Centre of Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Breisacher Strasse 117, Freiburg, Germany.
Blood. 2013 Apr 11;121(15):2943-51. doi: 10.1182/blood-2012-10-463166. Epub 2013 Feb 12.
Genetic disorders of lymphocyte cytotoxicity predispose patients to hemophagocytic lymphohistiocytosis (HLH). Reduced lymphocyte cytotoxicity has been demonstrated in Hermansky-Pudlak syndrome type 2 (HPS2), but only a single patient was reported who developed HLH. Because that patient also carried a potentially contributing heterozygous RAB27A mutation, the risk for HLH in HPS2 remains unclear. We analyzed susceptibility to HLH in the pearl mouse model of HPS2. After infection with lymphocytic choriomeningitis virus, pearl mice developed all key features of HLH, linked to impaired virus control caused by a moderate defect in CTL cytotoxicity in vivo. However, in contrast to perforin-deficient mice, the disease was transient, and all mice fully recovered and controlled the infection. An additional heterozygous Rab27a mutation did not aggravate the cytotoxicity defect or disease parameters. In the largest survey of 22 HPS2 patients covering 234 patient years, we identified only 1 additional patient with HLH and 2 with incomplete transient HLH-like episodes, although cytotoxicity or degranulation was impaired in all 16 patients tested. HPS2 confers a risk for HLH that is lower than in Griscelli or Chediak-Higashi syndrome, probably because of a milder defect in cytotoxicity. Preemptive hematopoietic stem cell transplantation does not appear justified in HPS2.
淋巴细胞细胞毒性遗传缺陷使患者易患噬血细胞性淋巴组织细胞增生症 (HLH)。Hermansky-Pudlak 综合征 2 型 (HPS2) 已证实存在淋巴细胞细胞毒性降低，但仅有一例报道的患者发生 HLH。由于该患者还携带潜在致病的杂合性 RAB27A 突变，因此 HPS2 发生 HLH 的风险仍不清楚。我们分析了 HPS2 珍珠鼠模型对 HLH 的易感性。感染淋巴细胞性脉络丛脑膜炎病毒后，珍珠鼠出现了 HLH 的所有关键特征，这与体内 CTL 细胞毒性的中度缺陷导致病毒控制受损有关。然而，与穿孔素缺陷小鼠不同的是，该疾病是短暂的，所有小鼠均完全恢复并控制了感染。另外一个杂合性 Rab27a 突变并没有加重细胞毒性缺陷或疾病参数。在对 22 名 HPS2 患者进行的 234 名患者年的最大调查中，我们仅发现 1 名患者发生 HLH，2 名患者发生不完全的短暂 HLH 样发作，尽管所有 16 名接受测试的患者的细胞毒性或脱颗粒均受损。HPS2 发生 HLH 的风险低于 Griscelli 或 Chediak-Higashi 综合征，可能是因为细胞毒性缺陷较轻。因此，在 HPS2 中，预防性造血干细胞移植似乎没有理由。
