Mast cells are hematopoietic cells that reside in virtually all vascularized tissues and that represent potential sources of a wide variety of biologically active secreted products, including diverse cytokines and growth factors. There is strong evidence for important non-redundant roles of mast cells in many types of innate or adaptive immune responses, including making important contributions to immediate and chronic IgE-associated allergic disorders and enhancing host resistance to certain venoms and parasites. However, mast cells have been proposed to influence many other biological processes, including responses to bacteria and virus, angiogenesis, wound healing, fibrosis, autoimmune and metabolic disorders, and cancer. The potential functions of mast cells in many of these settings is thought to reflect their ability to secrete, upon appropriate activation by a range of immune or non-immune stimuli, a broad spectrum of cytokines (including many chemokines) and growth factors, with potential autocrine, paracrine, local, and systemic effects. In this review, we summarize the evidence indicating which cytokines and growth factors can be produced by various populations of rodent and human mast cells in response to particular immune or non-immune stimuli, and comment on the proven or potential roles of such mast cell products in health and disease.

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.

Ticks are ectoparasitic arthropods that can transmit a variety of microorganisms to humans and animals during blood feeding, causing serious infectious disorders, including Lyme disease. Acaricides are pharmacologic agents that kill ticks. The emergence of acaricide-resistant ticks calls for alternative control strategies for ticks and tick-borne diseases. Many animals develop resistance to ticks after repeated infestations, but the nature of this acquired anti-tick immunity remains poorly understood. Here we investigated the cellular and molecular mechanisms underlying acquired resistance to Haemaphysalis longicornis ticks in mice and found that antibodies were required, as was IgFc receptor expression on basophils but not on mast cells. The infiltration of basophils at tick-feeding sites occurred during the second, but not the first, tick infestation. To assess the requirement for basophil infiltration to acquired tick resistance, mice expressing the human diphtheria toxin receptor under the control of the mast cell protease 8 (Mcpt8) promoter were generated. Diphtheria toxin administration to these mice selectively ablated basophils. Diphtheria toxin-mediated basophil depletion before the second tick infestation resulted in loss of acquired tick resistance. These data provide the first clear evidence, to our knowledge, that basophils play an essential and nonredundant role in antibody-mediated acquired immunity against ticks, which may suggest new strategies for controlling tick-borne diseases.

The recruitment of basophils into the sites of allergic inflammation is often observed. However, no definitive evidence has been provided that basophils are crucially involved in the pathogenesis of chronic allergic disorders. Here, we show that basophils are responsible for the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. 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. Mast cells were essential for the immediate- and late-phase ear swelling but dispensable for the delayed one. T cells were also dispensable for the latter. Transfer of FcRI-expressing basophils into FcRI-deficient mice restored the development of the delayed-onset allergic inflammation. These findings indicate a novel mechanism of development of chronic allergic inflammation that is induced by basophils through the interaction of antigen, IgE, and FcRI.

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...

IntroductionMyeloid cell leukemia sequence 1 (Mcl-1) 1 has been identified as an intracellular antiapoptotic factor in a variety of hematopoietic cells, both in vitro and in vivo. [2][3][4][5][6] Human mast cells express 7,8 and Mcl-1 can promote the survival of some populations of human neoplastic mast cells in vitro. 7 Basophils, granulocytes with many characteristics and functions that partially overlap with those of tissue mast cells, [9][10][11][12] can also express Mcl-1. 13 However, it is not clear to what extent Mcl-1 is important in the development and/or survival of mast cells or basophils in vivo.Opferman et al showed that the genetic manipulation of Mcl-1 can be used to delete individual hematopoietic cell populations in mice. 4 We therefore used this approach to examine the effects of reducing expression of Mcl-1 in the mast cell lineage in vivo. To attempt to delete Mcl-1 selectively in mast cells, we used the promoter for the peptidase carboxypeptidase A3 (CPA3; originally named mast cell carboxypeptidase A 14 ). CPA3 is highly expressed in mast cells, 15 but is also expressed in basophils 16 and can be expressed in some populations of T-cell progenitors and thymic T cells 17,18 and in certain hematopoietic progenitor cells. 19 We generated C57BL/6 mice in which a segment of the Cpa3 promoter drives expression of Cre recombinase, and then mated these Cpa3-Cre transgenic mice to mice bearing a floxed allele of Mcl-1. 4 We found that C57BL/6-Cpa3-Cre; Mcl-1 fl/fl mice are severely deficient in mast cells and have a marked deficiency in basophils, and also exhibit striking impairment in mast cell-or basophil-and IgE-dependent biologic responses. Methods MiceAll animal experiments were carried out following protocols approved by the Stanford University Administrative Panel on Laboratory Animal Care. B6-Tg(Cpa3-cre)3Glli (Cpa3-Cre-transgenic mice) were generated by microinjecting the Cpa3-Cre transgene into embryonic stem cells in the B6 background (Stanford University). Gt(ROSA)26Sor tm4(ACTB-tdTomato,-EGFP)Luo /J(mT/mG) mice, obtained from The Jackson Laboratory, were crossed to Cpa3-Cre mice for Cre expression analysis. Mcl-1 ϩ/fl (B6;129-Mcl1 tm3sjk J) animals were obtained from The Jackson Laboratory. Mcl-1 ϩ/fl mice were bred to progeny from 2 Cpa3-Cre founder lines (founder lines #4 and #5) to obtain Cpa3-Cre; Mcl-1 ϩ/ϩ , Cpa3-Cre; Mcl-1 ϩ/fl , and Cpa3-Cre; Mcl-1 fl/fl animals, but only the Cpa3-Cre; Mcl-1 fl/fl mice derived from founder line #4 exhibited a substantial mast cell deficiency. Therefore, the mice used were derived from crosses between founder line #4 (subsequently referred to as Cpa3-Cre mice) and Mcl-1 fl animals, and these mice had been intercrossed a minimum of 6 generations into the C57BL/6 background. Heterozygous Cpa3-Cre mice were determined to have 5 copies of the Cpa3-Cre transgene by real-time PCR. To emphasize that Cpa3-Cre; Mcl-1 fl/fl mice have deficiencies in mast cells and basophils that are independent of mutations affecting Kit, we call them informally in our labo...

Monocytes and macrophages are important effectors and regulators of inflammation, and both can be divided into distinct subsets based on their phenotypes. The developmental and functional relationship between individual subsets of monocytes and those of macrophages has not been fully elucidated, although Ly6C(+)CCR2(+) inflammatory and Ly6C(-)CCR2(-) resident monocytes are generally thought to differentiate into M1 (classically activated) and M2 (alternatively activated) macrophages, respectively. Here we show that inflammatory monocytes recruited to allergic skin acquired an M2-like phenotype in response to basophil-derived interleukin-4 (IL-4) and exerted an anti-inflammatory function. CCR2-deficient mice unexpectedly displayed an exacerbation rather than alleviation of allergic inflammation, in spite of impaired recruitment of inflammatory monocytes to skin lesions. Adoptive transfer of inflammatory monocytes from wild-type but not IL-4 receptor-deficient mice dampened the exacerbated inflammation in CCR2-deficient mice. Thus, inflammatory monocytes can be converted from being proinflammatory to anti-inflammatory under the influence of basophils in allergic reactions.

No abstract