Kostova Elena B, Beuger Boukje M, Veldthuis Martijn, van der Werff Ten Bosch Jutte, Kühnle Ingrid, van den Akker Emile, van den Berg Timo K, van Zwieten Rob, van Bruggen Robin
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands.
Laboratory for Red Blood Cell Diagnostics, Sanquin, Amsterdam, The Netherlands.
Exp Hematol. 2015 Dec;43(12):1072-1076.e2. doi: 10.1016/j.exphem.2015.08.007. Epub 2015 Aug 28.
Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is a rare genetic disorder caused by mutations in STXBP2/Munc18-2. Munc18-2 plays a role in the degranulation machinery of natural killer cells and cytotoxic T lymphocytes. Mutations in STXBP2/Munc18-2 lead to impaired killing of target cells by natural killer cells and cytotoxic T lymphocytes, which in turn results in elevated levels of the inflammatory cytokine interferon γ, macrophage activation, and hemophagocytosis. Even though patients with FHL-5 present with anemia and hemolysis, no link between the disease and the erythroid lineage has been established. Here we report that red blood cells express Munc18-2 and that erythroid cells from patients with FHL-5 exhibit intrinsic defects caused by STXBP2/Munc18-2 mutations. Red blood cells from patients with FHL-5 expose less phosphatidylserine on their surface upon Ca(2+) ionophore ionomycin treatment. Furthermore, cultured erythroblasts from patients with FHL-5 display defective erythropoiesis characterized by decreased CD235a expression and aberrant cell morphology.
5型家族性噬血细胞性淋巴组织细胞增生症（FHL-5）是一种由STXBP2/Munc18-2基因突变引起的罕见遗传性疾病。Munc18-2在自然杀伤细胞和细胞毒性T淋巴细胞的脱颗粒机制中发挥作用。STXBP2/Munc18-2基因突变导致自然杀伤细胞和细胞毒性T淋巴细胞对靶细胞的杀伤受损，进而导致炎性细胞因子干扰素γ水平升高、巨噬细胞活化和噬血细胞现象。尽管FHL-5患者表现出贫血和溶血，但尚未确定该疾病与红系谱系之间的联系。在此我们报告红细胞表达Munc18-2，且FHL-5患者的红系细胞表现出由STXBP2/Munc18-2突变引起的内在缺陷。FHL-5患者的红细胞在经钙离子载体离子霉素处理后，其表面暴露的磷脂酰丝氨酸较少。此外，FHL-5患者培养的成红细胞表现出有缺陷的红细胞生成，其特征为CD235a表达降低和异常的细胞形态。
