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The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7. Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative Ly6Clo macrophages toward increased numbers of inflammatory Ly6Chi monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were accompanied by lower cardiac levels of IL-4 and IL-13, two major cytokines secreted by basophils. Mice with basophil-specific IL-4/IL-13 deficiency exhibited a similarly altered myeloid response with an increased fraction of Ly6Chi monocytes and aggravated cardiac function after MI. In contrast, IL-4 induction in basophils via administration of the glycoprotein IPSE/α-1 led to improved post-MI healing. These results in mice were corroborated by the finding that initially low counts of blood basophils in patients with acute MI were associated with a worse cardiac outcome after 1 year, characterized by a larger scar size. In conclusion, we show that basophils promoted tissue repair after MI by increasing cardiac IL-4 and IL-13 levels.

Alterations in commensal bacteria are associated with an increased risk of allergic disease. David Artis and his colleagues now report that commensal-derived signals influence basophil development and T H 2 cytokine–dependent allergic airway inflammation by suppressing serum IgE levels. Individuals with hyper IgE syndrome also have elevated circulating basophil numbers, suggesting a mechanistic link between commensal bacteria, B cell–mediated production of IgE and basophil hematopoiesis. Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (T H 2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated T H 2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell–intrinsic expression of myeloid differentiation factor 88 (MyD88) was required to limit serum IgE concentrations and circulating basophil populations in mice. Commensal-derived signals were found to influence basophil development by limiting proliferation of bone marrow–resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal-derived signals influence basophil hematopoiesis and susceptibility to T H 2 cytokine–dependent inflammation and allergic disease.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. It has generally been considered a non-Th2-type lung disorder, characterized by progressive airflow limitation with inflammation and emphysema, but its cellular and molecular mechanism remains ill defined, compared with that of asthma characterized by reversible airway obstruction. Here we show a previously unappreciated role for basophils at the initiation phase of emphysema formation in an elastase-induced murine model of COPD in that basophils represent less than 1% of lung-infiltrating cells. Intranasal elastase instillation elicited the recruitment of monocytes to the lung, followed by differentiation into interstitial macrophages (IMs) but rarely alveolar macrophages (AMs). Matrix metalloproteinase-12 (MMP-12) contributing to emphysema formation was highly expressed by IMs rather than AMs, in contrast to the prevailing assumption. Experiments using a series of genetically engineered mice suggested that basophil-derived IL-4, a Th2 cytokine, acted on lung-infiltrating monocytes to promote their differentiation into MMP-12–producing IMs that resulted in the destruction of alveolar walls and led to emphysema development. Indeed, mice deficient for IL-4 only in basophils failed to generate pathogenic MMP-12–producing IMs and hence develop emphysema. Thus, the basophil-derived IL-4/monocyte–derived IM/MMP-12 axis plays a crucial role in emphysema formation and therefore may be a potential target to slow down emphysema progression at the initiation phase of COPD.

It has been known for about 50 years that a proportion of human basophils does not release histamine or leukotrienes or upregulates activation markers in response to IgE‐dependent stimuli. This group of so‐called nonresponders with unresponsive basophils is found in up to 20% of tests conducted. There seems to be no relation to clinical symptoms. The nonresponder status is not defined in a standardized manner, but basophils are often considered nonresponsive if they release less than 5% to 10% of their histamine content or show activation of less than or equal to 10% CD63+ basophils after Fc ε RI cross‐linking. Results from nonresponder patients should be regarded as false negatives. Different genetic factors between reactive and anergic basophils appear to play a minor role because various other factors allow a conversion from the nonresponder status to the responder status in one individual (IL‐3, low‐Na + medium, natural changes over time, etc.). In most studies reduced levels of Lyn and Syk proteins in nonreleasers were observed. Therefore, it was assumed that translational or posttranslational regulatory mechanisms (proteasomal degradation), especially specific to the Lyn and Syk levels, are responsible for the nonresponder status. Further biochemical studies, along with mechanistic experiments and multiomics approaches, should be conducted to clarify IgE unresponsiveness.

Preincubation of peripheral leukocytes from atopies and normals significantly enhanced histamine release induced by anti-IgE and calcium ionophore. On the other hand, there was a significant inhibition (ca. 40%) of C5a-induced histamine release by indomethacin both in atopies and controls. In the group of patients with atopic eczema, anti-IgE-induced histamine release was significantly higher than in controls both without and with indomethacin.

: MGN-3/Biobran (BRM4, Lentin Plus or Ribraxx) is a natural, rice bran-derived arabinoxylan immunoceutical that modulates the adaptive immune response to viral infections. In response to bacterial infections, basophils act as \"first responders\" and are also associated with modulation of the adaptive immune response. The maturation of pluripotent CD34 stem cells into basophils is supported by the cytokine interleukin-3 (IL-3). The aim was to test the hypothesis that modulation of the adaptive immune response in bacterial infection by MGN-3/Biobran entails a basophilic response. The tick-related disorder Lyme borreliosis was chosen as the disease model; tick bites are associated with cutaneous IL-3-mediated basophil recruitment. : A three-month randomised double-blind placebo-controlled trial was conducted in patients with a history of borreliosis who were suffering from symptoms attributable to this disorder. The immunoceutical group received oral Biobran; the dosage for both groups was 1 g thrice daily. Both groups were matched for age, sex, and ethnicity. A higher percentage of basophil count occurred in the immunoceutical group ( = 0.038). The final general linear model included the group (immunoceutical/placebo) and change in fatigue assessed by the 11-item Chalder Fatigue Questionnaire (CFQ) ( = 0.63; = 0.0066). The change in basophil count was positively correlated with CFQ change ( = 0.633; = 0.020); only the immunoceutical group showed a positive correlation. : These results support the hypothesis being tested. Basophils may modulate the adaptive immune response by acting as immunoregulatory cells. They can regulate the functioning of type 2 T-helper lymphocytes, enhance immunological memory, and present antigens to CD8 T lymphocytes. Further studies are needed to clarify potential mechanistic factors and the timing of this basophilic response.

Basophils act as effector cells in immunoglobulin E–mediated hypersensitivity responses. Artis, Nakanishi and Medzhitov and their colleagues report that basophils present antigen and induce T helper type 2 responses to helminths, allergens and immunoglobulin E immune complexes. T helper type 2 (T H 2)-mediated immune responses are induced after infection with multicellular parasites and can be triggered by a variety of allergens. The mechanisms of induction and the antigen-presenting cells involved in the activation of T H 2 responses remain poorly defined, and the innate immune sensing pathways activated by parasites and allergens are largely unknown. Basophils are required for the in vivo induction of T H 2 responses by protease allergens. Here we show that basophils also function as antigen-presenting cells. We show that although dendritic cells were dispensable for allergen-induced activation of T H 2 responses in vitro and in vivo , antigen presentation by basophils was necessary and sufficient for this. Thus, basophils function as antigen-presenting cells for T H 2 differentiation in response to protease allergens.

Key Points Mast cells and basophils are phenotypically and functionally related cell types that promote protective immunity to helminths, but that can also cause pathology during allergic inflammation. Mast cells and basophils might have evolved from a common precursor cell, such as the mast cell/basophil-like (MCBL) cell or the test cell, which were identified in the urochordate Styela plicata . A basophil/mast cell progenitor (BMCP) cell population was isolated from the spleen of adult mice, and the timed expression of the transcription factors GATA-binding protein 2 and CCAAT/enhancer-binding protein-α in these progenitor cells might determine whether they eventually mature into basophils or mast cells. New mouse models have been developed in which mast cells or basophils can be constitutively or conditionally depleted. These models allow more specific targeting of mast cells and basophils, compared with the Kit -mutant mouse strains and depleting antibody strategies which were previously used to assess mast cell and basophil functions in vivo . Therefore, these new mouse models will help to further clarify the true biological roles of basophils and mast cells. Although mast cells and basophils can express interleukin-4, CD40 ligand and low levels of MHC class II under certain conditions, they seem to have no major role in driving the induction of adaptive type 2 immune responses. Mast cells and basophils cooperate to provide protection during secondary infestation with ticks. In addition, both cell types contribute, to various degrees, to protective immunity during gastrointestinal helminth infections in mice. IgE-mediated anaphylaxis is strictly mast cell-dependent, whereas IgG1-mediated anaphylaxis in mice results from the activation of monocytes, neutrophils or basophils. Basophils are recruited to the skin in a mouse model of atopic dermatitis and they induce IgE-mediated chronic allergic inflammation of the skin in the absence of mast cells. Mast cells and basophils are associated with protective immunity to helminths, but can also drive pathological immune responses in asthma and allergy. This Review covers the recent advances that have improved our understanding of the origins of these cells and of their biological functions in both health and disease. Mast cells and basophils are potent effector cells of the innate immune system, and they have both beneficial and detrimental functions for the host. They are mainly implicated in pro-inflammatory responses to allergens but can also contribute to protection against pathogens. Although both cell types were identified more than 130 years ago by Paul Ehrlich, their in vivo functions remain poorly understood. The precursor cell populations that give rise to mast cells and basophils have recently been characterized and isolated. Furthermore, new genetically modified mouse strains have been developed, which enable more specific targeting of mast cells and basophils. Such advances offer new opportunities to uncover the true in vivo activities of these cells and to revisit their previously proposed effector functions.

Food allergy is a major health issue, affecting the lives of 8% of U.S. children and their families. There is an urgent need to identify the environmental and endogenous signals that induce and sustain allergic responses to ingested allergens. Acute reactions to foods are triggered by the activation of mast cells and basophils, both of which release inflammatory mediators that lead to a range of clinical manifestations, including gastrointestinal, cutaneous, and respiratory reactions as well as systemic anaphylaxis. Both of these innate effector cell types express the high affinity IgE receptor, FcϵRI, on their surface and are armed for adaptive antigen recognition by very-tightly bound IgE antibodies which, when cross-linked by polyvalent allergen, trigger degranulation. These cells also express inhibitory receptors, including the IgG Fc receptor, FcγRIIb, that suppress their IgE-mediated activation. Recent studies have shown that natural resolution of food allergies is associated with increasing food-specific IgG levels. Furthermore, oral immunotherapy, the sequential administration of incrementally increasing doses of food allergen, is accompanied by the strong induction of allergen-specific IgG antibodies in both human subjects and murine models. These can deliver inhibitory signals via FcγRIIb that block IgE-induced immediate food reactions. In addition to their role in mediating immediate hypersensitivity reactions, mast cells and basophils serve separate but critical functions as adjuvants for type 2 immunity in food allergy. Mast cells and basophils, activated by IgE, are key sources of IL-4 that tilts the immune balance away from tolerance and towards type 2 immunity by promoting the induction of Th2 cells along with the innate effectors of type 2 immunity, ILC2s, while suppressing the development of regulatory T cells and driving their subversion to a pathogenic pro-Th2 phenotype. This adjuvant effect of mast cells and basophils is suppressed when inhibitory signals are delivered by IgG antibodies signaling via FcγRIIb. This review summarizes current understanding of the immunoregulatory effects of mast cells and basophils and how these functions are modulated by IgE and IgG antibodies. Understanding these pathways could provide important insights into innovative strategies for preventing and/or reversing food allergy in patients.

Eosinophilic esophagitis (EoE) is characterized by esophageal eosinophilia, but the underlying mechanisms promoting eosinophil accumulation remain unclear. David Artis and his colleagues describe a new mouse model of EoE-like disease. The development of EoE-like disease is dependent on thymic stromal lymphopoietin (TSLP) and basophils, whereas inhibition of TSLP or depletion of basophils attenuates established disease. Moreover, individuals with EoE have increased TSLP expression and basophils in the esophagus, suggesting that the TSLP-basophil axis can be targeted in patients with EoE. Eosinophilic esophagitis (EoE) is a food allergy–associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.