| The innate immune system senses the presence of infection through detection of pathogen associated molecular patterns by pattern recognition receptors (PRRs) and instructs the adaptive immune system on when, how and to which antigens to respond. We examined innate and adaptive immune responses to two classes of non-infectious antigens---haptenated proteins and venoms. Haptenated proteins are used to elicit T-dependent antibody responses. Although adaptive responses to many infections and immunizations require Toll-like receptor (TLR)-dependent innate instruction, we found that T helper cell and antibody responses to haptenated proteins were independent of known pattern recognition receptors, including TLRs. Therefore, haptenated proteins either bypass the requirement for innate instruction of adaptive immunity, or trigger an alternative innate immune sensing pathway. Venoms consist of complex mixtures of toxic components delivered to their victims via bites or stings, and are used by various animals (e.g., insects and snakes) for defense and predation. Venoms are also well known as allergens. Notably, many classes of allergens, including venoms, are highly noxious. We hypothesized that the innate immune system might sense these 'noxious xenobiotics' via detection of their toxic activities and instruct innate and adaptive immune responses that would promote their detoxification and clearance. We found that bee venom and the cell-lytic peptide melittin from bee venom could trigger activation of the NLRP3-inflammasome, leading to Caspase 1 activation and IL-1beta secretion. Strikingly, Caspase 1-deficient mice were hypersensitive to the toxic effects of bee and snake venom, suggesting that an inflammasome-dependent immune response can promote venom detoxification and clearance. Bee venom and bee venom phospholipase A2 (bvPLA2) also induced IgE production and a T helper type-2 (Th2) response. These responses were independent of TLRs and Caspase-1. However, bee venom and bvPLA2 could stimulate basophil IL-4-production in vitro, and basophil depletion attenuated the Th2 response to bvPLA2 in vivo . Taken together, these data suggest that the innate immune system can sense noxious xenobiotics, such as venoms, via detection of their toxic activities and can enhance resistance to their noxious effects. The detection of venoms also results in the instruction of Th2 and IgE responses, which may promote detoxification and clearance (as well as condition future avoidance) of noxious xenobiotics by mediating an allergic response. These data demonstrate a new role for the immune response that is separate from defense against infection and suggest a potential reinterpretation of the purpose of the allergic response. |
