Publications (112) View all
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Article: Advances in mechanisms of allergy and clinical immunology in 2012.
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ABSTRACT: Manuscripts published in the "Mechanisms of allergy and clinical immunology" section of the Journal of Allergy and Clinical Immunology during 2012 enhanced our knowledge of the involvement of cytokines and other mediators in allergic disorders and described novel approaches for understanding mechanisms of allergic and immunologic diseases. Also published were articles focused on mechanisms of allergen-specific immunotherapy and the development of novel antiallergic treatments, as well as strategies to achieve tolerance to allergens. The highlights of these studies and their potential clinical implications are summarized in this review.The Journal of allergy and clinical immunology 01/2013; · 9.17 Impact Factor -
Article: Rapid polyclonal desensitization with antibodies to IgE and FcεRIα
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ABSTRACT: BACKGROUND: Rapid desensitization, a procedure in which persons allergic to an antigen are treated at short intervals with increasing doses of that antigen until they tolerate a large dose, is an effective, but risky, way to induce temporary tolerance. OBJECTIVE: We wanted to determine whether this approach can be adapted to suppress all IgE-mediated allergies in mice by injecting serially increasing doses of monoclonal antibodies (mAbs) to IgE or FcεRIα. METHODS: Active and passive models of antigen- and anti-IgE mAb-induced IgE-mediated anaphylaxis were used. Mice were desensitized with serially increasing doses of anti-IgE mAb, anti-FcεRIα mAb, or antigen. Development of shock (hypothermia), histamine and mast cell protease release, cytokine secretion, calcium flux, and changes in cell number and FcεRI and IgE expression were evaluated. RESULTS: Rapid desensitization with anti-IgE mAb suppressed IgE-mediated immediate hypersensitivity; however, some mice developed mild anaphylaxis during desensitization. Rapid desensitization with anti-FcεRIα mAb that only binds FcεRI that is not occupied by IgE suppressed both active and passive IgE-mediated anaphylaxis without inducing disease. It quickly, but temporarily, suppressed IgE-mediated anaphylaxis by decreasing mast cell signaling through FcεRI, then slowly induced longer lasting mast cell unresponsiveness by removing membrane FcεRI. Rapid desensitization with anti-FcεRIα mAb was safer and longer lasting than rapid desensitization with antigen. CONCLUSION: A rapid desensitization approach with anti-FcεRIα mAb safely desensitizes mice to IgE-mediated anaphylaxis by inducing mast cell anergy and later removing all mast cell IgE. Rapid desensitization with an anti-human FcεRIα mAb may be able to prevent human IgE-mediated anaphylaxis.The Journal of allergy and clinical immunology 04/2013; · 9.17 Impact Factor -
Article: Cdc42 regulates neutrophil migration via crosstalk between WASp, CD11b, and microtubules.
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ABSTRACT: Chemotaxis promotes neutrophil participation in cellular defense by enabling neutrophil migration to infected tissue and is controlled by persistent cell polarization. One long-standing question of neutrophil polarity has been how the pseudopod and the uropod are coordinated. In our previous report, we suggested that Rho GTPase Cdc42 controls neutrophil polarity through CD11b signaling at the uropod, albeit through an unknown mechanism. Here, we show that Cdc42 controls polarity, unexpectedly, via its effector WASp. Cdc42 controls WASp activation and its distant localization to the uropod. At the uropod, WASp regulates the reorganization of CD11b integrin into detergent resistant membrane domains; in turn, CD11b recruits the microtubule end binding protein EB1 to capture and stabilize microtubules at the uropod. This organization is necessary to maintain neutrophil polarity during migration and is critical for neutrophil emigration into inflamed lungs. These results suggest unrecognized mechanism of neutrophil polarity in which WASp mediates long-distance control of the uropod by Cdc42 to maintain a proper balance between the pseudopod and the uropod. Our study reveals a new function for WASp in the control of neutrophil polarity via crosstalk between CD11b and microtubules.Blood 08/2012; 120(17):3563-74. · 9.90 Impact Factor -
Article: Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1.
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ABSTRACT: Complement is an ancient danger-sensing system that contributes to host defense, immune surveillance and homeostasis. C5a and its G protein-coupled receptor mediate many of the proinflammatory properties of complement. Despite the key role of C5a in allergic asthma, autoimmune arthritis, sepsis and cancer, knowledge about its regulation is limited. Here we demonstrate that IgG1 immune complexes (ICs), the inhibitory IgG receptor FcγRIIB and the C-type lectin-like receptor dectin-1 suppress C5a receptor (C5aR) functions. IgG1 ICs promote the association of FcγRIIB with dectin-1, resulting in phosphorylation of Src homology 2 domain-containing inositol phosphatase (SHIP) downstream of FcγRIIB and spleen tyrosine kinase downstream of dectin-1. This pathway blocks C5aR-mediated ERK1/2 phosphorylation, C5a effector functions in vitro and C5a-dependent inflammatory responses in vivo, including peritonitis and skin blisters in experimental epidermolysis bullosa acquisita. Notably, high galactosylation of IgG N-glycans is crucial for this inhibitory property of IgG1 ICs, as it promotes the association between FcγRIIB and dectin-1. Thus, galactosylated IgG1 and FcγRIIB exert anti-inflammatory properties beyond their impact on activating FcγRs.Nature medicine 08/2012; · 27.14 Impact Factor -
Article: Food-induced anaphylaxis: mast cells as modulators of anaphylactic severity.
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ABSTRACT: A food-induced anaphylactic reaction can occur within seconds to a few hours following exposure to the causal food allergen and often affects multiple organ systems including gastrointestinal, cutaneous, respiratory, and cardiovascular. A conundrum in the allergy field is that consumption of the same allergen can cause reactions of vastly different severity in separate individuals; one patient may experience a mild non-life-threatening reaction characterized by pruritis of lips or urticaria whereas another may experience a life-threatening reaction that involves respiratory and cardiovascular compromise leading to loss of consciousness and sometimes death. While there are tests available to determine the predictive risk value of a positive food challenge test or clinical reactivity, there is currently no reliable method to distinguish between individuals who are at risk of mild non-life-threatening versus life-threatening reaction. Recent research has significantly advanced our understanding of the involvement of immune pathways in the effector phase of food-induced anaphylaxis; a void remains regarding our understanding of the contribution of these pathways to severity of disease. In this review, we discuss mild non-life-threatening versus life-threatening food-induced anaphylaxis and factors (co-morbidities and immune activation) that predispose individuals to more severe disease. Furthermore, we summarize recent advancements in our understanding of the involvement of underlying immune pathways in systemic and food-induced anaphylaxis in mouse systems and discuss how these pathways may contribute to more severe disease phenotype.Seminars in Immunopathology 08/2012; 34(5):643-53. · 6.27 Impact Factor
