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摘要: 噬血细胞性淋巴组织细胞增生症(hemophagocytic lymphohistiocytosis，HLH)即噬血细胞综合征，是一种罕见的危及生命的免疫失调综合征，以细胞毒性T细胞、自然杀伤细胞和巨噬细胞过度活化为特征，引起细胞因子风暴，导致一系列的临床症状、器官损伤甚至死亡。HLH可分为原发性和继发性，前者存在致病基因(淋巴细胞毒性缺陷、炎症小体异常活化等)，后者可由多种因素触发(感染、肿瘤、自身免疫疾病、医源性因素等)。早期敏锐的识别和及时治疗对提高生存率至关重要，目前的诊断使用最广泛的是HLH-2004标准和Hscore积分。本文系统讨论和更新了HLH的病因、实验室相关检查以及诊断方法。
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关键词:
- 噬血细胞性淋巴组织细胞增生症 /
- 噬血细胞综合征 /
- 巨噬细胞活化综合征 /
- 免疫失调
Abstract: Hemophagocytic lymphohistiocytosis(HLH) is a rare and life-threatening hyperinflammatory syndrome characterized by the overactivation of cytotoxic T cells, natural killer cells, and macrophages arising in cytokine storms, a range of clinical symptoms, organ damage, and even death. HLH can be divided into primary and secondary, with the former having susceptibility genes(lymphocyte cytotoxicity defects, abnormalities of inflammasome activation, etc.) and the latter being triggered by a variety of factors(infections, malignancy, iatrogenic factors, etc.). Prompt diagnosis and treatment are essential to improve survival. The HLH-2004 criteria and the Hscore are two widely used diagnostic tools in clinical practice. In this review, we discussed the etiology, laboratory tests, and diagnosis of HLH. -
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表 1 HLH的相关致病基因
疾病/类型 基因 遗传方式 蛋白 功能 淋巴细胞毒性缺陷 FHLH-1 9q21.3-q22 AR — — FHLH-2 PRF1 AR 穿孔素 靶细胞的孔道形成 FHLH-3 UNC13D AR Munc13-4 囊泡启动 FHLH-4 STX11 AR Syntaxin-11 囊泡融合 FHLH-5 STXBP2 AR Munc18-2 囊泡融合 Chediak-Higashi综合征 LYST AR LYST 囊泡转运 Hermansky-Pudlak综合征 AP3B1 AR AP-3复合物β3A亚单位 囊泡转运 Griscelli综合征2型 RAB27A AR Rab27A 囊泡对接 炎症小体异常活化 自身炎症性疾病 NLRC4 AD NLRC4 炎症小体激活 XLP2 BIRC4 XLR XIAP 信号通路 EBV感染失调 XLP1 SH2D1A XLR SAP 信号转导 IL-2诱导的T细胞激酶缺陷 ITK AR ITK T细胞的信号转导 CD27缺乏 CD27 AR CD27 淋巴细胞共刺激分子 XMEN MAGT1 — 镁转运体1 通过T细胞受体激活T细胞 PIDD相关基因 Wiskott-Aldrich综合征 WAS XLR WASP 肌动蛋白聚合的激活剂 Omenn综合征 RAG1/2 AR RAG1/2 V(D)J重组 LRBA缺乏 LRBA AR LRBA 调控CTLA4囊泡运输 DOCK8缺乏 DOCK8 AR DOCK8 影响B细胞、NK细胞和各种T细胞亚群 CARMIL2/RLTPR缺乏 CARMIL2 — CARMIL2 影响Treg细胞、Th17细胞、CD4+T细胞和NK细胞 TTC7A缺乏 TTC7A — TTC7A RhoA信号通路 STAT1/2/3缺陷 STAT1/2/3 — STAT1/2/3 信号转导 p110δ缺陷 PIK3CD — 磷脂酰肌醇3激酶p110δ亚单位 信号转导 MCM3AP缺陷 MCM3AP — GANP DNA修复 ALPS-CASP10 CASP10 — Caspase 10 细胞凋亡 DIAP相关基因 NALP12缺陷 NLRP12 — NALP12 炎症信号通路 NLRP4缺陷 NLRP4 — NLRP4 调控Ⅰ型干扰素信号通路 NLRC3缺陷 NLRC3 — NLRC3 抑制toll样受体依赖的转录因子NF-κB的激活 RALD NRAS NRAS RAS信号通路 代谢性疾病相关基因 MSD SUMF1 AR FGE 硫酸酯酶的转录激活 氰钴胺素C疾病 MMACHC AR MMACHC 维生素B12的代谢 赖氨酸尿蛋白不耐受症 SLC7A7 AR y+LAT-1 氨基酸转运 高免疫球蛋白D综合征 MVK AR 甲羟戊酸激酶 胆固醇和脂质合成 血红素加氧酶1缺乏 HMOX1 AR HMOX1 血红素氧化为胆绿素 其他候选基因 ARHGEF6、ERCC4、G3BP1、IL16、RASGRP3、STAT4、TREM2 XLP2：X连锁淋巴细胞增生综合征2型；XLP1：X连锁淋巴细胞增生综合征1型；XMEN：X连锁免疫缺陷伴镁缺陷；PIDD：原发性免疫缺陷症；ALPS：自身免疫性淋巴增生综合征；DIAP：免疫激活或增殖失调；RALD：Ras相关自身免疫性白细胞增殖性疾病；MSD：多种硫酸酯酶缺乏症；AR：常染色体隐性遗传；AD：常染色体显性遗传；XLR：X连锁隐性遗传。 
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表 2 继发性HLH的相关因素
感染 病毒 EBV、CMV、HIV、HHV-8、单纯疱疹病毒1型和2型、新型布尼亚病毒、BK病毒、登革热病毒、水痘带状疱疹病毒、风疹病毒、流感病毒、汉坦病毒、甲型肝炎病毒、乙型肝炎病毒、腺病毒、麻疹病毒、细小病毒B19、SARS、COVID-19 细菌 巴尔通体、布鲁氏菌、屎肠球菌、肺炎克雷伯菌、鲍曼不动杆菌、流感嗜血杆菌、G组链球菌、梅毒、贝纳特氏立克次体、埃立克体、钩端螺旋体、鸟分枝杆菌、结核杆菌、支原体、软弱贫养菌 原虫 巴贝西虫、疟原虫、弓形虫、利什曼原虫 真菌 组织胞浆菌、马尔尼菲青霉菌、白色念珠菌、曲霉菌、灰色小克银汉霉 肿瘤 血液系统 T/B细胞淋巴瘤、T/B细胞白血病、NK细胞淋巴瘤/白血病、霍奇金淋巴瘤、髓样肿瘤、急/慢性单核细胞白血病 其他 神经母细胞瘤、横纹肌肉瘤、肾癌、前列腺癌、结肠直肠癌、肺癌、肝细胞癌、鳞状细胞癌 自身免疫性疾病 AOSD、自身免疫性肝炎、类风湿性关节炎、SLE、sJIA、川崎病、血管炎、抗磷脂综合征、干燥综合征、皮肌炎、混合性结缔组织病、肺出血肾炎综合征、坏死性淋巴结炎、炎症性肠病 医源性因素 CAR-T细胞治疗、细胞毒性T细胞治疗、利妥昔单抗、基因治疗、ICIs、异基因造血干细胞移植、器官移植、化疗(氟达拉滨和环磷酰胺)、派姆单抗、纳武利尤单抗、伊匹木单抗、拉莫三嗪、苯巴比妥、苯海拉明、疫苗接种 其他 妊娠 CMV：巨细胞病毒；HHV-8：人疱疹病毒8；HIV：人免疫缺陷病毒；SARS：严重急性呼吸综合征；COVID-19：冠状病毒2019；AOSD：成人Still病；SLE：系统性红斑狼疮；sJIA：全身型幼年特发性关节炎；ICIs：免疫检查点抑制剂。
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表 3 HLH的相关检查项目
建立临床诊断 病因筛查 常规实验室检验与检查 原发性HLH ·血常规 基于流式细胞术的快速筛查* ·凝血功能 ·穿孔素 ·甘油三酯 ·CD107a ·铁蛋白 ·SAP ·肝功能(转氨酶/胆红素/LDH) ·XIAP ·sCD25 基因检测(相关基因见表 1) ·NK细胞活性 ·全基因组测序 ·肝脾超声或CT ·全外显子测序 ·基于panel的基因检测 病史和体格检查 继发性HLH ·体温 感染 ·脏器肿大(肝、脾) ·病毒：PCR或血清学检查 ·病史(HLH家族史、复发性HLH、反复EBV感染、间断发热等) ·细菌：血培养，其他标本培养(如结核杆菌：痰培养) ·其他临床表现(如咽痛、皮疹、关节痛、部分白化病、神经退行性变合并严重免疫缺陷等) ·真菌：常见于免疫抑制状态的患者 ·原虫：血涂片(疟原虫、巴贝西虫)，PCR(利什曼原虫) ·微生物宏基因组高通量测序 自身免疫性疾病 ·相关免疫学检查，如ANCA、抗核抗体、抗组蛋白抗体、类风湿因子等 ·肿瘤筛查、用药史等 其他 应用HLH-2004或Hscore积分；阳性病史有助于原发性HLH的诊断；原发性HLH的典型临床表现可辅助诊断 *有助于F-HLH2、F-HLH3、XLP1、XLP2的快速筛查 影像学检查 骨髓穿刺、组织活检 ·CT ·噬血细胞现象的形态学评价 ·PET ·X线 ·淋巴结超声 PET有助于淋巴瘤等肿瘤的排查 排查血液系统恶性肿瘤；以及微生物培养 LDH：乳酸脱氢酶；SAP：信号传导淋巴细胞活化分子相关蛋白；ANCA：抗中性粒细胞胞质抗体。
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