Maud A W Hermans1, Jorn J Heeringa2, Sigrid G A Swagemakers3, Benjamin Schrijver4, Paul L A van Daele5, Peter J van der Spek3, P Martin van Hagen5, Menno C van Zelm6, Wim A Dik4. 1. Department of Internal Medicine, Section of Allergy & Clinical Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: m.hermans@erasmusmc.nl. 2. Department of Internal Medicine, Section of Allergy & Clinical Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands. 3. Department of Pathology and Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands. 4. Laboratory of Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands. 5. Department of Internal Medicine, Section of Allergy & Clinical Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands; Laboratory of Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands. 6. Department of Immunology and Pathology, Central Clinical School, Monash University and Alfred Hospital, Melbourne, Australia.
Abstract
BACKGROUND: Indolent systemic mastocytosis (ISM) is characterized by pathologic accumulation of mast cells. The mechanism behind its phenotypic heterogeneity is not well understood. Interaction of mast cells with other immune cells might cause systemic inflammation and thereby associated symptoms. OBJECTIVE: We investigated peripheral leukocyte compartments and serum immune proteome in ISM. METHODS: Peripheral blood leukocyte phenotyping using flow cytometry in a cohort of 18 adults with ISM and 12 healthy controls. Targeted proteomics was performed to measure 169 proteins associated with inflammation on serum of another 20 ISM patients and 20 healthy controls. RESULTS: Proportions of plasmacytoid dendritic cells and monocytes were significantly decreased while TH2 cells were increased in peripheral blood of ISM patients. Furthermore, a shift from naive to memory T cells was observed. Hierarchical clustering of the serum proteome revealed 2 distinct subgroups within ISM patients. In subgroup A (n = 8), 62 proteins were significantly overexpressed, whereas those of subgroup B (n = 12) were comparable to healthy controls. Patients in subgroup A displayed upregulated signaling pathways downstream of Toll-like receptor 4, TNF-α, and IFN-γ. Fatigue was more often present in subgroup A compared to B (75% vs 33% respectively, P = .06). CONCLUSIONS: Altered distribution of leukocyte subsets and a proinflammatory proteome were observed in subsequent 2 cohorts of ISM patients. We hypothesize that neoplastic mast cells recruit and activate plasmacytoid dendritic cells, monocytes, and T cells, leading to a vicious cycle of inflammation.
BACKGROUND: Indolent systemic mastocytosis (ISM) is characterized by pathologic accumulation of mast cells. The mechanism behind its phenotypic heterogeneity is not well understood. Interaction of mast cells with other immune cells might cause systemic inflammation and thereby associated symptoms. OBJECTIVE: We investigated peripheral leukocyte compartments and serum immune proteome in ISM. METHODS: Peripheral blood leukocyte phenotyping using flow cytometry in a cohort of 18 adults with ISM and 12 healthy controls. Targeted proteomics was performed to measure 169 proteins associated with inflammation on serum of another 20 ISM patients and 20 healthy controls. RESULTS: Proportions of plasmacytoid dendritic cells and monocytes were significantly decreased while TH2 cells were increased in peripheral blood of ISM patients. Furthermore, a shift from naive to memory T cells was observed. Hierarchical clustering of the serum proteome revealed 2 distinct subgroups within ISM patients. In subgroup A (n = 8), 62 proteins were significantly overexpressed, whereas those of subgroup B (n = 12) were comparable to healthy controls. Patients in subgroup A displayed upregulated signaling pathways downstream of Toll-like receptor 4, TNF-α, and IFN-γ. Fatigue was more often present in subgroup A compared to B (75% vs 33% respectively, P = .06). CONCLUSIONS: Altered distribution of leukocyte subsets and a proinflammatory proteome were observed in subsequent 2 cohorts of ISM patients. We hypothesize that neoplastic mast cells recruit and activate plasmacytoid dendritic cells, monocytes, and T cells, leading to a vicious cycle of inflammation.
Authors: Alba Pérez-Pons; María Jara-Acevedo; Ana Henriques; Paula Navarro-Navarro; Andrés C García-Montero; Iván Álvarez-Twose; Carlos E Pedreira; Laura Sánchez-Muñoz; Daniela Damasceno; Carolina Caldas; Javier I Muñoz-González; Almudena Matito; Juan Flores-Montero; Oscar González-López; Ignacio Criado; Andrea Mayado; Alberto Orfao Journal: Clin Transl Allergy Date: 2022-06-14 Impact factor: 5.657