Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect
Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect
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DOI：
10.1182/blood.2019003664
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发表时间：
2020-07-30
期刊：
影响因子：
20.3
通讯作者：
Kaplanski, Gilles
中科院分区：
文献类型：
--
作者：
Carvelli, Julien;Piperoglou, Christelle;Kaplanski, Gilles
噬血细胞性淋巴组织细胞增生症（HLH）是一种危及生命的炎症性疾病。原发性HLH发生在生命早期，是单基因双等位基因突变影响淋巴细胞细胞毒性的结果。继发性HLH多发生于成人，继发于感染、淋巴瘤或风湿性疾病。在后一种情况下，淋巴细胞细胞毒性状态未知。我们对继发性HLH成人患者的自然杀伤（NK）细胞毒性进行了系统评价。对继发性HLH成人患者的总淋巴细胞计数和亚型、NK细胞表型、穿孔素表达和脱颗粒以及天然或抗体依赖性细胞毒性进行了前瞻性离体研究，并与受相同基础疾病影响但无HLH的患者（疾病对照[DC]）和健康对照（HC）进行了比较。系统地进行细胞毒性基因的变体的筛选。68例患者被纳入HLH组，DC和HC组各34例。在HLH患者中，观察到严重和短暂的淋巴细胞减少症，活化的NK细胞表型（例如，CD 69，ICAM-1，HLADR和CCR 5表达增加），以及干扰素7产生能力降低;平均穿孔素表达正常;脱粒试验和NK细胞毒性与DC中的无差异。在几乎50%的患者中观察到影响淋巴细胞细胞毒性基因或穿孔素变体A91 V的不确定意义的单等位基因变体。与DCs相比，我们在继发性HLH患者中未检测到主要的内在细胞毒性功能障碍，也未检测到预测的致病基因变异。与干扰素7产生减少相关的活化NK表型特征似乎与其他炎症性疾病如败血症或全身性幼年特发性关节炎相似。
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condi-tion. Primary HLH occurs early in life as a result of monogenic biallelic mutations affecting lymphocyte cytotoxicity. Secondary HLH occurs mostly in adults secondary to infection, lymphoma, or rheumatic disease. In this latter setting, lymphocyte cytotoxicity status is not known. We conducted a systematic evaluation of natural killer (NK) cell cytotoxicity in adult patients with secondary HLH. Adult patients with secondary HLH were prospectively studied ex vivo for total lymphocyte count and subtype, NK cell phenotype, perforin expression and degranulation, and natural or antibody-dependent cell cytotoxicity, in comparison with patients affected by the same underlying disease without HLH (disease controls [DCs]) and with healthy controls (HCs). Screening for variants of cytotoxity genes was systematically performed. 68 patients were included in the HLH group and 34 each in the DC and HC groups. In HLH patients, severe and transient lymphopenia, activated NK cell phenotype (eg, increased CD69, ICAM-1, HLADR, and CCR5 expression), and decreased capacity of interferon 7 production were observed; mean perforin expression was normal; and degranulation tests and NK cell cytotoxicity were not different from those in DCs. A monoallelic variant of uncertain significance affecting a lymphocyte cytotoxicity gene or the perforin variant A91V was observed in almost 50% of the patients. We detected no major intrinsic cytotoxicity dysfunction in secondary HLH patients compared with DCs and no predicted pathogenic gene variant. The activated NK phenotype profile associated with decreased interferon 7 production seems similar to those of other hyperinflammatory diseases such as sepsis or systemic juvenile idiopathic arthritis.