Cells In Allergy Research Articles

Memory B cells in allergy: ontogeny, phenotype and plasticity

Memory B cells in allergy: ontogeny, phenotype and plasticity

Memory B cells in allergy: B cell activation and response

Memory B cells in allergy: B cell activation and response

Innate lymphoid cells in allergy

Innate lymphoid cells in allergy

Tissue-Resident Memory T Cells in Allergy.

Tissue-resident memory T (TRM) cells constitute a distinct subset within the memory T cell population, serving as the vanguard against invading pathogens and antigens in peripheral non-lymphoid tissues, including the respiratory tract, intestines, and skin. Notably, TRM cells adapt to the specific microenvironment of each tissue, predominantly maintaining a sessile state with distinctive phenotypic and functional attributes. Their role is to ensure continuous immunological surveillance and protection. Recent findings have highlighted the pivotal contribution of TRM cells to the modulation of adaptive immune responses in allergic disorders such as allergic rhinitis, asthma, and dermatitis. A comprehensive understanding of the involvement of TRM cells in allergic diseases bears profound implications for allergy prevention and treatment. This review comprehensively explores the phenotypic characteristics, developmental mechanisms, and functional roles of TRM cells, focusing on their intricate relationship with allergic diseases.

Bioactivity-Guided Fraction from Viscera of Abalone, Haliotis discus hannai Suppresses Cellular Basophils Activation and Anaphylaxis in Mice.

Basophils and mast cells are specialized effector cells in allergic reactions. Haliotis discus hannai (abalone), is valuable seafood. Abalone male viscera, which has a brownish color and has not been previously reported to show anti-allergic activities, was extracted with acetone. Six different acetone/hexane fractions (0, 10, 20, 30, 40, and 100%) were obtained using a silica column via β-hexosaminidase release inhibitory activity-guided selection in phorbol myristate acetate and a calcium ionophore, A23187 (PMACI)-induced human basophils, KU812F cells. The 40% acetone/hexane fraction (A40) exhibited the strongest inhibition of PMACI-induced-β-hexosaminidase release. This fraction dose-dependently inhibited reactive oxygen species (ROS) production and calcium mobilization without cytotoxicity. Western blot analysis revealed that A40 down-regulated PMACI-induced MAPK (ERK 1/2, p-38, and JNK) phosphorylation, and the NF-κB translocation from the cytosol to membrane. Moreover, A40 inhibited PMACI-induced interleukin (IL)-1β, IL-6, and IL-8 production. Anti-allergic activities of A40 were confirmed based on inhibitory effects on IL-4 and tumor necrosis factor alpha (TNF-α) production in compound (com) 48/80-induced rat basophilic leukemia (RBL)-2H3 cells. A40 inhibited β-hexosaminidase release and cytokine production such as IL-4 and TNF-α produced by com 48/80-stimulated RBL-2H3 cells. Furthermore, it's fraction attenuated the IgE/DNP-induced passive cutaneous anaphylaxis (PCA) reaction in the ears of BALB/c mice. Our results suggest that abalone contains the active fraction, A40 is a potent therapeutic and functional material to treat allergic diseases.

Drug delivery targets and strategies to address mast cell diseases

ABSTRACT Introduction Current and developing mast cell therapeutics are reliant on small molecule drugs and biologics, but few are truly selective for mast cells. Most have cellular and disease-specific limitations that require innovation to overcome longstanding challenges to selectively targeting and modulating mast cell behavior. This review is designed to serve as a frame of reference for new approaches that utilize nanotechnology or combine different drugs to increase mast cell selectivity and therapeutic efficacy. Areas covered Mast cell diseases include allergy and related conditions as well as malignancies. Here, we discuss the targets of existing and developing therapies used to treat these disease pathologies, classifying them into cell surface, intracellular, and extracellular categories. For each target discussed, we discuss drugs that are either the current standard of care, under development, or have indications for potential use. Finally, we discuss how novel technologies and tools can be used to take existing therapeutics to a new level of selectivity and potency against mast cells. Expert opinion There are many broadly and very few selectively targeted therapeutics for mast cells in allergy and malignant disease. Combining existing targeting strategies with technology like nanoparticles will provide novel platforms to treat mast cell disease more selectively.

Heterogeneity, subsets, and plasticity of T follicular helper cells in allergy

Antibody responses are critical for protection against pathogens. However, diseases such as allergic rhinitis or food allergy result from aberrant production of IgE antibodies against otherwise innocuous environmental antigens. The production of allergen-specific IgE requires interaction between B cells and CD4⁺ T cells, and a granular understanding of these interactions is required to develop novel therapies for allergic disease. CD4⁺ T cells are exceptionally heterogeneous in their transcriptional, epigenetic, and proteomic profiles, which poses significant challenges when attempting to define subsets relevant to the study of allergy among a continuum of cells. Defining subsets such as the T follicular helper (T_FH) cell cluster provides a shorthand to understand the functions of CD4⁺ T cells in antibody production and supports mechanistic experimentation for hypothesis-driven discovery. With a focus on allergic disease, this Rostrum article broadly discusses heterogeneity among CD4⁺ T cells and provides a rationale for subdividing T_FH cells into both functional and cytokine-skewed subsets. Further, it highlights the plasticity demonstrated by T_FH cells during the primary response and after recall, and it explores the possibility of harnessing this plasticity to reprogram immunity for therapeutic benefit in allergic disease.

An eosinophil-Sos1-RAS axis licenses corticosteroid resistance in patients with allergic rhinitis

BackgroundCorticosteroid resistance (CR) is a serious disadvantage in treating many chronic inflammatory conditions. Eosinophils are the main inflammation cells in allergic reactions. Environmental pollution, such as PM2.5, is associated with the pathogenesis of allergic disorders. The objective of this study is to elucidate the mechanism by which the exposure to PM2.5 confers eosinophil CR status. MethodsPatients with allergic rhinitis were recruited and assigned to corticosteroid sensitive (CS) and CR groups. Eosinophils were purified from nasal lavage fluids collected from patients with allergic rhinitis. A murine AR mouse model was developed with dust mite allergens and PM2.5 as the sensitization reagents. ResultsCR status was detected in about 60% eosinophil collected in patients with AR. Upon exposure to eosinophil activators, CS eosinophils released a large quantity of mediators, which was suppressed by the presence of steroids in the culture. CR eosinophils demonstrated resistance to steroidal therapy. RAS activation levels in eosinophils were higher in CR eosinophils than in CS eosinophils. Higher expression of the Son of sevenless-1 (Sos1) was detected in CR eosinophils, which formed a complex with RAS and glucocorticoidreceptor-α in CR eosinophils to prevent the binding between steroids and glucocorticoidreceptor-α. The presence of an Sos1 inhibitor dissociated glucocorticoid receptor-α from RAS/Sos1 complex, that restored the sensitivity to steroids in eosinophils. Administering the Sos1 inhibitor effectively attenuated the experimental allergic rhinitis. ConclusionsCR status was detected in approximately 1/3 eosinophils sampled from patients with allergic rhinitis. Sos1 was instrumental in the development and perseverance of CR in eosinophils. Sos1 inhibition restored sensitivity to steroids in CR eosinophils, which effectively reduced experimental allergic rhinitis.

Sargahydroquinoic acid isolated from Sargassum serratifolium as inhibitor of cellular basophils activation and passive cutaneous anaphylaxis in mice

Basophils and mast cells are characteristic effector cells in allergic reactions. Sargahydorquinoic acid (SHQA), a compound isolated from Sargassum serratifolium (marine alga), possesses various biochemical properties, including potent antioxidant activities. The objective of the present study was to investigate inhibitory effects of SHQA on the activation of human basophilic KU812F cells induced by phorbol myristate acetate and A23187 (PMACI), a calcium ionophore. Furthermore, we confirmed the inhibitory effects of SHQA on the activation of rat basophilic leukemia (RBL)–2H3 cells induced by compound 48/80 (com 48/80), bone marrow-derived mast cells (BMCMCs) induced by anti-dinitrophenyl(DNP)-immunoglobulin E (IgE)/DNP-bovine serum albumin (BSA), DNP/IgE and on the reaction of passive cutaneous anaphylaxis (PCA) mediated by IgE. SHQA reduced PMACI-induced intracellular reactive oxygen species (ROS) and calcium levels. Western blot analysis revealed that SHQA downregulated the activation of ERK, p38, and NF-κB in a dose-dependent manner. Moreover, SHQA suppressed the production and gene expression of various cytokines, including interleukin (IL)-1 β, IL-4, IL-6, and IL-8 in PMACI-induced KU812F cells and IL-4 and tumor necrosis factor (TNF)- α in com 48/80-induced RBL-2H3 cells. It also determined the inhibition of PMACI, com 48/80- and IgE/DNP-induced degranulation by reducing the release of β -hexosaminidase. Furthermore, it attenuated the IgE/DNP-induced PCA reaction in the ears of BALB/c mice. These results suggest that SHQA isolated from S. serratifolium is a potential therapeutic functional food material for inhibiting effector cell activation in allergic reactions and anaphylaxis in animal model.

Immune metabolism in allergies, does it matter?-A review of immune metabolic basics and adaptations associated with the activation of innate immune cells in allergy.

Type I allergies are pathological, type 2 inflammatory immune responses against otherwise harmless environmental allergens that arise from complex interactions between different types of immune cells. Activated immune cells undergo extensive changes in phenotype and function to fulfill their effector functions. Hereby, activation, differentiation, proliferation, migration, and mounting of effector responses require metabolic reprogramming. While the metabolic changes associated with activation of dendritic cells, macrophages, and T cells are extensively studied, data about the metabolic phenotypes of the other cell types critically involved in allergic responses (epithelial cells, eosinophils, basophils, mast cells, and ILC2s) are rather limited. This review briefly covers the basics of cellular energy metabolism and its connection to immune cell function. In addition, it summarizes the current state of knowledge in terms of dendritic cell and macrophage metabolism and subsequently focuses on the metabolic changes associated with activation of epithelial cells, eosinophils, basophils, mast cells, as well as ILC2s in allergy. Interestingly, the innate key cell types in allergic inflammation were reported to change their metabolic phenotype during activation, shifting to either glycolysis (epithelial cells, M1 macrophages, DCs, eosinophils, basophils, acutely activated mast cells), oxidative phosphorylation (M2 macrophages, longer term activated mast cells), or fatty acid oxidation (ILC2s). Therefore, immune metabolism is of relevance in allergic diseases and its connection to immune cell effector function needs to be considered to better understand induction and maintenance of allergic responses. Further progress in this field will likely improve both our understanding of disease pathology and enable new treatment targets/strategies.

Functional characterization of gamma-delta (γδ) T cells in allergy

Abstract Despite a growing consensus on the involvement of γδ T cells in allergy and other human immunological disorders, the detailed mechanisms remain hypothetical due to lack of investigative tools. Herein, we sought to develop functional assays to study the role of γδ T cells in allergy. Using an Activation-Induced Marker (AIM) assay, based on the upregulation of 4-1BB (CD137) and CD69, we were able to detect ex vivo allergen-specific responses from γδ T cells to multiple allergen extracts in human PBMCs, including mouse, cockroach (CR), house dust mite (HDM) and timothy grass (TG) allergens, which were reproducible and observed in multiple allergic cohorts. The magnitude of allergen-reactive γδ T cells differed between allergic and non-allergic cohorts with HDM and TG allergy, but not mouse or CR allergy. Further characterization showed that the γδ T cells reactive to mouse allergen were mostly the Vδ2 subset and from effector memory (Tem and Temra) compartments. Interestingly, in mouse-specific allergic donors we found differential polarized responses for γδ and ab T cells, with a Th1 and Th2 pattern, respectively. Using a complementary AIM assay for CD40L (CD154) combined with intracellular staining (ICS), we observed that Th1 polarization (INFg and TNFa) in responses to mouse extract was also common in non-allergic donors. Conversely, In the case of CR responses, Th1 polarization of Vδ2 T cells was only observed in the allergic cohort. Overall, these results suggest that allergen-specific Vδ2 T cells are potential to skew dysregulated cytokine responses in immunotherapy. In conclusion, we developed new functional assays that serve as tools for in-depth characterization and deciphering the roles of γδ T cells in allergy.

B regulatory cells in allergy.

B cells have classically been recognized for their unique and indispensable role in the production of antibodies. Their potential as immunoregulatory cells with anti-inflammatory functions has received increasing attention during the last two decades. Herein, we highlight pioneering studies in the field of regulatory B cell (Breg) research. We will review the literature on Bregs with a particular focus on their role in the regulation of allergic inflammation.

A novel ELISA method to determine human MrgX2 in chronic urticaria

BackgroundMas-related G-protein coupled receptor member X2 (MrgX2) directly mediates drug-induced pseudo allergic reactions. Skin mast cell MrgX2 is upregulated in severe chronic urticaria (CU). Mast cells and leukocytes are key effector cells in allergic reactions and undergo degranulation upon stimulation. It is unknown whether circulating MrgX2 expression can be detected occurs in the whole blood of CU patients and reflects pseudo-allergic reaction. There is no effective method for its detection. Therefore, an enzyme-linked immuno-sorbent assay (ELISA) for MrgX2 was developed.MethodsMonoclonal and polyclonal MrgX2 specific antibodies were obtained from rabbits and mice immunized by MrgX2 peptides prepared. Indirect ELISA and Dot blot were used to determine antibody titers before a sandwich ELISA for MrgX2 was established. The whole blood from healthy subjects and CU patients was used to detect MrgX2 concentrations. The use of feasibility of this MrgX2-ELISA as a clinical detection tool was explored and diagnostic purposes was assessed.ResultsThe sandwich antibody ELISA method for MrgX2 was established with good linearity regression (R2 = 0.9910). The lowest detection limit was 3.125 ng/mL. The quantification limit was 6.25 ng/mL. The sandwich ELISA for MrgX2 have good stability and high specificity. The initial truncation value of MrgX2 was 60.91 ng/mL (95% confidence interval). The whole blood MrgX2 concentrations in CU patients (median 98.01 ± 4.317 ng/mL, n = 75) was significantly increased compared to healthy subjects (58.09 ± 1.418 ng/mL, n = 75), with significant difference (p < 0.0001) and higher accuracy of (AUC = 0.8795). Comprehensive the frequency analysis of MrgX2 expression in 75 CU patients reference frequency distribution and ROC curve analysis, determined the threshold for CU patients as 71.23 ng/mL, with 81.33% sensitivity and 90.67% specificity.ConclusionMrgX2-ELISA provides a useful and convenient method for detecting MrgX2 in whole blood samples. The MrgX2-ELISA will help improve the understanding of the role of MrgX2 in regulating chronic urticaria.

Fetal mast cells mediate postnatal allergic responses dependent on maternal IgE.

Mast cells (MCs) are central effector cells in allergic reactions that are often mediated by immunoglobulin E (IgE). Allergies commonly start at an early age, and both MCs and IgE are detectable in fetuses. However, the origin of fetal IgE and whether fetal MCs can degranulate in response to IgE-dependent activation are presently unknown. Here, we show that human and mouse fetal MCs phenotypically mature through pregnancy and can be sensitized by maternal IgE. IgE crossed the placenta, dependent on the fetal neonatal Fc receptor (FcRN), and sensitized fetal MCs for allergen-specific degranulation. Both passive and active prenatal sensitization conferred allergen sensitivity, resulting in postnatal skin and airway inflammation after the first allergen encounter. We report a role for MCs within the developing fetus and demonstrate that fetal MCs may contribute to antigen-specific vertical transmission of allergic disease.

Single-cell transcriptomic analysis of allergen-specific T cells in allergy and asthma.

CD4+ T helper (TH) cells and regulatory T (Treg) cells that respond to common allergens play an important role in driving and dampening airway inflammation in patients with asthma. Until recently, direct, unbiased molecular analysis of allergen-reactive TH and Treg cells has not been possible. To better understand the diversity of these T cell subsets in allergy and asthma, we analyzed the single-cell transcriptome of ~50,000 house dust mite (HDM) allergen-reactive TH cells and Treg cells from asthmatics with HDM allergy and from three control groups: asthmatics without HDM allergy and nonasthmatics with and without HDM allergy. Our analyses show that HDM allergen-reactive TH and Treg cells are highly heterogeneous and certain subsets are quantitatively and qualitatively different in individuals with HDM-reactive asthma. The number of interleukin-9 (IL-9)-expressing HDM-reactive TH cells is greater in asthmatics with HDM allergy compared with nonasthmatics with HDM allergy, and this IL-9-expressing TH subset displays enhanced pathogenic properties. More HDM-reactive TH and Treg cells expressing the interferon response signature (THIFNR and TregIFNR) are present in asthmatics without HDM allergy compared with those with HDM allergy. In cells from these subsets (THIFNR and TregIFNR), expression of TNFSF10 was enriched; its product, tumor necrosis factor-related apoptosis-inducing ligand, dampens activation of TH cells. These findings suggest that the THIFNR and TregIFNR subsets may dampen allergic responses, which may help explain why only some people develop TH2 responses to nearly ubiquitous allergens.

The suppressive effect of dabrafenib, a therapeutic agent for metastatic melanoma, in IgE-mediated allergic inflammation

The functional inhibition of mast cells, which serve as a key effector cells in allergic reactions may be a specific target for treating immunoglobulin (Ig)E-mediated allergic reactions, which occur in various allergic diseases including anaphylaxis, asthma, and atopic dermatitis. In this study, we demonstrated the effects of dabrafenib, a therapeutic agent used to treat metastatic melanoma, with a focus on mast cell activation and local cutaneous anaphylaxis. In two types of mast cells (RBL-2H3 and mouse bone marrow-derived mast cells), dabrafenib (0.01, 0.1, 1 μM) pretreatment significantly decreased IgE-induced degranulation, intracellular calcium influx, and the activity of intracellular signaling molecules, such as Lyn, Syk, Akt, and PLCγ. Dabrafenib ameliorated mRNA and protein expression levels of interleukin-4 and tumor necrosis factor-α by the reduction of nuclear localization of nuclear factor-κB and nuclear factor of activated T-cells. In passive cutaneous anaphylaxis, oral administration of dabrafenib (0.1, 1, 10 mg/kg) reduced local pigmentation and ear thickness in a dose-dependent manner. Taken together, these results suggest that dabrafenib is a therapeutic drug candidate that controls IgE-mediated allergic inflammatory diseases through suppression of mast cell activity.

Localization-Specific Expression of CCR1 and CCR5 by Mast Cell Progenitors.

Mast cells are powerful immune cells found predominately in barrier tissues. They play an important role in immune surveillance and act as effector cells in allergic reactions. Mast cells develop from mast cell progenitors (MCp), which migrate to the peripheral tissues via the blood circulation. Presumably, the homing of MCp to the peripheral sites and localization is regulated by chemotactic signals. Due to the scarce abundance of these cells, chemotactic receptors have not been previously characterized on primary MCp. Here, mRNA transcripts for CCR1 and CX3CR1 were identified in mouse bone marrow and lung MCp in a gene expression screen of chemotactic receptors. However, surface expression of CCR1 was only found in the bone marrow MCp. Flow cytometry-based screening identified distinct surface expression of CCR5 by mouse peritoneal mast cells and MCp, while surface expression of CXCR2-5, CX3CR1, CCR1-3, CCR6-7, and CCR9 was not detected. Low surface expression of CCR5 was detected in mouse MCp in the bone marrow, spleen, and lung. To translate the findings to human, blood and bone marrow MCp from healthy donors were analyzed for possible CCR1 and CCR5 expression. Human MCp showed distinct surface expression of both CCR1 and CCR5. The expression levels of these chemokine receptors were higher in human bone marrow MCp than in the peripheral blood, suggesting that CCR1 and CCR5 may mediate retention in the bone marrow. In conclusion, mouse and human MCp show differential expression of CCR1 and CCR5 depending on their localization.

Enriched‐Baicalein Attenuates Allergy in Cells and Mice

Enriched‐baicalein (baicalein) from baicalin was prepared by fermentation of an SB extract with mycelium of Laetiporus sulphureus. To investigate the pharmacologic effects of baicalein, its antiallergic effect was measured in vitro and in vivo. Allergy was induced by intraperitoneal injection of ovalbumin (OVA) into Balb/c mice. As a result, baicalein showed antiallergic effects by inhibiting the release of β‐hexosaminidase from immunoglobulin E‐ (IgE‐) stimulated rat basophilic leukemia (RBL‐2H3) mast cells without cytotoxicity after the methodology. After four weeks, the decrease of OVA‐specific IgE level, decrease of histamine and tryptase level in serum, and then the decrease of the levels of T helper type 2 (Th2) cell‐derived cytokines interleukin‐ (IL‐) 4 and IL‐13 in the splenocyte were observed. In a histological analysis for lung, baicalein excellently reduced eosinophil infiltration with the inhibition of characteristic lesions and inflammation including OVA‐induced necrosis, numbers of inflammatory cells, and pulmonary edema. Therefore, these results showed that baicalein had excellent efficacy in the antiallergic activity.

Mast Cells as Key Players in Allergy and Inflammation.

Mast cells (MCs) are a key structural and functional component of both the innate and the adaptive immune systems. They are involved in many different processes, but play a major role in the response to infections and in inflammatory reactions. In addition, MCs are the main effector cells in allergy. MC biology is far more complex than initially believed. Thus, MCs may act directly or indirectly against pathogens and show a wide variety of membrane receptors with the ability to activate cells in response to various stimuli. Depending on where MCs complete the final stages of maturation, the composition of their cytoplasmic granules may vary considerably, and the clinical symptoms associated with tissue MC activation and degranulation may be also different. MCs are activated by complex signalling pathways characterized by multimolecular activating and inhibitory interactions. This article provides a comprehensive overview of MC biology, focusing predominantly on mechanisms of MC activation and the role of MCs in the pathogenesis of allergic diseases.

Social Networking of Group Two Innate Lymphoid Cells in Allergy and Asthma.

Allergic diseases including asthma, chronic rhinosinusitis, and atopic dermatitis are common conditions worldwide. While type 2 immune responses induced by T-cells significantly cause allergic inflammation, the recently identified group two innate lymphoid cells (ILC2s) are emerging as critical players in the development of allergy. Upon allergen exposure, ILC2s are rapidly activated by cytokines released by epithelial cells. Activated ILC2s release various effector cytokines altogether contributing to the pathogenesis of allergy and can even cause inflammation in the absence of T-cells, as observed in asthma. Although the factors inducing ILC2 activation have been identified, evidence suggests that multiple factors can enhance or repress ILC2 proliferation, trafficking, or secretion of effector cytokines upon allergic inflammation. In this review, we discuss the recent findings that influence ILC2 activation and the resulting effects on the pathogenesis of allergy. A better understanding of how ILC2s are modulated will open the door to the development of new therapeutic strategies against allergic diseases.