Anaphylaxis is an acute, severe, and potentially fatal systemic allergic reaction. Immunoglobulin E (IgE), mast cells, and histamine have long been associated with anaphylaxis, but an alternative pathway mediated by IgG has been suggested to be more important in the elicitation of anaphylaxis. Here, we showed that basophils, the least common blood cells, were dispensable for IgE-mediated anaphylaxis but played a critical role in IgG-mediated, passive and active systemic anaphylaxis in mice. In vivo depletion of basophils but not macrophages, neutrophils, or NK cells ameliorated IgG-mediated passive anaphylaxis and rescued mice from death in active anaphylaxis. Upon capture of IgG-allergen complexes, basophils released platelet-activating factor (PAF), leading to increased vascular permeability. These results highlight a pivotal role for basophils in vivo and contrast two major, distinct pathways leading to allergen-induced systemic anaphylaxis: one mediated by basophils, IgG, and PAF and the other "classical" pathway mediated by mast cells, IgE, and histamine.

IntroductionBasophils are the least common leukocytes in the peripheral blood and account for only approximately 0.5% of all leukocytes. Like mast cells, basophils express the high-affinity IgE receptor Fc⑀RI on their cell surface, and they release chemical mediators such as histamine and leukotriene C4 upon stimulation. [1][2][3][4][5] Therefore, basophils have often been neglected or considered minor and possibly redundant "circulating mast cells" and analyzed as a surrogate of the less accessible tissue mast cells. 6 However, basophils and mast cells differ in their natural history. Even though both originate from hematopoietic stem cells in the bone marrow, basophils complete their differentiation in the bone marrow, whereas mast cells do so in the peripheral tissues. 5,7 Basophils circulate in the peripheral blood and do not migrate into the peripheral tissues under physiologic conditions, while mature mast cells reside in the peripheral tissues and do not circulate in the peripheral blood. The lifespan of basophils is several days, much shorter than that of mast cells, and basophils do not proliferate once they mature, unlike mast cells. These differences strongly suggest that basophils and mast cells play distinct roles in vivo.Mast cells and basophils have long been considered primary effector cells in allergic disorders such as anaphylaxis, hay fever, and asthma. 5,7 Recent works demonstrated that mast cells actively participate in the innate immune responses to many pathogens, including bacteria and virus. 8 In addition to such roles as effector cells, recent evidence indicates that mast cells can also play immunoregulatory roles. 9 Mast cells influence the sensitization phase of some acquired immune responses, 10 and contribute to the pathology of autoimmune disorders [11][12][13] and to the expression of peripheral tolerance. 14 Compared with extensive investigation on mast cells and advances in our understanding of mast cell functions, the in vivo roles of basophils are far less studied and defined.A clue to clarifying critical and nonredundant roles of basophils has been provided by the recent finding that basophils readily generate large quantities of T helper 2 (Th2) cytokines such as IL-4 and IL-13 in both humans and mice. [15][16][17][18] These cytokines are the key regulators in conditioning the immune response to the Th2 type. Basophil-derived IL-4 has been shown to drive the differentiation of naive CD4 T cells to Th2 cells in vitro and in vivo. 19,20 Basophils also stimulate B cells to synthesize IgE in vitro in an IL-4-and CD40L-dependent manner. 21,22 We recently identified a novel type of chronic allergic inflammation designated IgEmediated chronic allergic inflammation (IgE-CAI) that requires the presence of basophils, but not mast cells or T cells. 23 A single subcutaneous injection of multivalent antigens elicited not only immediate-and late-phase ear swelling but also delayed-onset ear swelling with massive eosinophil infiltration in mice sensitized with antigen-specific IgE or in mi...

Basophils are the rarest granulocytes and represent less than 1% of peripheral blood leukocytes. They are evolutionarily conserved in many animal species, but their functional significance remained an enigma long after their discovery by Paul Ehrlich in 1879. Studies of basophils were hindered by their rarity, by difficulties in identifying them, and by the paucity of useful analytical tools. Because basophils display several characteristics shared by tissue-resident mast cells, they were often considered minor and possibly redundant relatives of mast cells or even blood-circulating precursors of mast cells. However, newly developed tools for their functional analysis, including basophil-depleting antibodies and genetically engineered mice deficient only in basophils, have fueled basophil research and defined previously unrecognized functions of basophils. We now appreciate that basophils play nonredundant roles in acquired immunity regulation, protective immunity to pathogens, and immunological disorders such as allergy and autoimmunity.

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with epithelial-cell cancers and B cell lymphomas. An effective EBV vaccine is not available. We found that antibodies to the EBV glycoprotein gH/gL complex were the principal components in human plasma that neutralized infection of epithelial cells and that antibodies to gH/gL and gp42 contributed to B cell neutralization. Immunization of mice and nonhuman primates with nanoparticle vaccines that displayed components of the viral-fusion machinery EBV gH/gL or gH/gL/gp42 elicited antibodies that potently neutralized both epithelial-cell and B cell infection. Immune serum from nonhuman primates inhibited EBV-glycoprotein-mediated fusion of epithelial cells and B cells and targeted an epitope critical for virus-cell fusion. Therefore, unlike the leading EBV gp350 vaccine candidate, which only protects B cells from infection, these EBV nanoparticle vaccines elicit antibodies that inhibit the virus-fusion apparatus and provide cell-type-independent protection from virus infection.