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Medical Principles and Practice :... 2022IgE-mediated type I hypersensitivity reactions have many reported beneficial functions in immune defense against parasites, venoms, toxins, etc. However, they are best... (Review)
Review
IgE-mediated type I hypersensitivity reactions have many reported beneficial functions in immune defense against parasites, venoms, toxins, etc. However, they are best known for their role in allergies, currently affecting almost one third of the population worldwide. IgE-mediated allergic diseases result from a maladaptive type 2 immune response that promotes the synthesis of IgE antibodies directed at a special class of antigens called allergens. IgE antibodies bind to type I high-affinity IgE receptors (FcεRI) on mast cells and basophils, sensitizing them to get triggered in a subsequent encounter with the cognate allergen. This promotes the release of a large variety of inflammatory mediators including histamine responsible for the symptoms of immediate hypersensitivity. The development of type 2-driven allergies is dependent on a complex interplay of genetic and environmental factors at barrier surfaces including the host microbiome that builds up during early life. While IgE-mediated immediate hypersensitivity reactions are undoubtedly at the origin of the majority of allergies, it has become clear that similar responses and symptoms can be triggered by other types of adaptive immune responses mediated via IgG or complement involving other immune cells and mediators. Likewise, various nonadaptive innate triggers via receptors expressed on mast cells have been found to either directly launch a hypersensitivity reaction and/or to amplify existing IgE-mediated responses. This review summarizes recent findings on both IgE-dependent and IgE-independent mechanisms in the development of allergic hypersensitivities and provides an update on the diagnosis of allergy.
Topics: Humans; Anaphylaxis; Mast Cells; Immunoglobulin E; Hypersensitivity; Basophils; Hypersensitivity, Immediate
PubMed: 36219943
DOI: 10.1159/000527481 -
Allergy Jun 2021Basophils and mast cells contribute to the development of allergic reactions. Whereas these mature effector cells are extensively studied, the differentiation...
BACKGROUND
Basophils and mast cells contribute to the development of allergic reactions. Whereas these mature effector cells are extensively studied, the differentiation trajectories from hematopoietic progenitors to basophils and mast cells are largely uncharted at the single-cell level.
METHODS
We performed multicolor flow cytometry, high-coverage single-cell RNA sequencing analyses, and cell fate assays to chart basophil and mast cell differentiation at single-cell resolution in mouse.
RESULTS
Analysis of flow cytometry data reconstructed a detailed map of basophil and mast cell differentiation, including a bifurcation of progenitors into two specific trajectories. Molecular profiling and pseudotime ordering of the single cells revealed gene expression changes during differentiation. Cell fate assays showed that multicolor flow cytometry and transcriptional profiling successfully predict the bipotent phenotype of a previously uncharacterized population of peritoneal basophil-mast cell progenitors.
CONCLUSIONS
A combination of molecular and functional profiling of bone marrow and peritoneal cells provided a detailed road map of basophil and mast cell development. An interactive web resource was created to enable the wider research community to explore the expression dynamics for any gene of interest.
Topics: Animals; Basophils; Bone Marrow Cells; Cell Differentiation; Mast Cells; Mice; Stem Cells
PubMed: 33078414
DOI: 10.1111/all.14633 -
Frontiers in Immunology 2019Urticaria (hives) is a highly prevalent skin disorder that can occur with or without associated angioedema. Chronic spontaneous urticaria (CSU) is a condition which... (Review)
Review
Urticaria (hives) is a highly prevalent skin disorder that can occur with or without associated angioedema. Chronic spontaneous urticaria (CSU) is a condition which persists for more than 6 weeks in duration and occurs in the absence of an identifiable provoking factor. CSU results from pathogenic activation of mast cells and basophils, which gives rise to the release of proinflammatory mediators that support the generation of urticaria. Several theories have been put forth regarding the pathogenesis of CSU with much evidence pointing toward a potential autoimmune etiology in up to 50% of patients with this condition. In this review, we highlight the evidence surrounding the autoimmune pathogenesis of chronic urticaria including recent data which suggests that CSU may involve contributions from both immunoglobin G (IgG)-specific and immunoglobulin E (IgE)-specific autoantibodies against a vast array of antigens that can span beyond those found on the surface of mast cells and basophils.
Topics: Animals; Basophils; Chronic Urticaria; Humans; Immunoglobulin E; Immunoglobulin G; Mast Cells; Models, Immunological
PubMed: 30984191
DOI: 10.3389/fimmu.2019.00627 -
Frontiers in Immunology 2020Food 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... (Review)
Review
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 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 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.
Topics: Allergens; Animals; Basophils; Desensitization, Immunologic; Food Hypersensitivity; Humans; Immunoglobulin E; Immunoglobulin G; Mast Cells; Phenotype; Receptors, Fc; Signal Transduction; Treatment Outcome
PubMed: 33362785
DOI: 10.3389/fimmu.2020.603050 -
Frontiers in Immunology 2022Despite being prone to reverse causation and having unmeasured confounding factors, many clinical observational studies have highlighted the critical association between...
BACKGROUND
Despite being prone to reverse causation and having unmeasured confounding factors, many clinical observational studies have highlighted the critical association between basophils, eosinophils, and lymphocytes and atopic dermatitis (AD). Whether these cells play a causal role in AD development remains uncertain.
METHODS
Data were obtained from the UK Biobank and the Blood Cell Consortium, from a large publicly available genome-wide association study (GWAS) with more than 500,000 subjects of European ancestry and for AD from three independent cohorts with more than 700,000 subjects of European ancestry. We performed single-variable Mendelian randomization (SVMR), followed by multivariable Mendelian randomization (MVMR) to assess the total and direct effects of immune cell counts on AD risk.
RESULTS
SVMR estimates showed that genetically predicted higher eosinophil [odds ratio (OR): 1.23, 95% confidence interval (CI): 1.17-1.29, = 5.85E-16] and basophil counts (OR: 1.11, 95% CI: 1.03-1.19, = 0.004) had an adverse effect on the risk of AD, while a higher lymphocyte count (OR: 0.93, 95% CI: 0.89-0.98, = 0.006) decreased the risk. Reverse MR analysis showed higher basophil (beta: 0.04, 95% CI: 0.01-0.07, = 0.014) and lower lymphocyte counts (beta: -0.05, 95% CI: -0.09 to -0.01, = 0.021) in patients with AD. In MVMR, the effects of eosinophils (OR: 1.19, 95% CI: 1.09-1.29, = 8.98E-05), basophils (OR: 1.19, 95% CI: 1.14-1.24, = 3.72E-15), and lymphocytes (OR: 0.93, 95% CI: 0.89-0.98, = 0.006) were still significant.
DISCUSSION
Mendelian randomization (MR) findings suggest that an increase in the eosinophil and basophil counts and a decrease in the lymphocyte counts are potential causal risk factors for AD. These risk factors are independent of each other.
Topics: Humans; Eosinophils; Basophils; Dermatitis, Atopic; Genome-Wide Association Study; Mendelian Randomization Analysis; Lymphocytes
PubMed: 36569933
DOI: 10.3389/fimmu.2022.1001911 -
Allergology International : Official... Jul 2023Chronic spontaneous urticaria (CSU) is a common skin disease without an etiology in the vast majority of cases. The similarity of symptoms and pathology to... (Review)
Review
Chronic spontaneous urticaria (CSU) is a common skin disease without an etiology in the vast majority of cases. The similarity of symptoms and pathology to allergen-induced skin reactions supports that skin mast cell IgE receptor activation is also involved in CSU. Accumulating evidence also supports a role for blood basophils in disease expression. Blood basopenia is noted in active CSU disease with the recruitment of blood basophils to skin lesion sites. Blood basophils further display altered IgE receptor mediated degranulation patterns in two phenotypes that improve in remission. In active CSU subjects, changes in IgE receptor signaling molecule expression levels accompany the altered degranulation function in blood basophils. The success of therapies targeting IgE in CSU patients have also shown that altered blood basophil phenotypes and enumeration have potential use as a disease biomarker.
Topics: Humans; Basophils; Receptors, IgE; Chronic Disease; Urticaria; Chronic Urticaria
PubMed: 37221123
DOI: 10.1016/j.alit.2023.05.001 -
Cell Nov 2018Lung development and function arises from the interactions between diverse cell types and lineages. Using single-cell RNA sequencing (RNA-seq), we characterize the...
Lung development and function arises from the interactions between diverse cell types and lineages. Using single-cell RNA sequencing (RNA-seq), we characterize the cellular composition of the lung during development and identify vast dynamics in cell composition and their molecular characteristics. Analyzing 818 ligand-receptor interaction pairs within and between cell lineages, we identify broadly interacting cells, including AT2, innate lymphocytes (ILCs), and basophils. Using interleukin (IL)-33 receptor knockout mice and in vitro experiments, we show that basophils establish a lung-specific function imprinted by IL-33 and granulocyte-macrophage colony-stimulating factor (GM-CSF), characterized by unique signaling of cytokines and growth factors important for stromal, epithelial, and myeloid cell fates. Antibody-depletion strategies, diphtheria toxin-mediated selective depletion of basophils, and co-culture studies show that lung resident basophils are important regulators of alveolar macrophage development and function. Together, our study demonstrates how whole-tissue signaling interaction map on the single-cell level can broaden our understanding of cellular networks in health and disease.
Topics: Animals; Basophils; Cell Communication; Cell Differentiation; Cell Line, Tumor; Cells, Cultured; Female; Genomic Imprinting; Granulocyte-Macrophage Colony-Stimulating Factor; Interleukin-33; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Single-Cell Analysis; Transcriptome
PubMed: 30318149
DOI: 10.1016/j.cell.2018.09.009 -
The Journal of Allergy and Clinical... May 2024Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for more than 6 weeks. Mast cells and... (Review)
Review
Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for more than 6 weeks. Mast cells and basophils are the key pathogenic drivers of CSU; their activation results in histamine and cytokine release with subsequent dermal inflammation. Two overlapping mechanisms of mast cell and basophil activation have been proposed in CSU: type I autoimmunity, also called autoallergy, which is mediated via IgE against various autoallergens, and type IIb autoimmunity, which is mediated predominantly via IgG directed against the IgE receptor FcεRI or FcεRI-bound IgE. Both mechanisms involve cross-linking of FcεRI and activation of downstream signaling pathways, and they may co-occur in the same patient. In addition, B-cell receptor signaling has been postulated to play a key role in CSU by generating autoreactive B cells and autoantibody production. A cornerstone of FcεRI and B-cell receptor signaling is Bruton tyrosine kinase (BTK), making BTK inhibition a clear therapeutic target in CSU. The potential application of early-generation BTK inhibitors, including ibrutinib, in allergic and autoimmune diseases is limited owing to their unfavorable benefit-risk profile. However, novel BTK inhibitors with improved selectivity and safety profiles have been developed and are under clinical investigation in autoimmune diseases, including CSU. In phase 2 trials, the BTK inhibitors remibrutinib and fenebrutinib have demonstrated rapid and sustained improvements in CSU disease activity. With phase 3 studies of remibrutinib ongoing, it is hoped that BTK inhibitors will present an effective, well-tolerated option for patients with antihistamine-refractory CSU, a phenotype that presents a considerable clinical challenge.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Chronic Urticaria; Signal Transduction; Mast Cells; Animals; Receptors, IgE; Basophils; Protein Kinase Inhibitors
PubMed: 38141832
DOI: 10.1016/j.jaci.2023.12.008 -
Seminars in Immunology Mar 2021It has been appreciated that basophilia is a common feature of helminth infections for approximately 50 years. The ability of basophils to secrete IL-4 and other type 2... (Review)
Review
It has been appreciated that basophilia is a common feature of helminth infections for approximately 50 years. The ability of basophils to secrete IL-4 and other type 2 cytokines has supported the prevailing notion that basophils contribute to antihelminth immunity by promoting optimal type 2 T helper (Th2) cell responses. While this appears to be the case in several helminth infections, emerging studies are also revealing that the effector functions of basophils are extremely diverse and parasite-specific. Further, new reports now suggest that basophils can restrict type 2 inflammation in a manner that preserves the integrity of helminth-affected tissue. Finally, exciting data has also demonstrated that basophils can regulate inflammation by participating in neuro-immune interactions. This article will review the current state of basophil biology and describe how recent studies are transforming our understanding of the role basophils play in the context of helminth infections.
Topics: Animals; Basophils; Cytokines; Helminths; Humans; Inflammation; Th2 Cells
PubMed: 34815162
DOI: 10.1016/j.smim.2021.101529 -
The Journal of Allergy and Clinical... Sep 2020The management of food allergy is complicated by the lack of highly predictive biomarkers for diagnosis and prediction of disease course. The measurement of... (Review)
Review
The management of food allergy is complicated by the lack of highly predictive biomarkers for diagnosis and prediction of disease course. The measurement of food-specific IgE is a useful tool together with clinical history but is an imprecise predictor of clinical reactivity. The gold standard for diagnosis and clinical research is a double-blind placebo-controlled food challenge. Improvement in our understanding of immune mechanisms of disease, development of high-throughput technologies, and advances in bioinformatics have yielded a number of promising new biomarkers of food allergy. In this review, we will discuss advances in immunoglobulin measurements, the utility of the basophil activation test, T-cell profiling, and the use of -omic technologies (transcriptome, epigenome, microbiome, and metabolome) as biomarker tools in food allergy.
Topics: Allergens; Basophils; Biomarkers; Food Hypersensitivity; Humans; Immunoglobulin E; Randomized Controlled Trials as Topic; Skin Tests
PubMed: 32888527
DOI: 10.1016/j.jaip.2020.04.054