Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases
Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases
复制标题
DOI：
10.3324/haematol.2010.029389
复制
发表时间：
2010-12-01
期刊：
影响因子：
--
通讯作者：
Ehl, Stephan
中科院分区：
文献类型：
--
作者：
Rohr, Jan;Beutel, Karin;Ehl, Stephan
家族性噬血细胞淋巴组织细胞增多症是一种遗传性淋巴细胞毒性疾病，通常在出生后两年出现，除非进行造血干细胞移植治疗，否则预后不良。设计与方法我们分析了8例非典型家族性噬血细胞淋巴组织细胞增生症患者的疾病表现、NK细胞和T细胞毒性和脱颗粒、T细胞活化和B细胞分化标志物以及由于UNC13D和STXBP2基因突变引起的自然杀伤T细胞。在大多数患者中，吞噬血细胞淋巴组织细胞增多症的发作之前或之后都有典型的与免疫缺陷有关的临床特征，如慢性活动性EB病毒感染，对细菌感染的易感性增加，肉芽肿性肺或肝脏疾病，脑炎或淋巴瘤。8例患者中有5例出现低丙种球蛋白血症和记忆B细胞减少。大多数患者以活化的CD8(+)T细胞为主，自然杀伤T细胞数量较少。与典型的家族性噬血细胞淋巴组织细胞增多症患者相比，患者的NK细胞杀伤活性、NK细胞和CTL脱颗粒功能受损程度相似。结论非典型家族性噬血细胞淋巴组织细胞增生症的临床和免疫学特征与原发免疫缺陷疾病(特别是常见的变异性免疫缺陷和X连锁淋巴组织综合征)有重要的重叠，因此必须在各种临床表现中加以考虑。我们认为脱颗粒试验是有助于鉴别此类患者的筛查试验。
BackgroundFamilial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed.Design and MethodsWe analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2.ResultsAll but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2. In most patients episodes of hemophagocytic lymphohistiocytosis were preceded or followed by clinical features typically associated with immunodeficiency, such as chronic active Epstein Barr virus infection, increased susceptibility to bacterial infections, granulomatous lung or liver disease, encephalitis or lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced memory B cells. Most patients had a predominance of activated CD8(+) T cells and low numbers of Natural Killer T cells. When compared to patients with typical familial hemophagocytic lymphohistiocytosis, NK-cell cytotoxicity and NK-cell and CTL degranulation were impaired to a similar extent. However, in patients with an atypical course NK-cell degranulation could be partially reconstituted by interleukin-2 and cytotoxic T-cell cytotoxicity in vitro was normal.ConclusionsClinical and immunological features of atypical familial hemophagocytic lymphohistiocytosis show an important overlap to primary immunodeficiency diseases (particularly common variable immunodeficiency and X-linked lymphoproliferative syndrome) and must, therefore, be considered in a variety of clinical presentations. We show that degranulation assays are helpful screening tests for the identification of such patients.