Alberto Orfao

Background Systemic mastocytosis (SM) is a heterogeneous disease characterized by an expansion of KIT ‐mutated mast cells (MC). KIT ‐mutated MC display activated features and release MC mediators that might act on the tumour microenvironment and other immune cells. Here, we investigated the distribution of lymphocyte subsets in blood of patients with distinct subtypes of SM and determined its association with other disease features. Methods We studied the distribution of TCD4 + and TCD4 − cytotoxic cells and their subsets, as well as total NK‐ and B cells, in blood of 115 SM patients—38 bone marrow mastocytosis (BMM), 67 indolent SM (ISM), 10 aggressive SM (ASM)‐ and 83 age‐matched healthy donors (HD), using spectral flow cytometry and the EuroFlow Immunomonitoring panel, and correlated it with multilineage KIT D816V , the alpha‐tryptasemia genotype (HαT) and the clinical manifestations of the disease. Results SM patients showed decreased counts (vs. HD) of TCD4 − cytotoxic cells, NK cells and several functional subsets of TCD4 + cells (total Th1, Th2‐effector memory, Th22‐terminal effector and Th1‐like Tregs), together with increased T‐follicular‐helper and Th1/Th17‐like Treg counts, associated with different immune profiles per diagnostic subtype of SM, in multilineal versus MC‐restricted KIT D816V and in cases with a HαT + versus HαT − genotype. Unique immune profiles were found among BMM and ISM patients with MC‐restricted KIT D816V who displayed HαT, anaphylaxis, hymenoptera venom allergy, bone disease, pruritus, flushing and GI symptoms. Conclusion Our results reveal altered T‐ and NK‐cell immune profiles in blood of SM, which vary per disease subtype, the pattern of involvement of haematopoiesis by KIT D816V , the HαT genotype and specific clinical manifestations of the disease.