Search

Basophils are the rarest granulocytes representing less than 1% of peripheral blood leukocytes. Even though basophils have been discovered more than 140 years ago, their roles in immune reactions had long been an enigma, partly because of their rarity and the similarity to tissue-resident mast cells. However, recent development of the analytical tools for basophil research, such as basophil-depletion antibody and basophil-related engineered mice, has uncovered the unique roles of basophils in various immune reactions. Basophils are now appreciated as a critical immune cell in various type 2-immune responses including the induction of chronic allergic inflammation and protective immunity against parasites. In this review, we summarize the recent understandings in the roles of basophils in allergic inflammation with especial focus on skin inflammation. We then focus on our recent findings in the differentiation and maturation pathways of basophils.

Basophils are the rarest granulocytes and have long been overlooked in immunological research due to their rarity and similarities with tissue-resident mast cells. In the last two decades, non-redundant functions of basophils have been clarified or implicated in a broad spectrum of immune responses, particularly by virtue of the development of novel analytical tools for basophils. Basophils infiltrate inflamed tissues of patients with various disorders, even though they circulate in the bloodstream under homeostatic conditions. Depletion of basophils results in the amelioration or exaggeration of inflammation, depending on models of disease, indicating basophils can play either beneficial or deleterious roles in a context-dependent manner. In this review, we summarize the recent findings of basophil pathophysiology under various conditions in mice and humans, including allergy, autoimmunity, tumors, tissue repair, fibrosis, and COVID-19. Further mechanistic studies on basophil biology could lead to the identification of novel biomarkers or therapeutic targets in a broad range of diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miyake, Ito and Karasuyama.)

Basophils are the rarest granulocytes which represent <1% of peripheral blood leukocytes. Basophils bear several phenotypic similarities to tissue-resident mast cells and therefore had been erroneously considered as blood-circulating mast cells. However, recent researches have revealed that basophils play nonredundant roles in allergic inflammation, protective immunity against parasitic infections and regulation of innate and acquired immunity. Basophils are recruited to inflamed tissues and activated in an IgE-dependent or IgE-independent manner to release a variety of effector molecules. Such molecules, including IL-4, act on various types of cells and play versatile roles, including the induction and termination of allergic inflammation and the regulation of immune responses. Recent development of novel therapeutic agents has enabled us to gain further insights into basophil biology in human disorders. In this review, we highlight the recent advances in the field of basophil biology with a particular focus on the role of basophils in allergic inflammation. Further studies on basophils and their effector molecules will help us identify novel therapeutic targets for treating allergic disorders., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

A hapten is a small molecule that is not immunogenic on its own but can stimulate the production of antibodies at the sensitization phase when conjugated to carrier proteins. The hapten then reacts specifically with the antibodies generated against it to elicit an immune or allergic response at the challenge phase. Here, we compared various carrier proteins conjugated with the same hapten in their ability to induce hapten-specific IgE-mediated allergic responses in vitro and in vivo, and characterized the nature of carrier proteins that determines the magnitude of response at the challenge phase of allergic reactions. Hapten 2,4,6-trinitrophenol (TNP)-conjugated ovalbumin (TNP-OVA) and bovine serum albumin (TNP-BSA) elicited TNP-specific, mast cell-dependent, immediate-type allergic reactions at a comparable level in mice that had been passively sensitized with TNP-specific IgE. In contrast, TNP-OVA but not TNP-BSA efficiently induced a basophil-dependent, IgE-mediated chronic allergic inflammation (IgE-CAI), even though both proteins could stimulate basophils in vitro at a comparable level. By comparing different carrier proteins and structurally modifying them, we found that the formation of large aggregates is crucial for TNP-conjugated carrier proteins to efficiently elicit IgE-CAI, regardless of the type of protein. Thus, the aggregation status of carrier proteins appears to determine the magnitude of allergic response at the challenge phase of hapten-specific IgE-CAI. Our findings suggest that the allergenicity of substances is a matter of importance not only at the sensitization but also at the challenge phase in a certain type of allergy including a basophil-mediated allergic inflammation.

Until recently, basophils had often been neglected in immunologic studies because of their minority status among immune cells or confused with tissue-resident mast cells because of some phenotypic similarities between them in spite of different anatomic localization. It is now appreciated that basophils and mast cells are distinct cell lineages and that basophils play important and nonredundant roles distinct from those played by mast cells. On the one hand, basophils contribute beneficially to protective immunity, particularly against parasitic infections. On the other hand, basophils are involved in the development of various disorders, including allergy and autoimmune disease. Basophils interact with other immune cells and nonhematopoietic cells through cell-to-cell contact or basophil-derived factors, such as cytokines and proteases, contributing to the regulation of immune and allergic responses. In this review article we highlight recent advances in our understanding of basophil pathophysiology in human subjects and animal models by consolidating research findings reported during the past 5 years. Further studies on basophils and their products will help identify suitable targets for novel therapeutics in allergy and effective vaccines against parasitic infection., (Copyright © 2017. Published by Elsevier Inc.)

Basophils have long been neglected in immunological studies because they were regarded as only minor relatives of mast cells. However, recent advances in analytical tools for basophils have clarified the non-redundant roles of basophils in allergic inflammation. Basophils play crucial roles in both IgE-dependent and -independent allergic inflammation, through their migration to the site of inflammation and secretion of various mediators, including cytokines, chemokines, and proteases. Basophils are known to produce large amounts of IL-4 in response to various stimuli. Basophil-derived IL-4 has recently been shown to play versatile roles in allergic inflammation by acting on various cell types, including macrophages, innate lymphoid cells, fibroblasts, and endothelial cells. Basophil-derived serine proteases are also crucial for the aggravation of allergic inflammation. Moreover, recent reports suggest the roles of basophils in modulating adaptive immune responses, particularly in the induction of Th2 differentiation and enhancement of humoral memory responses. In this review, we will discuss recent advances in understanding the roles of basophils in allergic inflammation., (Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Recent studies have identified nonredundant roles for basophils in immune responses including allergy and protective immunity. It is well known that activated basophils release granule contents such as histamine and proteases as do mast cells. However, the functional significance of basophil-derived proteases remains poorly understood in contrast to those released from mast cells. For this study we generated a line of knockout (KO) mice deficient for mouse mast cell protease-11 (mMCP-11) that is preferentially expressed by basophils rather than mast cells. In spite of normal development of basophils, the mMCP-11-deficient mice showed amelioration of immunoglobulin E-mediated chronic allergic inflammation (IgE-CAI), with reduction of cutaneous swelling, microvascular permeability, and leukocyte infiltration in the skin lesion, when KO mice were compared with wild-type mice. Repeated administration of recombinant mMCP-11 in the skin induced infiltration of leukocytes, including basophils, in a tryptase activity-dependent manner. The transwell migration assay in vitro suggested that mMCP-11-mediated proteolytic products of serum protein promoted migration of basophils, eosinophils, and macrophages via 1 or more G protein-coupled receptors. Thus, basophil tryptase mMCP-11 is a crucial effector molecule for the induction of IgE-CAI. This is the first demonstration that the basophil-derived protease plays a significant role in vivo., (© 2016 by The American Society of Hematology.)

Basophils had long been neglected in immunological studies, because of their paucity and phenotypic similarity with tissue-resident mast cells. However, recent development of analytical tools has cast new light on this neglected minority, and revealed previously unappreciated roles of basophils, distinct from those of mast cells, in various immune responses. Primary function of basophils appears to be the protection against infections with parasites, including ticks and helminths. This is why basophils are evolutionally conserved well in many animal species, albeit a small number. Nevertheless, basophils sometimes exert host-deleterious functions in immunological disorders such as allergy. Here we summarize recent advance in our understanding of basophil ontogeny and their in vivo roles under physiological and pathological conditions., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Basophils are evolutionarily conserved in many animal species, in spite of the fact that they account for <1% of peripheral blood leukocyte. This suggests that basophils have an indispensable and nonredundant role in vivo, even though they show some phenotypic similarity with tissue-resident mast cells. However, their functional significance remained uncertain long after Paul Ehrlich discovered them as blood-circulating cells with basophilic granules more than 130 years ago. The study of basophils has been far behind that of mast cells, owing to the rarity of basophils and the paucity of tools for their detection and functional analysis. Recent development of novel analytical tools, including basophil-depleting antibodies and genetically engineered mice deficient only in basophils, has greatly advanced basophil research and illuminated previously unrecognized roles of basophils. We now appreciate that basophils and mast cells play distinct roles in immune responses. Basophils have crucial roles in the development of acute and chronic allergic responses, the protective immunity against ecto- and endoparasites, and the regulation of acquired immunity, including the augmentation of humoral memory responses and the initiation of Th2 responses. Thus, basophils are no longer the neglected minority and are key players in the immune system., (© 2011 John Wiley & Sons A/S.)

It has been over a hundred years since Shibasaburo Kitasato and Emil Adolf von Boehring's finding of a serum component that neutralizes bacterial toxins and the subsequent development of antiserum therapy. Over that time, many Japanese researchers have greatly contributed to our understanding of the molecular mechanisms for allergic and inflammatory diseases. This article is aimed at introducing such individual work and how these areas have contributed to our understanding of the mechanisms of allergic reactions.

Basophils are the least common granulocytes, and account for less than 1% of peripheral blood leukocytes. Because of this minority status and their phenotypic similarity to mast cells, basophils have often been neglected in immunological studies or considered to have minor, redundant roles in immune responses in vivo. We have recently demonstrated that basophils play critical roles in IgG-mediated systemic anaphylaxis and IgE-mediated chronic allergic inflammation. Basophils also promote the Th2 differentiation and enhance the humoral memory response. Thus, basophils are a key player in both immune regulation and allergic responses. Basophils and their products seem to be promising therapeutic targets for allergic disorders.

Basophils represent less than 1% of peripheral blood leukocytes. They are often recruited to the site of allergic inflammation, albeit in small numbers. However, it remained uncertain whether basophils play any significant role in allergic reactions or act as minor and redundant 'circulating mast cells'. We have recently demonstrated that basophils play critical roles in systemic anaphylaxis and chronic allergic inflammation, distinctively from mast cells. Basophils are one of the major players in the IgG- but not IgE-mediated systemic anaphylaxis, in contrast to mast cells. In response to the allergen-IgG immune complexes, basophils release the platelet-activating factor rather than histamine as the major chemical mediator to induce the systemic anaphylaxis. The depletion of basophils protects mice from death due to anaphylactic shock. Basophils also play a crucial role in the development of the IgE-mediated chronic allergic inflammation with massive eosinophil infiltration in the skin, independently of T cells and mast cells, even though basophils account for only approximately 2% of the infiltrates. The basophil depletion shows a therapeutic effect on on-going allergic inflammation. Accumulating evidence suggests that basophils function as initiators rather than effectors of the chronic allergic inflammation. Thus, basophils and their products seem to be promising therapeutic targets for allergic disorders.

Macrophage-derived chemokine (MDC) CCL22 is a potent chemoattractant for Th2 cells and has been implicated in Th2-predominant allergic inflammation. In the present study, we demonstrated that basophils produce MDC in response to monomeric IgE. In trinitrophenyl (TNP)-IgE transgenic mice, serum levels of MDC were persistently higher than in wild-type mice. The i.v. administration of TNP-specific IgE to wild-type mice transiently induced an elevation in serum MDC, which appeared to be mediated by Fc epsilonRI, as no increase in serum MDC was observed after IgE administration in FcRgamma (-/-) mice. However, the IgE-mediated increase in MDC was observed in mast cell-deficient mice. Freshly isolated bone marrow cells and bone marrow-derived basophils secreted MDC in response to TNP-IgE without Ag stimulation. Furthermore, MDC production was not observed in bone marrow-derived basophils isolated from FcRgamma (-/-) mice. IgE activated Lyn and ERK 1/2 in bone marrow-derived basophils. Treatment of TNP-IgE transgenic mice with a basophil-depletion Ab (Ba103) resulted in decreased serum MDC levels. Thus, IgE appears to be capable of stimulating basophils to produce MDC in the absence of a specific Ag, which may contribute to IgE-mediated and/or Th2-predominant allergic inflammation.

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.