Xiao Haijuan, Mou Wenjun, Zhang Rui, Guo Xin, Chen Heying, Zhang Liqiang, Liu Gang, Gui Jingang
Department of Infectious Diseases, Beijing Children's Hospital, Capital Medical University, Key Laboratory of Major Diseases in Children, Ministry of Education, National Center for Children's Health, Beijing, China.
Laboratory of Tumor Immunology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Scand J Immunol. 2023 Apr;97(4):e13256. doi: 10.1111/sji.13256. Epub 2023 Feb 9.
B cell expansion with NF-κB and T cell anergy (BENTA) is a disease genetically linked with heterozygous gain-of-function (GOF) mutations in the CARD11 gene with an autosomal dominant expression. Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of disorders characterized by systemic inflammation and hypercytokinaemia. Some BENTA patients share similar clinical manifestations as HLH in various aspects, including fever and splenomegaly. In this study, we reported a 15-month-old boy diagnosed as BENTA meeting with diagnostic criteria of HLH. The complications were resolved by antibiotics for controlling severe infection, together with the reduced format of dexamethasone and etoposide for subsiding HLH activities. While the patient was not subjected to disease recurrence and maintained free of infection, a persistent lymphocytosis derived mainly from the expansion of polyclonal B cells was ascertained. Flow cytometry analysis indicated that the subdued degranulation of NK cells prior to treatment had been restored as the HLH-related complications waned. With largely reduced number and ratios in CD4 and CD8 T cells, their proliferation and Vβ diversity remained in normal ranges. In vitro stimulation experiment revealed a functional abbreviation of T cells as the percentage of IFNγ-releasing CD3CD4 T cells augmented while the percentage reduced in CD3CD4 T cells. Whole exome sequencing revealed a de novo G123D missense mutation in the CARD11 gene. This new case of BENTA showcased a scenario of predominant HLH activities accompanied by a severe infection normally associated with BENTA. In addition, a brief treatment quenching HLH complication in cooperation with antibiotics for infection control was not able to solve the underlined T cell abnormality as well as B cell expansion caused by CARD11 mutation. A haematopoietic stem cell transplantation or gene therapy is still a pursuit to remedy this inborn error of immunity.
伴核因子κB的B细胞扩增与T细胞无能（BENTA）是一种与CARD11基因杂合功能获得性（GOF）突变存在遗传关联的疾病，呈常染色体显性表达。噬血细胞性淋巴组织细胞增生症（HLH）是一组异质性疾病，其特征为全身炎症和细胞因子血症。一些BENTA患者在包括发热和脾肿大等多个方面具有与HLH相似的临床表现。在本研究中，我们报告了一名15个月大的男孩，诊断为符合HLH诊断标准的BENTA。通过使用抗生素控制严重感染以及采用减量的地塞米松和依托泊苷来减轻HLH活动，并发症得到了解决。虽然患者未出现疾病复发且未再感染，但确定存在主要源于多克隆B细胞扩增的持续性淋巴细胞增多。流式细胞术分析表明，随着HLH相关并发症的消退，治疗前NK细胞脱颗粒减弱的情况已恢复。CD4和CD8 T细胞数量和比例大幅减少，但其增殖和Vβ多样性仍在正常范围内。体外刺激实验显示，随着释放IFNγ的CD3CD4 T细胞百分比增加而CD3CD4 T细胞百分比降低，T细胞功能出现异常。全外显子组测序揭示了CARD11基因存在一个新发的G123D错义突变。这例新的BENTA病例展现了以HLH活动为主并伴有通常与BENTA相关的严重感染的情况。此外，与用于控制感染的抗生素联合使用的短暂治疗虽能减轻HLH并发症，但无法解决由CARD11突变引起的潜在T细胞异常以及B细胞扩增问题。造血干细胞移植或基因治疗仍是纠正这种先天性免疫缺陷的努力方向。
