Defining Optimal Basophil Passive Sensitisation Parameters.

Background: Detecting drug-specific IgE (sIgE) is crucial for diagnosing immediate drug-induced hypersensitivity reactions. Basophil activation tests serve as a method to determine the presence of drug-sIgE, highlighting the importance of optimising the assay. Optimisation involves considering multiple factors to ensure sensitisation helps detect an antigen sIgE.

Peanut-specific IgG subclasses as biomarkers of peanut allergy in LEAP study participants.

Antigen-specific IgG2 and IgG3 are rarely measured in food allergy clinical trials despite known function in preventing mast cell and basophil activation. Our objective was to determine whether measuring peanut-specific IgG2 and IgG3 levels would correlate with peanut allergy status. Peanut-specific IgG subclasses were measured via ELISA assays in Learning Early About Peanut allergy (LEAP) trial participants at 5 years of age and were correlated with peanut allergy vs peanut sensitization vs non-peanut allergic and peanut consumption vs peanut avoidance.

A Skin Testing Strategy for Non-IgE-Mediated Reactions Associated With Vancomycin.

Background: Vancomycin infusion reaction (VIR), reportedly mediated through Mas-Related G Protein-Coupled Receptor-X2, is the primary vancomycin-induced immediate drug reaction. Clinically, distinguishing the underlying drug-induced immediate drug reaction mechanisms is crucial for future treatment strategies, including drug restriction, re-administration, and pretreatment considerations. However, the lack of validated diagnostic tests makes this challenging, often leading to unnecessary drug restriction.

A phase II study of Bruton's tyrosine kinase inhibition for the prevention of anaphylaxis.

BACKGROUNDIgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no currently FDA-approved preventative therapies. Bruton's tyrosine kinase (BTK) is an essential enzyme for IgE-mediated signaling pathways and is an ideal pharmacologic target to prevent allergic reactions. In this open-label trial, we evaluated the safety and efficacy of acalabrutinib, a BTK inhibitor that is FDA approved to treat some B cell malignancies, in preventing clinical reactivity to peanut in adults with peanut allergy.

Bruton's tyrosine kinase inhibition for the prevention of anaphylaxis: an open-label, phase 2 trial.

IgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no known preventative therapies. Bruton's tyrosine kinase (BTK) is an essential enzyme for IgE-mediated signaling pathways, and is an ideal pharmacologic target to prevent allergic reactions. In this open-label trial (NCT05038904), we evaluated the safety and efficacy of acalabrutinib, a BTK inhibitor that is FDA-approved to treat some B cell malignancies, in preventing clinical reactivity to peanut in adults with IgE-mediated peanut allergy.

The efficacy of omalizumab treatment in chronic spontaneous urticaria is associated with basophil phenotypes.

Background: The mechanisms underlying disease pathogenesis in chronic spontaneous urticaria (CSU) and improvement with omalizumab are incompletely understood.

Objectives: This study sought to examine whether the rate of clinical remission is concordant with baseline basophil features or the rate of change of IgE-dependent functions of basophils and/or plasmacytoid dendritic cells during omalizumab therapy.

Methods: Adults (n = 18) with refractory CSU were treated with omalizumab 300 mg monthly for 90 days.

Targeting the FcεRI Pathway as a Potential Strategy to Prevent Food-Induced Anaphylaxis.

Despite attempts to halt it, the prevalence of food allergy is increasing, and there is an unmet need for strategies to prevent morbidity and mortality from food-induced allergic reactions. There are no known medications that can prevent anaphylaxis, but several novel therapies show promise for the prevention of food-induced anaphylaxis through targeting of the high-affinity IgE receptor (FcϵRI) pathway. This pathway includes multiple candidate targets, including tyrosine kinases and the receptor itself.

Dependence of Optimal Histamine Release on Cell Surface IgE Density on Human Basophils: Nature of the Stimulus.

Background: The characteristics of the aggregation reaction that follows allergen binding to cell surface IgE on basophils and mast cells depend on a variety of factors that include the density of IgE and the affinity of the allergen for IgE. For simple bivalent stimuli, one prediction is that the location of the optimum for aggregation is not dependent on IgE density, only the affinity for IgE. However, this behavior does not occur for stimulation with an anti-IgE antibody (Ab) during the treatment of patients with omalizumab.

Basophil activation testing.

Both the treatment of patients with allergic diseases and the study of allergic disease mechanisms depend on a wide variety of assays that in various ways assess the presence and function of IgE antibody. The study of allergic diseases could benefit from the study of its 2 principle cellular participants, mast cells and basophils, but the basophil is more accessible than mast cells for ex vivo studies. Its functionality is tested by using 2 predominant methodologies: the secretion of mediators of allergic inflammation and the expression of proteins on the plasma membrane after stimulation.

Omalizumab increases the intrinsic sensitivity of human basophils to IgE-mediated stimulation.

Background: Treatment of allergic patients with omalizumab results in a paradoxical increase in their basophil histamine release (HR) response ex vivo to cross-linking anti-IgE antibody. It is not known whether this change in response is associated with an increase in intrinsic cellular sensitivity, which would be a paradoxical response.

Objective: We sought to determine whether the increase in response to anti-IgE antibody is a reflection of an increased cellular sensitivity expressed as molecules of antigen-specific IgE per basophil required to produce 50% of the maximal response.

Kinetics of mast cell, basophil, and oral food challenge responses in omalizumab-treated adults with peanut allergy.

Background: Monoclonal antibodies directed at IgE demonstrate clinical efficacy in subjects with peanut allergy, but previous studies have not addressed the kinetics of the clinical response or the role of mast cells and basophils in the food-induced allergic response.

Objective: We sought to determine the kinetics of the clinical response to omalizumab and whether clinical improvement is associated with either mast cell or basophil suppression.

Methods: Subjects with peanut allergy were treated with omalizumab for 6 months and assessed for clinical and cellular responses.

Suppression of the basophil response to allergen during treatment with omalizumab is dependent on 2 competing factors.

Background: A recent study of subjects with peanut allergy treated with omalizumab generated some results that were concordant with a study of subjects with cat allergy treated with omalizumab. However, there were differences that provided additional insight into the nature of the cellular responses in allergic subjects.

Objective: We sought to determine the cause for failure to suppress the allergen-induced basophil response during treatment with omalizumab.

IgE-dependent signaling as a therapeutic target for allergies.

Atopic diseases are complex, with many immunological participants, but the central element in their expression is IgE antibody. In an atopic individual, the immune system pathologically reacts to environmental substances by producing IgE, and these allergen-specific IgE antibodies confer to IgE receptor-bearing cells responsiveness to the environmental substances. Mast cells and basophils are central to the immediate hypersensitivity reaction that is mediated by IgE.

Assessing basophil functional measures during monoclonal anti-IgE therapy.

Assessing the impact of therapeutic interventions on the clinical and immunologic responses of allergic subjects is a topic of extensive investigation. Available approaches include the measurement of in vivo allergen challenge responses, serologic measures, or in vitro studies of cells that participate in the allergic reaction. Several decades of work support that measures of allergen responses of IgE-bearing peripheral blood basophils can reflect clinical expression of allergic disease.

Glycomic analysis of human mast cells, eosinophils and basophils.

In allergic diseases such as asthma, eosinophils, basophils and mast cells, through release of preformed and newly generated mediators, granule proteins and cytokines, are recognized as key effector cells. While their surface protein phenotypes, mediator release profiles, ontogeny, cell trafficking and genomes have been generally explored and compared, there has yet to be any thorough analysis and comparison of their glycomes. Such studies are critical to understand the contribution of carbohydrates to the induction and regulation of allergic inflammatory responses and are now possible using improved technologies for detecting and characterizing cell-derived glycans.

Regulation of Syk kinase and FcRbeta expression in human basophils during treatment with omalizumab.

Background: In human basophils from different subjects, maximum IgE-mediated histamine release and the level of Syk protein expression correlate well. Recent studies suggest that in some patients treated with omalizumab, the response to stimulation with anti-IgE antibody increases. In unrelated studies there is also evidence that the composition of FcepsilonRI in basophils differs among subjects.

IgE antibody-specific activity in human allergic disease.

IgE antibody concentration, affinity, clonality and specific activity (also known as the allergen-specific IgE to total IgE ratio) influence the translation of IgE responses into clinically evident allergic symptoms following allergen exposure. Reported IgE-specific activity levels >3-4% place allergic individuals undergoing anti-IgE (Omalizumab((R))) therapy at a disadvantage for poor resolution of their allergy symptoms following manufacturer's recommended dosing schemes. We investigated the hypothesis that the specific activity of the IgE antibody response is highly variable with respect to age, allergen specificity and an individual's total serum IgE level.

Regulation of Fc epsilon RI expression during murine basophil maturation: the interplay between IgE, cell division, and Fc epsilon RI synthetic rate.

Expression of Fc epsilonRI on basophils and mast cells is modulated by IgE Ab. Previous studies have noted in vivo receptor expression dynamics that are discordant with expectations derived from in vitro studies. The current study presents a formal hypothesis to explain the discordant observations and tests two assumptions that underlie a proposed model of receptor dynamics.

Effects of omalizumab on basophil and mast cell responses using an intranasal cat allergen challenge.

Background: Omalizumab treatment suppresses FcepsilonRI expression faster on blood basophils than skin mast cells.

Objective: We used omalizumab to elucidate the relative contributions of basophil versus mast cell FcepsilonRI activation in a nasal allergen challenge (NAC) model.

Methods: Eighteen subjects with cat allergy were enrolled in a 3.

Syk expression in peripheral blood leukocytes, CD34+ progenitors, and CD34-derived basophils.

In human basophils from different subjects, maximum IgE-mediated histamine release and the level of syk protein expression correlate well. It is not clear when in the basophil's lifetime the set-point for syk expression is reached or how expression levels are determined for a given individual. An examination of syk expression in peripheral blood eosinophils, neutrophils, monocytes, B and T cells, DCs, and NK cells showed that with the exception of T cells, basophils were unique in expressing low levels of syk.

Self-termination/anergic mechanisms in human basophils and mast cells.

All cellular reactions include feedback loops, both positive and negative. Following all receptor-mediated stimulation there are events that activate the cell response and events that dampen the receptor response back to resting conditions. IgE-mediated activation of mast cells and basophils necessarily includes a variety of signaling events that serve to terminate the activation processes.