Metabolome and lipidome derangements during a severe mast cell activation event in a patient with indolent systemic mastocytosis

Abstract

Background: The number of mast cells in various organs is elevated manifold in individuals with systemic mastocytosis. Degranulation can lead to life-threatening symptomatology. No data about the alterations of the metabolome and lipidome during an attack have been published. Objective: Our aim was to analyze changes in metabolomics and lipidomics during the acute phase of a severe mast cell activation event. Methods: A total of 43 metabolites and 11 lipid classes comprising 200 subvariants from multiple plasma samples in duplicate, covering 72 hours of a severe mast cell activation attack with nausea and vomiting, were compared with 2 baseline samples by using quantitative liquid chromatographymass spectrometry. Results: A strong enterocyte dysfunction reflected in an almost 20-fold reduction in the functional small bowel length was extrapolated from strongly reduced ornithine and citrulline concentrations and was very likely secondary to severe endothelial cell dysfunction with hypoperfusion and extensive vascular leakage. Highly increased histamine and lactate concentrations accompanied the peak in clinical symptoms. Elevated asymmetric and symmetric dimethylarginine levels combined with reduced arginine levels compromised endothelial nitric oxide synthase activity and nitric oxide signaling. Specific and extensive depletion of many lysophosphatidylcholine variants indicates localized autotaxin activation and lysophosphatidic acid release. A strong correlation of clinical parameters with histamine concentrations and symptom reduction after 100-fold elevated plasma diamine oxidase concentrations implies that histamine is the key driver of the acute phase.Conclusions: Rapid elimination of elevated histamine concentrations through use of recombinant human diamine oxidase, supplementation of lysophosphatidylcholine for immunomodulation, inhibition of autotaxin activity, and/or blockade of lysophosphatidic acid receptors might represent new treatment options for life-threatening mast cell activation events. (J Allergy Clin Immunol 2021;nnn:nnn-nnn.)

Massive release of TH2 cytokines induced a cytokine storm during a severe mast cell activation event in a patient with indolent systemic mastocytosis

“…I). 7 Several chemokines demonstrated a similar pattern of an increase followed by a flattening or even a decrease at the histamine peak (Fig A similar analysis using chemokine and cytokine data from 2 additional MCA events without diagnosis of an underlying infection is presented in Fig 2, along with corresponding P values. The patterns of cytokine elevation were comparable between the severe F18 and N14 events, but the magnitude was reduced in the N14 event.…”

“…Additional chemokine as well as T H 1-and T H 2-associated cytokine data from this event are shown in Fig E8 and The functional small bowel length reflects the metabolic health of the jejunal and ileal epithelial cells. 7 The main component for calculating this bowel length is the citrulline concentration, which is only synthesized by gastrointestinal epithelial cells and was strongly decreased during the acute phase of the F18 event. 7…”

“…A detailed description of the metabolome and lipidome derangements and medications administered for the most severe event, which occurred in February 2018, is provided elsewhere. 7 Briefly, 250 mg of prednisolone was administered at admission, and 100 mg prednisolone was administered 7, 14, and 26 hours after admission. Diphenhydramine was infused at admission (60 mg) and after 7 (30 mg), 9 (30 mg), 18 (30 mg), and 26 (30 mg) hours.…”

“…Protracted MCA in mastocytosis patients can last for a few days. 6,7 Excessive histamine release might significantly contribute to clinical symptomatology during protracted MCA, but is unlikely to be the sole culprit, considering the release of many other mediators during MC degranulation or activation. 1,7,8 MCs can release many chemokines and cytokines, although we caution that human in vivo data are missing in many cases.…”

“…6,7 Excessive histamine release might significantly contribute to clinical symptomatology during protracted MCA, but is unlikely to be the sole culprit, considering the release of many other mediators during MC degranulation or activation. 1,7,8 MCs can release many chemokines and cytokines, although we caution that human in vivo data are missing in many cases. 8 The cytokines IL-2, IL-6, and IL-10 were moderately elevated during classical anaphylaxis comparing moderate and severe reactions, as were tryptase and histamine, but the medium time from exposure to reaction onset was less than 10 minutes.…”