or animal venoms) or associated proteins (allergens). Three studies recently reported a protective role of mast cells in the innate immune responses against venoms from different species of animals, including the honey bee, the Gila monster lizard, two scorpions, and several snakes. However, it is not known at this point whether an adaptive immune response to venoms also can be beneficial for the host. The genetic background of an individual can result in a Th 2 bias which increases the risk of allergy but might also influence the immune response to venoms. It is the first aim of our study to investigate and characterize the adaptive immune response to bee venom (BV) and Russell`s viper venom (RVV) and to determine whether it is influenced by mast cells, IgE, or genetic background. We will immunize wild type C57BL/6 and BALB/c (representing Th 1 and Th 2 dominant mouse strains) mice, as well as different transgenic mice with mast cell or IgE deficiency, with sub-lethal doses of BV or RVV and characterize the development of specific antibody subclasses as well as their contribution to subsequent challenge with LD50 of venom. The second major aim of our study focuses on the potential function of mast cells in the innate host response to envenomation by RVV, a venom which is associated with thousands of deaths every year. If, as expected, we find a protective role for mast cells against RVV using mast cell deficient mouse strains, we will characterize the associated mechanism. This mechanism might be based on venom degradation by mast cell derived proteases (as reported for other snake venoms) and/or neutralization and local restriction of venom components by complex formation with mast cell-derived heparin. We will investigate this hypothesis by using mouse strains lacking mast cell specific proteases and by using pharmacological approaches to neutralize heparin. Our proposed studies promise to increase our understanding of adaptive and innate immune responses against venoms, and possibly to reveal whether the allergy module indeed has a physiologic function during envenomation.