IgE epitope proximity determines immune complex shape and effector cell activation capacity

Gieras, Anna; Linhart, Birgit; Roux, Kenneth H.; Dutta, Moumita; Khodoun, Marat; Zafred, Domen; Cabauatan, Clarissa R.; Lupinek, Christian; Weber, Milena; Focke‐Tejkl, Margarete; Keller, Walter; Finkelman, Fred D.; Valenta, Rudolf

doi:10.1016/j.jaci.2015.08.055

Cited by 46 publications

(51 citation statements)

References 40 publications

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“…The severity of an allergic reaction may not only depend on the type of allergen, IgE levels, cytokine exposure, and the microenvironment but also on the total number of effector cells involved in the reaction . Conditions with high numbers of BA and MC include chronic inflammation, certain neoplastic states, and specific neoplasms, including basophilic leukemias and mastocytosis.…”

Section: Discussionmentioning

confidence: 99%

BTK inhibition is a potent approach to block IgE‐mediated histamine release in human basophils

Smiljkovic

Blatt

Stefanzl

et al. 2017

Allergy

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BackgroundRecent data suggest that Bruton's tyrosine kinase (BTK) is an emerging therapeutic target in IgE receptor (IgER)‐cross‐linked basophils.MethodsWe examined the effects of four BTK inhibitors (ibrutinib, dasatinib, AVL‐292, and CNX‐774) on IgE‐dependent activation and histamine release in blood basophils obtained from allergic patients (n=11) and nonallergic donors (n=5). In addition, we examined the effects of these drugs on the growth of the human basophil cell line KU812 and the human mast cell line HMC‐1.ResultsAll four BTK blockers were found to inhibit anti‐IgE‐induced histamine release from basophils in nonallergic subjects and allergen‐induced histamine liberation from basophils in allergic donors. Drug effects on allergen‐induced histamine release were dose dependent, with IC 50 values ranging between 0.001 and 0.5 μmol/L, and the following rank order of potency: ibrutinib>AVL‐292>dasatinib>CNX‐774. The basophil‐targeting effect of ibrutinib was confirmed by demonstrating that IgE‐dependent histamine release in ex vivo blood basophils is largely suppressed in a leukemia patient treated with ibrutinib. Dasatinib and ibrutinib were also found to counteract anti‐IgE‐induced and allergen‐induced upregulation of CD13, CD63, CD164, and CD203c on basophils, whereas AVL‐292 and CNX‐774 showed no significant effects. Whereas dasatinib and CNX‐774 were found to inhibit the growth of HMC‐1 cells and KU812 cells, no substantial effects were seen with ibrutinib or AVL‐292.Conclusions BTK‐targeting drugs are potent inhibitors of IgE‐dependent histamine release in human basophils. The clinical value of BTK inhibition in the context of allergic diseases remains to be determined.

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Section: Discussionmentioning

confidence: 99%

BTK inhibition is a potent approach to block IgE‐mediated histamine release in human basophils

Smiljkovic

Blatt

Stefanzl

et al. 2017

Allergy

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“…36,40,41 Gieras et al demonstrated that closer proximity of epitopes results in a stronger IgE-dependent mediator release. 42 This knowledge can be used to develop novel tools for prediction of disease progress and possibly response to interventions. In a prospective, longitudinal study on tolerance development in children with cow's milk allergy, IgG4 and IgE to specific milk epitopes bind with higher intensity and with broader diversity in children with persistent milk allergy.…”

Section: Novel Data On Clinical Markers and Biomarkers Of Food Allergymentioning

confidence: 99%

Recent developments and highlights in food allergy

Eiwegger

Hung

Diego

et al. 2019

Allergy

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The achievement of long-lasting, safe treatments for food allergy is dependent on the understanding of the immunological basis of food allergy. Accurate diagnosis is essential for management. In recent years, data from oral food challenges have revealed that routine allergy testing is poor at predicting clinical allergy for tree nuts, almonds in particular. More advanced antigen-based tests including component-resolved diagnostics and epitope reactivity may lead to more accurate diagnosis and selection of therapeutic intervention. Additional diagnostic accuracy may come from cellular tests such as the basophil activation test or mast cell approaches. In the context of clinical trials, cellular tests have revealed specific T-cell and B-cell populations that are more abundant in food-allergic individuals with distinct mechanistic features.Awareness of clinical markers, such as the ability to eat baked forms of milk and egg, continues to inform the understanding of natural tolerance development.Mouse models have allowed for investigation into multiple mechanisms of food allergy including modification of epithelial metabolism, and the induction of regulatory cell subsets and the microbiome. Increasing numbers of children who underwent food immunotherapy enlarged the body of evidence on mechanisms and predictors of treatment success. Experimental immunological markers in conjunction with clinical determinants such as lower age and lower initial specific IgE appear to be of benefit.More research on the optimal dose, preparation, and route of application integrating a high-level safety and efficacy is demanded. Alternatively, biologics blocking TSLP, IL-33, IL-4 and IL-13, or IgE may help to achieve that. K E Y W O R D Sallergy treatment, biologics, food allergy, immune tolerance, immunotherapy | 2357 EIWEGGER Et al.

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“…In vivo, during a passive cutaneous anaphylaxis response, this differential responsiveness translated to an altered cell recruitment at the inflammatory site. Besides antigen concentrations and affinity, the distance of epitopes recognized by IgE is also a crucial parameter [20]. This was shown by engineering epitopes onto a protein carrier at different distances.…”

Section: Fcεri-mediated Signalling: An Intricacy Of Positive Signallimentioning

confidence: 99%

Positive and Negative Signals in Mast Cell Activation

Bulfone–Paus∥

Nilsson

Dráber

et al. 2017

Trends in Immunology

117

106

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Mast cells are powerful immune modulators of the tissue microenvironment. Within seconds of activation, these cells release a variety of preformed biologically active products, followed by a wave of mediator synthesis and secretion. Increasing evidence suggests that an intricate network of inhibitory and activating receptors, specific signaling pathways, and adaptor proteins governs mast cell responsiveness to stimuli. Here, we discuss the biological and clinical relevance of negative and positive signaling modalities that control mast cell activation, with an emphasis on novel FcεRI regulators, immunoglobulin E (IgE)-independent pathways [e.g., Mas-related G protein-coupled receptor X2 (MRGPRX2)], tetraspanins, and the CD300 family of inhibitory and activating receptors.

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IgE epitope proximity determines immune complex shape and effector cell activation capacity

Cited by 46 publications

References 40 publications

BTK inhibition is a potent approach to block IgE‐mediated histamine release in human basophils

BTK inhibition is a potent approach to block IgE‐mediated histamine release in human basophils

Recent developments and highlights in food allergy

Positive and Negative Signals in Mast Cell Activation

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