Ⅲ型家族性噬血细胞性淋巴组织细胞增生症易感基因UNC13D参与同源重组修复

本研究从DNA双链断裂同源重组修复角度探讨UNC13D（秀丽新小杆线虫）基因参与Ⅲ型家族性噬血细胞性淋巴组织细胞增生症（familial hemophagocytic lymphohistiocytosis type 3,FHL3）的发病机制。利用DNA同源重组修复方法,检测正常对照组及UNC13D基因下调后DR-U2OS细胞同源重组修复率的变化情况,并研究此基因的相关功能。结果表明：下调DR-U2OS细胞的UNC13D基因表达后,同源重组修复率较正常对照组明显下降,且差异有统计学意义（P〈0.05）,提示UNC13D编码蛋白Munc13-4不仅参与到细胞毒颗粒的胞吐过程中,而且在DNA双链断裂修复中也起作用。结论：UNC13D基因突变可能通过抑制细胞毒颗粒的胞吐和降低DNA双链断裂后的同源重组修复率参与FHL3发病过程,这一研究结果为揭示FHL3的发病机制提供新的理论基础。     

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1概述噬血细胞淋巴组织细胞增生症(hemophagocytic lymphohistiocytosis,HLH)是一组单核-巨噬细胞系统反应性增生而发生过度的炎症反应,造成多组织器官损害的综合征。目前,其病因及发病机制未完全阐明。促炎症反应的细胞因子不断生成,巨噬细胞和细胞毒性T淋巴细胞浸润多组织是其最显著特点[1]。1.1发病率及发病机制HLH可分为家族性HLH     

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目的探讨儿童EB病毒感染相关噬血细胞淋巴组织细胞增生症(Epstein-Barr virus associated hemophagocytic lymphohistiocytosis,EBV-HLH)的主要死因及相关危险因素。方法回顾性分析首都医科大学附属北京儿童医院2003年6月至2010年10月收治的103例EBV-HLH患儿临床资料,并对其转归进行随访。采用单因素及多因素分析方法进行统计学分析。结果本组失访13例。随访成功的90例患儿中,存活32例,死亡58例,病死率为64.4%。其中未进行化疗的36例患儿病死率高达87.8%,其中33例在诊断后2个月内死亡;接受化疗患儿(化疗组)的病死率为44.9%。化疗组8例诊断后早期死亡病例,其中7例发生重症感染;6例发生严重的凝血功能障碍;7例发生脏器功能衰竭。14例晚期死亡病例中,9例患儿在化疗后病情持续不缓解并最终死亡;4例在停药后出现复发而死亡。单因素分析显示死亡组较存活组患儿的纤维蛋白原水平更低,而乳酸脱氢酶更高(P1=0.033、P2=0.005,均<0.05);Logistics回归分析显示,发病-诊断时间大于4周、未进行化疗及低纤维蛋白原均为与EBV-HLH患儿死亡相关的危险因素,其死亡危险度分别为3.436、11.09和1.866。结论儿童EBV-HLH预后差、病死率高。重症感染、凝血功能障碍及脏器功能衰竭是早期死亡主要原因;持续疾病活动及复发为晚期死亡的主要原因。发病-诊断时间大于4周、未进行化疗及低纤维蛋白原水平为与EBV-HLH死亡相关的危险因素。     

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Los Angeles County

Data on Epstein–Barr virus‐related hemophagocytic lymphohistiocytosis (EBV‐HLH) in adults in the United States remain very limited. A cluster of four cases of EBV‐HLH was observed in a 4‐month period at a tertiary center in Los Angeles County (LA County) and the clinical and molecular characteristics identified in these cases are being described. EBV typing, immunophenotypic and molecular genetic studies were performed. Diagnostic criteria that may be used to identify EBV as a cause of HLH in adults are also being suggested. Finally, the crude incidence rate for HLH in LA County was determined and was compared to the worldwide crude incidence rate for HLH. The cases each occurred in young male adult residents of California and were associated with evidence of EBV reactivation and ferritin levels of >20,000 µg/L. A higher rate of cases of EBV‐HLH in 2010 was found at UCLA Medical Center than for 2007–2009 (4.9/10,000 hospital discharges vs. 0.14/10,000 hospital discharges, respectively; P = 0.0017). The cases were associated with EBV type 1, and the insertion of the codon CTC (leucine) was found in numerous of the EBNA‐2 gene sequences. The annual incidence of secondary, non‐familial HLH was estimated to be 0.9 cases per million persons >15 years of age in LA County. Although EBV‐HLH is a rare disease, the incidence in adults in Western countries may be underestimated. J. Med. Virol. 84:777–785, 2012. © 2012 Wiley Periodicals, Inc.     

成人起病嗜血细胞综合征中枢神经系统受累1例报告

嗜血细胞综合征亦称嗜血细胞性淋巴组织细胞增生症(HPG),1979年首先由Risdall等报道,分为原发性和继发性两类,前者为常染色体隐性遗传病,后者可由感染、免疫或肿瘤所致[1]。嗜血细胞综合征的诊断标准如下:发热超过1周,热峰≥38.5℃;肝脾肿大,全血细胞减少,累及≥2     

Rotavirus infection following post‐transplantation cyclophosphamide based haploidentical hematopoietic cell transplantation in children is associated with hemophagocytic syndrome and high mortality

We evaluated the incidences and consequences of rotavirus induced diarrhea in a cohort of 115 patients undergoing T‐cell replete haploidentical transplantation. Four out of 115 patients developed rotavirus‐induced diarrhea between 47 and 147 days. The incidence of rotavirus infection was 9.7% in children compared to none in adults (P = .01). This was 25.3% in those with GVHD compared to 1.2% in those without GVHD (P = .001). Rotavirus infection was followed by post–transplantation hemophagocytic syndrome (PTHPS) at a median of 4 days (range, 3‐10 days) in all four patients. Three patients succumbed to the complications related to PTHPS. Only one patient, who is long‐term survivor, was able to eliminate this virus after 2 weeks. Children undergoing T‐replete haploidentical hematopoietic cell transplantation who develop GVHD are at a higher risk of community‐acquired rotavirus infection which was strongly associated with PTHPS with poor outcome.     

Spontaneous resolution of Epstein–Barr virus‐associated hemophagocytic lymphohistiocytosis

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a reactive, proliferative disorder of the immune system resulting in lymphohistiocytic proliferation, hemophagocytosis, and cytokine dysregulation. The most common infectious trigger in sHLH is Epstein–Barr virus (EBV‐HLH). Current treatment protocols for EBV‐HLH have a cure rate of approximately 75%; however, there are significant toxicities associated with these therapies. We present two patients with EBV‐HLH who experienced spontaneous resolution of their disease prior to the initiation of therapy, suggesting there may be a subgroup of patients with EBV‐HLH who do well with conservative management and can avoid potentially toxic therapies. Pediatr Blood Cancer. 2010;55:754–756. © 2010 Wiley‐Liss, Inc.