A Beneficial Role for Immunoglobulin E in Host Defense Against Honeybee Venom
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Immunity Article A Beneficial Role for Immunoglobulin E in Host Defense against Honeybee Venom Thomas Marichal,1,5 Philipp Starkl,1,5 Laurent L. Reber,1 Janet Kalesnikoff,1 Hans C. Oettgen,3 Mindy Tsai,1 Martin Metz,1,4,* and Stephen J. Galli1,2,* 1Department of Pathology 2Department of Microbiology & Immunology Stanford University School of Medicine, Stanford, CA 94305, USA 3Division of Immunology, Boston Children’s Hospital, Boston, MA 02115, USA 4Department of Dermatology and Allergy, Allergie-Centrum-Charite´ , Charite´ -Universita¨ tsmedizin Berlin, Berlin, 10117 Germany 5These authors contributed equally to this work *Correspondence: [email protected] (M.M.), [email protected] (S.J.G.) http://dx.doi.org/10.1016/j.immuni.2013.10.005 SUMMARY sure of certain sensitized individuals can induce anaphylaxis, an acute, catastrophic, and potentially fatal systemic reaction (Fin- Allergies are widely considered to be misdirected kelman, 2007; Portier and Richet, 1902). Because most allergens type 2 immune responses, in which immunoglobulin do not represent a threat to the nonsensitized host, Th2 cell E (IgE) antibodies are produced against any of a responses resulting in antigen-specific IgE antibodies to such broad range of seemingly harmless antigens. How- allergens are widely considered to be misdirected and maladap- ever, components of insect venoms also can sensi- tive immune responses (Artis et al., 2012; Holgate and Polosa, tize individuals to develop severe IgE-associated 2008). In 1991, Margie Profet suggested that the common feature of allergic reactions, including fatal anaphylaxis, upon most allergens is their origin from sources (such as nuts, subsequent venom exposure. We found that mice in- seafood, or venoms), which either might (e.g., foods) or always jected with amounts of honeybee venom similar to (e.g., venoms) contain toxins (Profet, 1991). Profet also pro- that which could be delivered in one or two stings posed that allergic reactions (manifested as immediately occur- developed a specific type 2 immune response that ring symptoms, such as coughing or diarrhea) evolved as a increased their resistance to subsequent challenge defense mechanism that allows the sensitized host to respond with potentially lethal amounts of the venom. Our immediately to, and to neutralize and/or avoid, noxious sub- data indicate that IgE antibodies and the high affinity stances that might be indicative of potentially life-threatening IgE receptor, FcεRI, were essential for such acquired situations (Profet, 1991). However, until recently (Palm et al., resistance to honeybee venom. The evidence that 2012), Profet’s ‘‘toxin hypothesis’’ was largely ignored by the IgE-dependent immune responses against venom scientific community and, to date, supporting experimental evi- dence has been missing. can enhance survival in mice supports the hypothe- In mammals, venoms provoke an innate inflammatory sis that IgE, which also contributes to allergic disor- response and pathology related to the biological activities of ders, has an important function in protection of the the toxic components (Habermann, 1972; Mukherje et al., host against noxious substances. 2000; Risch et al., 2009). Venoms also can induce allergic sensi- tization and development of specific IgE antibodies (Annila, 2000; Charavejasarn et al., 1975; Jarisch et al., 1979; Saelinger INTRODUCTION and Higginbotham, 1974; Wadee and Rabson, 1987), which bind to the high affinity IgE receptor, FcεRI, on tissue mast cells Allergies, which afflict 20%–30% of people worldwide, are detri- (MCs) and blood basophils, priming them to release mediators of mental immune responses against any of a large variety of envi- allergy and anaphylaxis upon subsequent venom exposure ronmental antigens (Pawankar et al., 2012). Such antigens (Charavejasarn et al., 1975; Finkelman, 2007; Galli and Tsai, (called allergens) share the ability to elicit acquired type 2 2012; Oettgen and Geha, 1999; Saelinger and Higginbotham, immune responses, which are orchestrated by CD4+ T helper 1974). MCs also can be activated directly by certain venoms, type 2 (Th2) cells and include the production of allergen-specific in the absence of specific IgE, and work in mice indicates that immunoglobulin E (IgE) antibodies (Galli and Tsai, 2012; Paul and innate functions of MCs, including degradation of venom toxins Zhu, 2010; Pulendran and Artis, 2012). During infections with hel- by MC-derived proteases, can enhance host resistance to the minthes and certain other parasites, IgE-associated Th2 cell- venoms of certain arthropods (including the honeybee) and rep- mediated responses are thought to contribute to host defense tiles (Akahoshi et al., 2011; Metz et al., 2006; Schneider et al., (Finkelman et al., 2004; Fitzsimmons and Dunne, 2009; Pulen- 2007). However, it is not known whether acquired type 2 immu- dran and Artis, 2012; Stetson et al., 2004). However, when IgE- nity against venoms also can enhance host defense. associated immune responses are directed against other types We found that a type 2 immune response and associated IgE of allergens, such as those in foods or medicines, allergen expo- antibodies against honeybee venom were able to increase host Immunity 39, 963–975, November 14, 2013 ª2013 Elsevier Inc. 963 Immunity IgE Can Contribute to Defense against Venom resistance to challenge with a potentially lethal dose of venom, total IgE (p < 0.05, Figure 2F) antibodies in C57BL/6 mice. Mice an effect that was mediated by FcεRI. Our data indicate that on the Th2 cell-prone BALB/c background also developed one function of IgE, which is best known for its role in allergic marked increases in BV-specific IgG1 (but without significant reactions, is to protect the host against noxious substances. increases in total IgE) when immunized with BV (Figures S2E and S2F). Together, our results show that mice can develop RESULTS type 2 immune responses after exposure to amounts of BV that mimic actual bee stings. Mice Develop an Antigen-Specific Th2 Cell Response after Immunization with Honeybee Venom Type 2 Immunity to Honeybee Venom Can Confer Honeybee (Apis mellifera) venom (BV) consists of a mixture of Increased Resistance to a High Dose of Venom cytolytic peptides (e.g., melittin), enzymes (e.g., phospholipase Because both IgE and IgG1 antibodies can orchestrate anaphy- A2 [PLA2; considered the main allergen in BV]), hyaluronidase, laxis and other allergic reactions in mice (Finkelman, 2007; Miya- neurotoxins, and bioactive amines (Habermann, 1972) and jima et al., 1997; Oettgen and Geha, 1999; Oettgen et al., 1994), accounts for the majority of venom allergies in humans (Bilo´ we speculated that a BV-induced Th2 cell response might prime et al., 2005). To assess their susceptibility to BV, we injected mice to exhibit exacerbated reactions to subsequent BV chal- naive wild-type (WT) Th1 cell response-prone C57BL/6 mice lenge. In contrast, we found that 3 weeks after they had received and Th2 cell response-prone BALB/c mice subcutaneously a sublethal dose of BV, such mice exhibited markedly increased (s.c.) with increasing total amounts of complete, unprocessed resistance to challenge with a potentially lethal dose of BV, i.e., BV at one to five different sites. Each injection contained 100 43 200 mg and 53 200 mg BV for C57BL/6 and BALB/c mice, to 200 mg of BV, mimicking the amount of venom typically found respectively (which caused death in 90% or 70%, respectively, in individual honeybees (our immunization dosages therefore of 6- to 8-week-old naive WT animals [Figures 1E and 1G]) (Fig- correspond to 1 to 5–10 honeybee stings; Metz et al., 2006; ures 2G and 2H; Figures S2G and S2H). For example, C57BL/6 Schmidt, 1995)(Figures 1A to 1C). Acute reactions to BV were mice that had been immunized with as little as 13 200 mgBV characterized by dose-dependent reductions in both body exhibited significantly less hypothermia (p < 0.001 at 1 and temperature (Figures 1D and 1F) and survival (Figures 1E and 6 hr, Figure 2G) and markedly enhanced survival after potentially 1G). Similar results were obtained with Russell’s viper venom, lethal BV challenge (Figure 2H). In BALB/c mice, even immuniza- which also induced dose-dependent toxicity (see Figures S1A tion with 13 100 mg BV induced enhanced protection (Figures to S1G available online). S2G and S2H). Honeybee stings can induce a Th2 cell-mediated immune Individual sera of protected mice obtained a week after BV response associated with BV-specific IgE antibodies, which challenge (Figure 2A; Figure S2A) contained BV-specific IgE can prime some individuals to exhibit anaphylaxis in response antibodies specific for BV (Figure 2I; Figure S2I) and for the major to a subsequent sting (Annila, 2000). Mice can develop Th2 BV allergen PLA2 (data not shown), and such sera also markedly cell-mediated responses to BV when they are immunized with increased the ability of bone-marrow-derived cultured mast cells BV admixed with adjuvants such as Freund’s complete adjuvant (BMCMCs) to degranulate in response to BV stimulation (Fig- (Saelinger and Higginbotham, 1974) or aluminum hydroxide ure 2J; Figure S2J). Pretreatment of such pooled immune serum (Charavejasarn et al., 1975). We tested whether injections of (collected from immunized and challenged mice) by heating (to whole BV (without added adjuvants) also could induce type 2 im- ablate IgE function [Ishizaka et al., 1986; Prouvost-Danon munity in mice (Figure 2A; Figure S2A). et al., 1977; Strait et al., 2006]) or by using an anti-mouse IgE We assessed responses to BV of primary T cells from draining antibody decreased its ability to sensitize BMCMCs to degranu- inguinal lymph nodes (ILNs) from C57BL/6 or BALB/c mice late in response to BV (i.e., 100 ng/ml and 1,000 ng/ml; Figure 2K; 5 days after injection of either PBS or a sublethal dose of BV Figure S2K), confirming that BV immunization induced produc- (i.e., one not resulting in the death of significant numbers of tion of functionally active BV-specific IgE antibodies.