Marcella Simone, Petraroli Angelica, Canè Luisa, Ferrara Anne Lise, Poto Remo, Parente Roberta, Palestra Francesco, Cristinziano Leonardo, Modestino Luca, Galdiero Maria Rosaria, Monti Maria, Marone Gianni, Triggiani Massimo, Varricchi Gilda, Loffredo Stefania
IRCCS SYNLAB SDN S.p.a., Naples 80143, Italy.
Department of Translational Medical Sciences, University of Naples Federico II, Naples 80131, Italy; World Allergy Organization (WAO) Center of Excellence, Naples 80131, Italy.
Eur J Intern Med. 2023 Nov;117:111-118. doi: 10.1016/j.ejim.2023.07.026. Epub 2023 Jul 26.
Mastocytosis is a heterogeneous disease associated to uncontrolled proliferation and increased density of mast cells in different organs. This clonal disorder is related to gain-of-function pathogenic variants of the c-kit gene that encodes for KIT (CD117) expressed on mast cell membrane. Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine, which plays a key role in allergic disorders and several cancers. TSLP is a survival and activating factor for human mast cells through the engagement of the TSLP receptor. Activated human mast cells release several preformed mediators, including tryptase. Increased mast cell-derived tryptase is a diagnostic biomarker of mastocytosis. In this study, we found that in these patients serum concentrations of TSLP were lower than healthy donors. There was an inverse correlation between TSLP and tryptase concentrations in mastocytosis. Incubation of human recombinant TSLP with sera from patients with mastocytosis, containing increasing concentrations of tryptase, concentration-dependently decreased TSLP immunoreactivity. Similarly, recombinant β-tryptase reduced the immunoreactivity of recombinant TSLP, inducing the formation of a cleavage product of approximately 10 kDa. Collectively, these results indicate that TSLP is a substrate for human mast cell tryptase and highlight a novel loop involving these mediators in mastocytosis.
肥大细胞增多症是一种异质性疾病，与不同器官中肥大细胞的不受控制的增殖和密度增加有关。这种克隆性疾病与编码在肥大细胞膜上表达的KIT（CD117）的c-kit基因的功能获得性致病变异有关。胸腺基质淋巴细胞生成素（TSLP）是一种多效性细胞因子，在过敏性疾病和几种癌症中起关键作用。TSLP通过TSLP受体的结合是人类肥大细胞的存活和激活因子。活化的人类肥大细胞释放几种预先形成的介质，包括类胰蛋白酶。肥大细胞衍生的类胰蛋白酶增加是肥大细胞增多症的诊断生物标志物。在这项研究中，我们发现这些患者的血清TSLP浓度低于健康供体。肥大细胞增多症中TSLP和类胰蛋白酶浓度之间存在负相关。用来自肥大细胞增多症患者的血清（含有不断增加浓度的类胰蛋白酶）与人重组TSLP孵育，TSLP免疫反应性呈浓度依赖性降低。同样，重组β-类胰蛋白酶降低了重组TSLP的免疫反应性，诱导形成了一种约10 kDa的裂解产物。总的来说，这些结果表明TSLP是人类肥大细胞类胰蛋白酶的底物，并突出了肥大细胞增多症中涉及这些介质的一个新环路。
