重症联合免疫缺陷病临床病理分析

目的探讨重症联合免疫缺陷病(severe combined immunodeficiency,SCID)的临床病理特征。方法对6例SCID合并全身性巨细胞病毒(cytomegalovirus,CMV)感染患者的临床资料及尸检结果进行分析。结果6例SCID均为男性,平均年龄4个月。主要表现发热、咳嗽、腹泻、抽搐,实验室生化及免疫学检查均异常。淋巴细胞绝对值显著降低,平均(0·5±0·16)×109/L,免疫球蛋白IgG、IgM、IgA均明显降低。尸检发现共同特点是胸腺体积、重量极小,平均1·5g。镜下胸腺皮髓质分界不清,淋巴细胞稀少或缺如,无胸腺小体形成;脾、阑尾、回肠淋巴组织稀少,浆细胞少见;合并全身性CMV感染侵犯几乎所有内脏器官。患儿因重症肺炎、呼吸衰竭致死。结论SCID早期确诊困难,多因严重、反复感染死亡。合并的CMV感染具有脏器累及广泛、常合并其他病原菌混合感染和中枢神经系统的易感性等特点。     

获得性免疫缺陷综合征（AIDS）合并播散性弓形虫病尸检的病理学研究

报道美国纽约地区９例播散性弓形虫病尸检材料，均有脑部病变，８例累及心脏，４例累及肺脏，尚见胰腺、消化道、甲状腺、淋巴结、泌尿生殖器官等受累。其中弓形虫性脑炎９例，心肌炎４例，肺炎３例，胰腺炎２例。仅脑炎、肺炎产牛症状，经脑ＣＴ扫描、弓形虫抗体测定提示本病，并经涂片、骨髓活检和尸检证实，以查见弓形虫为依据。临床以神经精神症状和肺部感染症状为主。病变分为静止（潜伏）、组织坏死、炎症反应及增生修复四种状态，强调囊型弓形虫形态学识别的诊断意义。     

X连锁重症联合免疫缺陷病一家系遗传学分析

目的 X连锁重症联合免疫缺陷病是一种在临床上较为罕见的隐性遗传病,为了探究该病的遗传机制,以期降低家系中该患儿的出生风险,需要对患者家系相关成员进行全外显子测序以及遗传学分析。方法 经家属知情同意,采用全外显子组高通量测序检测技术对先证者进行基因检测,调查家族遗传图谱,进行遗传学分析。结果 家系图谱中由先证者曾祖母遗传下来的X连锁重症联合免疫缺陷病,患者均为男性,并且均在婴幼儿时期死亡,而大多数女性为携带者。该家系中一共有5人进行全外显子测序,检测到先证者IL2RG基因上发生c.854G>A半合子突变,先证者母亲和表姨发生杂合突变,父亲和表弟未突变,经家系分析和测序结果证实该位点变异遗传于母系。结论 X连锁重症联合免疫缺陷病在遗传上具有规律性,当临床上出现典型的症状以及指标时,应当进行基因检测及家系调查,尤其是女性携带者的检出,是预防本病的枢纽。     

中国Joseph病二例尸检观察

通过二例尸检首次确立了中国黄氏家系所发生Ｊｏｓｅｐｈ病的病理变化。二例的主要病变均位于大脑的苍白球和ｌｕｙｓ体，小脑的齿状核，脑干颅神经运动核，中脑黑质和红核。局部表现为神经细脱失，变性和胶质细胞增生。此外，脊髓前角和Ｃｌａｒｋｅ核神经元严重胶失，脊髓小脑前后束重度脱髓鞘，周围神经退变及脱髓鞘伴神经原性肌萎缩。说明中国Ｊｏｓｅｐｈ病的病理变化和欧美及日本报道相似。     

X-连锁严重联合免疫缺陷病一家系分析并文献复习

目的总结分析严重联合免疫缺陷病（SCID）的临床表现、诊断方法和治疗。方法对1例生后2个月内起病,严重感染,使用抗生素治疗效果不佳,生后5个月病死,常规实验室检查外周血淋巴细胞绝对计数减少,WBC总数2.8×10^9·L^-1,L1.9×10^9·L^-1的患儿,使用流式细胞仪检测患儿及其双亲的外周血淋巴细胞表达,并抽提出DNA,对IL-2受体γ链（IL2RG）进行基因分析。外周血淋巴细胞转化试验检测患儿舅舅淋巴细胞增殖能力。回顾分析患儿家族史,通过问诊进行初步家系调查。结果流式细胞仪检测患儿外周血CD3^＋T细胞为0;NK细胞（CD16^＋CD56^＋）为4%。患儿X染色体q13.1的IL2RG基因的第6个外显子存在突变,突变位为849位碱基G缺失导致阅读框架移位,氨基酸序列位于278半胱氨酸处,并在293位产生“TGA”的终止密码子。患儿母亲被证实为携带者,但不是单纯的杂合子,可能存在嵌合突变。患儿被诊断为X-连锁严重联合免疫缺陷病（X-SCID）。患儿的舅舅生后因严重感染治疗无效而病死,其淋巴细胞转化试验植物血凝素（PHA）刺激72h,外周血单个核细胞无增殖反应（CPM值为0）。病程中使用未经特殊处理的血制品后出现高热、皮疹和肝、脾肿大后病死。回顾分析家族史,患儿母系中近3代出生男性4例均因严重感染而在婴幼儿期夭折,考虑可能也是X-SCID,女性均健康。患儿妹妹经基因分析证实亦为携带者,为IL2RG基因的第6个外显子849位碱基嵌合型。患儿的舅舅使用未经特殊处理的血制品出现的临床表现为移植物抗宿主病可能。结论经基因分析确诊了1例X-SCID,通过初步家系调查,基因分析证实患儿母亲及妹妹均为嵌合型携带者。临床上对出生后6个月内严重感染,治疗效果不佳者应警惕SCID的可能,并应进行免疫功能评价。如果疑为SCID患儿则不能接种活疫苗和使用未经特殊处理的血制品。早期?     

尼美舒利引起严重肝损伤致死尸检1例

临床上,尼美舒利主要用于解热镇痛、抗炎,治疗风湿痛、头痛、外伤痛,癌症疼痛等,而且因消化道副作用较小而被临床广泛接受,尤其是在小儿解热镇痛剂的应用上比较广泛[1].由于其独特的药理作用机制该药曾被认为是一个安全性好(胃肠道反应少),有良好发展前景的非甾体抗炎药.但近年来,其严重肝毒性反应,国外多有报道.国内的研究报道较多的是有关尼美舒利对于食管癌、结肠癌和肝癌等多种肿瘤细胞的抗增殖和诱导凋亡的作用[2],但有关尼美舒利引起肝脏损害的报道则非常罕见.近年来,国外已陆续报道了多起与应用尼美舒利有关的重度肝脏损害的病例报告,严重者甚至可以引起死亡[3].现将2007年11月我们在尸检工作中遇到的1例冈服用尼美舒利引起严重肝损害而死亡的病例报道如下,希望能引起临床医生的足够重视.     

肺动脉栓塞12例尸检分析

目的 分析肺动脉栓塞的尸体解剖与临床病理特征,提高临床对肺动脉栓塞的认识水平,减少其漏诊、误诊率.方法 回顾分析信阳市1999年1月～2008年6月的12例肺动脉栓塞病例的尸体解剖及临床资料.结果 12例均存在血栓性疾病的相关危险因素.结论 规范、全面、细致的尸体解剖是暴露肺动脉栓塞的关键,临床上提高对肺动脉栓塞的认识,减少漏诊、误诊率,降低其临床死亡率是今后不可忽视的课题.     

90例接尘工人尸检资料分析

对９０例接尘工人尸检资料分析的结果表明：接尘工人的死亡年龄越大，尘肺确诊的阳性率越高，尘肺病理改变越重，６５岁以上年龄组１００％被确诊为尘肺。接尘工龄越长，病理诊断阳性率越高，１０年以上工龄者，阳性率平均达６７．９２％，３０年以上者，本组９３．３％诊断为尘肺。全部病例中，生前诊断尘肺者仅１３．３％，而６３．３％是经尸检由病理诊断的。提示尸检在尘肺诊断中的重要性。     

Antiviral T Cells for Adenovirus in the Pretransplant Period: A Bridge Therapy for Severe Combined Immunodeficiency

Viral infections can be life threatening in patients with severe combined immunodeficiency (SCID) and other forms of profound primary immunodeficiency disorders both before and after hematopoietic stem cell transplantation (HSCT). Adoptive immunotherapy with virus-specific T cells (VSTs) has been utilized in many patients in the setting of HSCT, but has very rarely been attempted for treatment of viral infections before HSCT. Here we describe the use of VSTs in an infant with RAG1 SCID who had developed disseminated adenovirus which failed to improve on cidofovir. Adenovirus cleared following 2 doses of VSTs and marrow infusion from a matched unrelated donor, without incidence of graft versus host disease. T cell receptor-b sequencing demonstrated expansion of adenovirus-specific T cell fraction of the VSTs, suggesting that infusion facilitated viral clearance. This report suggests that VSTs are likely safe in the pre-HSCT period, and may be a useful bridge therapy for infants with SCID and persistent viral infections.     

Selective defect of a T helper subpopulation in severe combined immunodeficiency

The case of an infant female aged 1 month with severe infections, failure to thrive, and skin erythroderma is reported. Immunological studies demonstrated a severe combined immunodeficiency (SCID) with B cells and normal serum IgM levels. Studies of T-cell subpopulations showed a defect of a subset of T helper cells. Possible pathogenetic mechanisms are discussed.     

A novel pathogenic mutation on Interleukin-7 receptor leading to severe combined immunodeficiency identified with newborn screening and whole exome sequencing

BackgroundPatients with severe combined immunodeficiency (SCID), which is caused by genetic defects in immune-related genes involved in the development or activation of the adaptive immune system, often died in infancy due to severe infections before definite molecular diagnosis could be made. Although recent improvement in early diagnosis has been achieved by newborn screening, the genetic basis of many of the patients is still unknown.MethodsHere we performed whole exome sequencing (WES) to investigate the underlying genetic causes of SCID in a proband identified with newborn screening. Inheritance of the mutation was confirmed with targeted sequencing of the parents. Homozygosity mapping from the WES was used to investigate the consanguinity of the parents. Immunoblotting was used to confirm the loss of expression of the mutant protein.ResultsA novel homozygous frameshift mutation of IL7R was identified through WES. Both parents are carriers for this 1-bp deletion. HLA typing and exome-wide homozygous stretch mapping suggested that the parents are consanguineous. Immunoblotting showed no expression of IL7Rα isoform in the whole blood sample of the proband. The proband received peripheral blood stem cell transplantation and her general condition became stable. Our results suggest that IL7R is essential for T cell development but dispensable for the development of certain human NK cells B cells and suggest that WES can be a useful tool for precise genetic diagnosis of SCID following newborn screening in the index patient without the need to screen other members of the whole family.     

Long-term follow-up in patients with severe combined immunodeficiency treated by bone marrow transplantation

Immune reconstitution was studied in 31 long-term surviving patients after bone marrow transplantation for severe combined immunodeficiency. Donors in 7 cases were HLA-identical and in 25 cases HLA-haploidentical family members, and in 13 of these latter cases cytoreductive conditioning had been used prior to transplantation. At a mean follow-up of 15 years after transplantation (range 10 to 22 years), T cell numbers and functions had remained stable and within normal limits in the majority of patients. Marked variability however was observed with regard to reconstitution of B cell immunity. Furthermore numbers of circulating naïve CD4+ T cells were variable and markedly diminished in a substantial proportion of patients at recent evaluations. Normal B cell immunity and persistently normal naïve T cell numbers were strongly correlated with the continued detection of donor type CD34+ precursor cells in the patients marrow, which were absent in non conditioned patients. These findings indicate that stable donor precursor cell engraftment in the marrow may be of relevance for complete and stable long-term immune reconstitution in transplanted SCID patients.     

The Wisconsin approach to newborn screening for severe combined immunodeficiency

Severe combined immunodeficiency (SCID) is a life-threatening disease of infants that is curable with hematopoietic cell transplantation if detected early. Population-based screening for SCID using the T-cell receptor excision circle (TREC) assay began in Wisconsin in 2008; 5 infants with SCID or other forms?of severe T-cell lymphopenia (TCL) have been detected, and no infants with SCID have been missed. This review will provide an overview of the TREC screening assay and an update of the findings from Wisconsin on all infants screened from January 1, 2008, until December 31, 2010. Importantly, we give practical recommendations regarding newborn population-based screening using the TREC assay, including the evaluation and care of infants detected.     

Appearance of multiple benign paraproteins during early engraftment of soy lectin T cell-depleted haploidentical bone marrow cells in severe combined immunodeficiency

Recent advances in the prevention of graft-versus-host disease through postthymic T-cell depletion have allowed the use of haploidentical bone marrow cells for immunologic reconstitution of severe combined immunodeficiency disease. We report a male infant with severe combined immunodeficiency (with normal adenosine deaminase) who developed two IgG kappa and one IgA lambda paraproteins 7 weeks following the administration of 1.4×10⁹ maternal bone marrow cells depleted of postthymic T cells by soy lectin agglutination and sheep erythrocyte rosetting. Serum IgG rose from 128 to 820 mg/dl, and IgA from 0 to 2400 mg/dl, peaking at 10 weeks postgrafting. By 14 weeks posttransplantation T-cell numbers and function had risen to normal (all dividing T cells had the donor karyotype) and paraprotein concentrations began to decline. These observations strongly suggest that the later-appearing T cells regulated the B-cell clones from which the paraproteins were derived. Failure of such function to appear could account for the increased incidence of B-cell lymphomas in severe combined immunodeficiency.     

Expansion of clonotype-restricted HLA-identical maternal CD4+ T cells in a patient with severe combined immunodeficiency and a homozygous mutation in the Artemis gene

We have observed a male infant with severe combined immunodeficiency (SCID) responsible for Artemis gene mutation, in whom marked expansion of the transplacentally grafted maternal CD4(+) T cells was observed in various tissues. His class I and II major histocompatibility antigens (MHC) were identical to his mother's. We analyzed the T-cell populations within target tissues at a molecular level in order to determine whether different T-cell clonotypes are expanded in different types of tissue. Prior to T-cell expansion, the T-cell receptor variable beta (TCRBV) 5.1 subfamily predominated in peripheral blood (PB) lymphocytes. Third complementarity determining region (CDR3) size spectratyping and amino acid sequencing showed that the range of T-cell clonotypes was very restricted. After T-cell expansion, different TCRBV subfamilies were found to predominate in different target tissues; these included TCRBV 5.1 and 17 in the PB, TCRBV 13 and 21.3 in the bone marrow, and TCRBV 17 in lymph nodes. CDR3 size analysis showed that the expression of different proliferating T-cell clonotypes remained restricted after T-cell expansion. These results indicate that highly restricted maternal T-cell clonotypes can markedly expand, possibly in response to tissue-specific antigens, in a MHC-identical recipient.