Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27
Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27
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DOI：
10.3324/haematol.2012.068791
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发表时间：
2013-03-01
期刊：
影响因子：
10.1
通讯作者：
Seidel, Markus G.
中科院分区：
文献类型：
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作者：
Salzer, Elisabeth;Daschkey, Svenja;Seidel, Markus G.
CD27是肿瘤坏死因子受体家族成员，与CD70相互作用，影响T、B和NK细胞功能。这一轴的紊乱损害了对包括爱泼斯坦-巴尔病毒(EBV)、流感等病毒的免疫和记忆生成。CD27通常被用作记忆B细胞的标志，用于B细胞缺陷的分类，包括常见的变异型免疫缺陷。流式细胞仪免疫表型分析包括CD27在淋巴细胞上的表达分析，然后对指标患者、他们的父母和未受影响的同胞进行CD27的毛细管测序。更全面的遗传分析采用了基于单核苷酸多态的纯合子作图和整个外显子组测序。外显子组测序数据的分析是在两个中心使用略有不同的数据分析管道进行的，每个管道都基于基因组分析工具包最佳实践版本3的建议。综合临床特征与基因分型相关。我们报告了在3个独立的家系(8例患者)中同时证实人类CD27缺乏的原因是通过整个外显子组测序发现了一个纯合子突变(p.Cys53Tyr)，导致了进化上保守的跨膜受体半胱氨酸结基序的中断。表型多样，从无症状记忆性B细胞缺陷(n=3)到EBV相关性吞血和淋巴增生性疾病(n=3)，以及恶性淋巴瘤(n=2；LPD后+1)。在EBV感染后，至少3名感染者出现低丙种球蛋白血症，同时可检测到特定的抗病毒和抗多糖抗体以及EBV特异性T细胞反应。在严重感染的患者中，iNKT细胞数量和NK细胞功能降低。其中2例死亡，2例异基因造血干细胞移植成功，1例反复接受抗CD20(利妥昔单抗)治疗。由于纯合性作图和外显子测序确实揭示了额外的修饰因素，我们的发现表明，功能CD27的缺乏容易导致与潜在的致命的EBV驱动的吞血、淋巴增殖和淋巴瘤发展相关的联合免疫缺陷。
CD27, a tumor necrosis factor receptor family member, interacts with CD70 and influences T-, B- and NK-cell functions. Disturbance of this axis impairs immunity and memory generation against viruses including Epstein Barr virus (EBV), influenza, and others. CD27 is commonly used as marker of memory B cells for the classification of B-cell deficiencies including common variable immune deficiency. Flow cytometric immunophenotyping including expression analysis of CD27 on lymphoid cells was followed by capillary sequencing of CD27 in index patients, their parents, and non-affected siblings. More comprehensive genetic analysis employed single nucleotide polymorphism-based homozygosity mapping and whole exome sequencing. Analysis of exome sequencing data was performed at two centers using slightly different data analysis pipelines, each based on the Genome Analysis ToolKit Best Practice version 3 recommendations. A comprehensive clinical characterization was correlated to genotype. We report the simultaneous confirmation of human CD27 deficiency in 3 independent families (8 patients) due to a homozygous mutation (p. Cys53Tyr) revealed by whole exome sequencing, leading to disruption of an evolutionarily conserved cystein knot motif of the transmembrane receptor. Phenotypes varied from asymptomatic memory B-cell deficiency (n=3) to EBV-associated hemophagocytosis and lymphoproliferative disorder (LPD; n=3) and malignant lymphoma (n=2; +1 after LPD). Following EBV infection, hypogammaglobulinemia developed in at least 3 of the affected individuals, while specific anti-viral and anti-polysaccharide antibodies and EBV-specific T-cell responses were detectable. In severely affected patients, numbers of iNKT cells and NK-cell function were reduced. Two of 8 patients died, 2 others underwent allogeneic hematopoietic stem cell transplantation successfully, and one received anti-CD20 (rituximab) therapy repeatedly. Since homozygosity mapping and exome sequencing did rick reveal additional modifying factors, our findings suggest that lack of functional CD27 predisposes towards a combined immunodeficiency associated with potentially fatal EBV-driven hemophagocytosis, lymphoproliferation, and lymphoma development.