The Pathogenesis, Diagnosis, and Treatment of Systemic Mast Cell Disorders

National Institute Of Allergy And Infectious Diseases

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Linked publications, trials & patents

Abstract

Patients with non-aggressive indolent systemic mastocytosis (ISM) are not in general, candidates for cytoreductive therapy and are commonly treated with symptomatic therapy that only partly decreases symptoms. There is, however, a documented association between severity of mastocytosis and elevated serum levels of interleukin IL-6. Furthermore, mast cells have been shown to double their rate of cell division and exhibit increased reactivity and release of mediators when cultured in the presence of IL-6. In 2019, we initiated a clinical trial of adults with ISM that are randomized and treated with sarilumab which binds to the IL-6 receptor and inhibits IL-6 associated human mast cell signaling, proliferation and reactivity (decreased mediator release). This extensive and carefully executed study was published in FY2025 in JACI-Global and highlights the imperative to conduct randomized blinded study to objectively determine safety and efficacy. Symptom manifestations in patients with ISM are associated with increased mast cell burden and release of mast cell derived mediators, yet basophils are generally normal in number. In FY2024 we examined basophil activation and noted an abnormal response to N-formylmethione-leucyl-phenylalanine (fMLP). To evaluate this observation, we isolated basophils from peripheral blood of 15 patients with ISM and 14 healthy volunteers were isolated and stimulated with fMLP or anti-IgE. CD63 expression to assess basophil activation and expression of FPRs were assessed by flow cytometry. fMLP induced expression of CD63 on basophils from patients with ISM, was elevated whereas responses to anti-IgE were similar between groups. Basophils from patients with ISM also had higher fMLP1 receptor (FPR1) expression, whereas FPR2 and FPR3 were not detected. fMLP blocked the binding of anti-FPR1 antibody to FPR1, consistent with the conclusion that fMLP signals through FPR1. Further investigation is needed to determine, whether such expression might serve as an additional surrogate marker in the diagnosis of ISM, and whether enhanced responses of basophils to fMPL might have some relationship to unexplained episodes of mediator release. These results have been published in FY2024 JACI-Global since the last Annual report. A symposium entitled, "The Evolution of Mast Cell Research: 1985-2022", to highlight and honor the retirement Dr. Dean Metcalfe, previous Lab Chief of the Laboratory of Allergic disease was organized. It was a major event and included 18 speakers, experts in the field of mast cell biology and disease that either trained or collaborated with staff in the LAD from across the globe including China, France, Germany, Austria and Israel presenting in different media forums (live, zoom, pre-recorded) with over 200 noted viewers. After the symposium, Dr. Zuhir Ballas (Editor in Chief of JACI) contacted us with the request to author and submit a synopsis of the talks, conclusions, and future directions to be published in the Journal of Allergy and Clinical Immunology in a review article. The speakers provided summaries which were integrated into a manuscript with a graphic summarized the major contribution and published in JACI as a workshop summary in 2025. In FY 2025, Our data obtained from patients with pediatric-onset mastocytosis continues to expand the knowledge of providers caring for these patients. There continues to be only a few centers in the world with pediatric expertise. We are often consulted on the management difficult to managed or very ill children.