As of the date of this report, patients with idiopathic anaphylaxis (IA) continue to be admitted for study. The majority of the patients are admitted to the inpatient unit and undergo a bone marrow procedure in an attempt to elucidate the etiology and evaluate the pathogenesis of their disease. Patients also have research blood drawn along with routine labs. In collaboration with the NIH Clinical Center's myeloid core facility, we assess all the patient bone marrow aspirates and biopsies obtained based on the current WHO criteria to diagnose systemic mastocytosis. Mast cells (MCs) derived from peripheral mononuclear cells are being cultured and examined for MC growth and activation studies in comparison to MCs from healthy volunteers. Patients with IA have been shown to have enhanced growth of MCs derived from peripheral CD34+ cells and these MCs demonstrated hyperresponsiveness with higher release of granule contents. These data provide a reason for continued exploration of the variability in human MC-dependent responses related to a specific phenotype. The randomized treatment protocol with omalizumab (09-I-0129) is in the patient accrual stage. There have been no serious adverse events contributed to the study drug, in particular drug-induced anaphylaxis. To explore the contribution of TRPC1 in MC-driven allergic reactions, we examined antigen-mediated anaphylaxis in Trpc1-/- and WT mice, and TRPC1 involvement in the activation of MCs cultured from the bone marrow (BMMCs) of these mice. In vivo, we observed a similar induction of passive systemic anaphylaxis in the Trpc1-/ - mice compared to WT controls, with a delay in recovery from this response in Trpc1-/- mice. In vitro, Trpc1-/- BMMCs responded to antigen with enhanced calcium signalling but with little defect in degranulation. In contrast, antigen-mediated production of TNF-alpha and other cytokines was enhanced in the Trpc1-/- BMMCs. Further, circulating levels of TNF-alpha in response to antigen were preferentially elevated in the Trpc1-/-mice, and administration of an anti-TNF-alpha antibody blocked the delay in recovery from anaphylaxis in these mice. These data thus provide evidence that TRPC1 promotes recovery from the anaphylactic response by repressing antigen-mediated TNF-alpha release from MCs.

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Carter, M C; Ruiz-Esteves, K N; Workman, L et al. (2018) Identification of alpha-gal sensitivity in patients with a diagnosis of idiopathic anaphylaxis. Allergy 73:1131-1134
Carter, Melody C; Desai, Avanti; Komarow, Hirsh D et al. (2018) A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis. J Allergy Clin Immunol 141:180-188.e3
Metcalfe, Dean D; Mekori, Yoseph A (2017) Pathogenesis and Pathology of Mastocytosis. Annu Rev Pathol 12:487-514
Hox, Valerie; O'Connell, Michael P; Lyons, Jonathan J et al. (2016) Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis. J Allergy Clin Immunol 138:187-99
Siebenhaar, F; von Tschirnhaus, E; Hartmann, K et al. (2016) Development and validation of the mastocytosis quality of life questionnaire: MC-QoL. Allergy 71:869-77
Muñoz-Cano, Rosa; Pascal, Mariona; Bartra, Joan et al. (2016) Distinct transcriptome profiles differentiate nonsteroidal anti-inflammatory drug-dependent from nonsteroidal anti-inflammatory drug-independent food-induced anaphylaxis. J Allergy Clin Immunol 137:137-146
Boyden, Steven E; Metcalfe, Dean D; Komarow, Hirsh D (2016) Vibratory Urticaria and ADGRE2. N Engl J Med 375:95
Kotarek, Joseph; Stuart, Christine; De Paoli, Silvia H et al. (2016) Subvisible Particle Content, Formulation, and Dose of an Erythropoietin Peptide Mimetic Product Are Associated With Severe Adverse Postmarketing Events. J Pharm Sci 105:1023-7
Lyons, Jonathan J; Yu, Xiaomin; Hughes, Jason D et al. (2016) Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet 48:1564-1569
Kirshenbaum, Arnold S; Cruse, Glenn; Desai, Avanti et al. (2016) Immunophenotypic and Ultrastructural Analysis of Mast Cells in Hermansky-Pudlak Syndrome Type-1: A Possible Connection to Pulmonary Fibrosis. PLoS One 11:e0159177

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