Defective cytotoxic lymphocyte degranulation in syntaxin-11-deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients
Defective cytotoxic lymphocyte degranulation in syntaxin-11-deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients
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DOI：
10.1182/blood-2007-02-074468
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发表时间：
2007-09-15
期刊：
影响因子：
20.3
通讯作者：
Ljunggren, Hans-Gustaf
中科院分区：
文献类型：
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作者：
Bryceson, Yenan T.;Rudd, Eva;Ljunggren, Hans-Gustaf
家族性噬血细胞性淋巴组织细胞增多症 (FHL) 是一种典型的早发性致命性疾病，其特征为脓毒症样疾病，伴有血细胞减少、肝脾肿大和淋巴细胞细胞毒性缺陷。已在编码穿孔素 (PRF1/FHL2)、Munc13-4 (UNC13D/FHL3) 和 Syntaxin-11 (STX11/FHL4) 的基因中鉴定出致病突变。与导致穿孔素和 Munc13-4 功能丧失的突变相比，syntaxin-11 功能丧失突变如何导致疾病尚不清楚。我们将新鲜分离的静息自然杀伤 (NK) 细胞和 CD8(+) T 细胞推入此处，表达 Syntaxin-11。在婴儿中，NK 细胞是主要的含穿孔素细胞类型。 FHL4 患者的 NK 细胞在遇到敏感靶细胞时无法脱粒。出乎意料的是，IL-2刺激部分恢复了NK细胞的脱颗粒和细胞毒性，这可以解释与FHL2和FHL3患者相比，FHL4患者中观察到的疾病进展较轻的原因。由于婴儿中的效应T细胞区室仍不成熟，我们的数据表明观察到的NK细胞脱颗粒缺陷可能有助于FHL的病理生理学，对疑似FHL患者的NK细胞脱颗粒进行评估可能有助于诊断，并且这些新见解可能提供新的治疗可能性。
Familial hemophagocytic lymphohistiocytosis (FHL) is typically an early onset, fatal disease characterized by a sepsislike illness with cytopenia, hepatosplenomegaly, and deficient lymphocyte cytotoxicity. Disease-causing mutations have been identified in genes encoding perforin (PRF1/FHL2), Munc13-4 (UNC13D/FHL3), and syntaxin-11 (STX11/FHL4). In contrast to mutations leading to loss of perforin and Munc13-4 function, it is unclear how syntaxin-11 loss-of-function mutations contribute to disease. We shove here that freshly isolated, resting natural killer (NK) cells and CD8(+) T cells express syntaxin-11. In infants, NK cells are the predominant perforin-containing cell type. NK cells from FHL4 patients fail to degranulate when encountering susceptible target cells. Unexpectedly, IL-2 stimulation partially restores degranulation and cytotoxicity by NK cells, which could explain the less severe disease progression observed in FHL4 patients, compared with FHL2 and FHL3 patients. Since the effector T-cell compartment is still immature in infants, our data suggest that the observed defect in NK-cell degranulation may contribute to the pathophysiology of FHL, that evaluation of NK-cell degranulation in suspected FHL patients may facilitate diagnosis, and that these new insights may offer novel therapeutic possibilities.