Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions
Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions
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DOI：
10.1182/blood-2004-08-3296
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发表时间：
2005-05-01
期刊：
影响因子：
20.3
通讯作者：
Yasukawa, M
中科院分区：
文献类型：
--
作者：
Ishii, E;Ueda, I;Yasukawa, M
穿孔素（PRF 1）和MUNC 13 -4基因的突变区分了2种形式的家族性噬血细胞性淋巴组织细胞增生症（分别为FHL 2和FHL 3），但这些基因型的临床和生物学相关性仍存在疑问。我们研究了35例FHL患者的呈递特征和细胞毒性T淋巴细胞/自然杀伤（CTU NK）细胞功能与不同亚型的关系。FHL 2（n = 11）比FHL 3（n = 8）或缺乏PRF 1或MUNC 13 -4突变的非FHL 2/FHL 3亚型（n = 16）具有更早的发病。在所有FHL 2的病例中，化疗后NK细胞活性持续缺乏，而一些FHL 3或非FHL 2/FHL 3亚型的患者在缓解期间表现出这种活性的部分恢复。同种抗原特异性CTL介导的细胞毒性在PRF 1无义突变的FHL 2患者中缺乏，在FHL 3患者中非常低，但在PRF 1错义突变的FHL 2患者中仅中度降低。这些发现与蛋白质印迹分析相关性很好，显示在具有PRF 1无义突变的FHL 2病例中不存在穿孔素，在FHL 3病例中不存在MUNC 13 -4，而在具有PRF 1错义突变的FHL 2病例中，存在少量的成熟穿孔素。这些结果表明FHL病例的基因突变类型与CTL细胞溶解活性的大小和发病年龄之间存在关联。(c)2005年，美国血液学会。
Mutations of the perforin (PRF1) and MUNC13-4 genes distinguish 2 forms of familial hemophagocytic lymphohistiocytosis (FHL2 and FHL3, respectively), but the clinical and biologic correlates of these genotypes remain in question. We studied the presenting features and cytotoxic T lymphocyte/natural killer (CTU NK) cell functions of 35 patients for their relationship to distinct FHL subtypes. FHL2 (n = 11) had an earlier onset than either FHL3 (n = 8) or the non-FHL2/FHL3 subtype lacking a PRF1 or MUNC13-4 mutation (n = 16). Deficient NK cell activity persisted after chemotherapy in all cases of FHL2, whereas some patients with FHL3 or the non-FHL2/FHL3 subtype showed partial recovery of this activity during remission. Alloantigen-specific CTL-mediated cytotoxicity was deficient in FHL2 patients with PRF1 nonsense mutations, was very low in FHL3 patients, but was only moderately reduced in FHL2 patients with PRF1 missense mutations. These findings correlated well with Western blot analyses showing an absence of perforin in FHL2 cases with PRF1 nonsense mutations and of MUNC13-4 in FHL3 cases, whereas in FHL2 cases with PRF1 missense mutations, mature perforin was present in low amounts. These results suggest an association between the type of genetic mutation in FHL cases and the magnitude of CTL cytolytic activity and age at onset. (c) 2005 by The American Society of Hematology.