1、IMMUNODEFICIENCYXiaodong Zhao,MD,Ph.DProfessor of PediatricsChildrens Hospital of Chongqing Medical University亚太免疫缺陷学会（亚太免疫缺陷学会（APSID）全球最后一个成立的免疫缺陷学会全球最后一个成立的免疫缺陷学会 当选为当选为8 8人理事会中国大陆理事人理事会中国大陆理事 临床工作委员会主席临床工作委员会主席 Review of basic ImmunologyReview of basic ImmunologyPhysiological features of immune f
2、unction in Physiological features of immune function in childhoodchildhoodDefinition of immunodeficiency diseaseDefinition of immunodeficiency diseaseClassification of Classification of PIDsPIDsCommon clinical presentationsCommon clinical presentationsScreening laboratory testsScreening laboratory t
3、estsPrinciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immunodeficiency OUTLINE Recognize self Reject non-selfImmune functionImmune function -Anti-infectionAnti-infection Clear infectious agents -Immune homeostasisImmune homeostasis Clear aged,damaged and dea
4、d cells,maintaining stability -Immune surveillanceImmune surveillance Identify and remove mutated cells and prevent tumor Classical Immunology Modern ImmunologyThree Integral parts of immunologyImmune functionsImmune functionsBy effecter functionBy effecter function Cellular immunity:hosted by cells
5、 Humoral immunity:carry out by fluid-borne moleculesBy antigen specificityBy antigen specificity Innate immunity:Non-antigen-specific,such as skin and mucosal barriers,interferons,NK cells,phagocytes,etc.Adaptive immunity:Antigen-specific,mediated only by lymphocytesSLSCProBCFUMPMNPletRBCPreBPTTBCD8
6、+PlasmaCD4+TH1TH2IgMBPlasmaIgAIgAIgMBPlasmaIgGIgGBPlasmaIgEIgETHYRUM Epi.Cytokines（IL-118，INF，IFN，IGF-1）Membrane markers（CD28-B7，CD40-CD40L，MHCI,，cytokine receptors）Adhesion molecules（ICAM-1，LFA-1，SELECTIN,and so on）ComplementsBMCD3+CD19/20Pluripotent stem cells 1st phase:Antigen presenting2nd phase
7、:proliferation of lymphocytes3rd phase:Effecter function4th phase:Apoptosis of activated lymphocytesImmune responseImmune responseAgMTH1CTLNKADCCBPMNIL-4，5，6，7，8，9，10，11，13，14，16，17AbImmune complexActivate complementEndothelialsOsteoblasts Osteoclasts Fibroblasts Mast cells Eosinophils TH2Ag CKs&med
8、iators InflammationTH0 IL-12,IL-18IL-1IL-10IL-4IL-2IFNIL-1，IL-6，TNFTr1TH3IL-10 Review of basic ImmunologyReview of basic ImmunologyPhysiological features of immune function in Physiological features of immune function in childhoodchildhoodDefinition of immunodeficiency diseaseDefinition of immunodef
9、iciency diseaseClassification of PIDClassification of PIDCommon clinical presentationsCommon clinical presentationsScreening laboratory testsScreening laboratory testsPrinciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immunodeficiency OUTLINE Phagocytosis -ma
10、crophages,dentritic cells(APC)-neutraphil T lymphocyte:-CD40L,CD28 expression -TH1/TH2 B lymphocyte:-maternal IgG cross placenta -IgG2 late development(after 2yo)complements 14 12 10 8 6 4 2g/L 1.8 0.61 2 3 4 5 6 7 8 9 10 11 12mosMaternal IgG Total IgG Baby IgG Development of IgG g/L14 12 10 8 6 4 2
11、 1.8-0.6 4 8 12ms 2 4 8 10 12 yrsIgGIgMIgAImmunoglobulin development in infants and childrensummary Nearly all branches of immune function are maturely developed at birth Transient dysfunction or immunocomprimise condition is mainly due to insufficient exposure to antigens and memory Review of basic
12、 ImmunologyReview of basic ImmunologyPhysiological features of immune function in Physiological features of immune function in childhoodchildhoodDefinition of immunodeficiency diseaseDefinition of immunodeficiency diseaseClassification of PIDClassification of PIDCommon clinical presentationsCommon c
13、linical presentationsScreening laboratory testsScreening laboratory testsPrinciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immunodeficiency OUTLINEA diverse group of illnesses that,as a result of one or more abnormalities of the immune system,increased susce
14、ptibility to infection.Definition of immunodeficiencyDefinition of immunodeficiency -Gene mutation associated:primary immunodeficiency,PID)-Environment-associated:Secondary immunodeficiency，SID or immunocompromise -HIV infection:Acquired immunodeficiency syndrome，AIDSThree types of immunodeficiency
15、Review of basic ImmunologyReview of basic ImmunologyPhysiological features of immune function in Physiological features of immune function in childhoodchildhoodDefinition of immunodeficiency diseaseDefinition of immunodeficiency diseaseClassification of PIDClassification of PIDCommon clinical presen
16、tationsCommon clinical presentationsScreening laboratory testsScreening laboratory testsPrinciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immunodeficiency OUTLINE Nomenclature -by name or place -by underlying genetic defects or immunological mechanisms Bruto
17、n disease(Bruton,1952)X linked agammaglobulinemia，XLA Swiss type agammaglobulinemia (Hitziget al,1958)Severe combined ID Milestones of PIDSyllaba&Henner：1926,ataxia-telangiectasiaThorpe&Handley：1929,chronic mucocutaneous candidiasisWiskott：1937,Wiskott-Aldrich syndromeGlanzmann&Riniker：1950,cellular
18、 immunodeficiencyBruton：1952,agamaglubulinemia,establishment of Pediatric Immunology Hitzig：1958,Swiss type of agamaglubulinemia,combined immunodeficiency 2011年PID分类：200种PID，由160余种基因突变所致；主要表现 为感染、自身免疫和易患肿瘤 患病率：重症1/2000活产婴，我国存活患儿5-10万，不足5%确诊 诊治困难、预后极差：确诊常需基因诊断，根治常需要免疫重 建；如不正规治疗，多数于幼年夭折或生活质量极其低下 多数患儿至
19、死未能确诊，导致家族中患儿再次出生 （139个家族史阳性PID家系仅2.2%确定了先证者）我国目前尚无防治规范：病人的要求、社会的需要 原发性免疫缺陷原发性免疫缺陷病病(Prymary Immunodeficiency Diseases,PIDs)Luigi D,et al.JACI 2009Boyle J M,et al.J Clin Endocrinol Metab.2002Newest classification of PIDJackson Hole,Wyo:8 categories（J Allergy Clin Immunol 2007）Combined T-cell and B-c
20、ell deficiencies Predominantly antibody deficiencies Other well defined immunodeficiency syndromes Diseases of immune dysregulaton Congenital defects of phagocyte number,function,or both Defects in innate immunity Autoinflammatory disorders Complement deficiencies Different features of infections in
21、 PIDDifferent features of infections in PIDJCAI 2009X-linked X-linked agammaglobulinemiaagammaglobulinemia(XLA)(XLA)Brutons disease Due to btk gene mutation,causing blockade of Pre-B to mature B cell Predominantly antibody deficiency Male Recurrent bacterial infections of respiratory tract or other
22、tissue Increased susceptibility to enteroviruses Profound decrease of all Igs Absence or 2%of B cells in the blood XLA case，19 years old Brain,throat wall,prevertebral abscess SLSCProBCFUMPMNPletRBCPreBPTTBCD8+PlasmaCD4+TH1TH2IgMBPlasmaIgAIgAIgMBPlasmaIgGIgGBPlasmaIgEIgETHYRUM Epi.Cytokines（IL-118，I
23、NF，IFN，IGF-1）Membrane markers（CD28-B7，CD40-CD40L，MHCI,，cytokine receptors）Adhesion molecules（ICAM-1，LFA-1，SELECTIN,and so on）ComplementsBMCD3+Hyper IgM symdrome Combined immunodeficiency X-linked or autosomal recessive Recurrent bacterial,fungal,protozoan infections Autoimmune:autoimmune hemolytic a
24、nemia,hepatosplenomegaly,neutrapenia Normal number of peripheral B cells Decreased IgG,IgA;normal or increased IgM Need stem cell transplantation(SCT)to reconstitute the immune functionIgAIgMIgGIgET CD40L TCR CD28 Ag I L-6 I L-5 I L-4B CD40 MHCB7ReceptorsSevere combined immunodeficiency(SCID)Combine
25、d immunodeficiency X-linked or autosomal recessive Onset in early months of life Life-threatening infection of almost all kinds of pathogens,disseminated infection of vaccine such as BCG Chronic diarrhea,failure to thrive Need SCT as early as possiblec IL-2R c IL-2,IL-4,IL-7,IL-9,IL-15 Jak-3T cellX-
26、linked severe combined immunodeficiencyX-linked severe combined immunodeficiency（IL-2 receptor common chain defect）Wiskott Aldrich syndrome Well defined immunodeficiency syndrome X-linked Triad:thrombocytopenia,eczema,increased susceptibility to infection Mild cases may present solely thrombocytopen
27、ia,so-called X-linked thrombocytopenia Typical cases need SCT to save lifeWASWAS例例5 5，男，男，1010月，家族史阳性，月，家族史阳性，20042004年年4 4月月5 5日入院日入院Long term outcome of WAS patientsLong term outcome of WAS patients051015202520002001200220032004200520062007200820092010移植死亡死亡移植存活存活原发性免疫缺陷病的相对发病率T细胞细胞/B细胞联合缺陷细胞联合缺陷
28、补体缺陷补体缺陷吞噬细胞缺陷吞噬细胞缺陷 T细胞缺陷细胞缺陷 2%50%20%10%18%抗体缺陷抗体缺陷PIDDGeneGenetictypeNo.Non-senseMis-senseInsertionDeletionSplicesitePromoterabnormalNovelmutationCarrierT-B+XSCIDcXR72417T-B+SCIDIL-7RAR11112T-B-SCIDRAG2AR11122Omenn RAG1AR21115XHIMCD40LXR63333XLABTKXR3171225411135ARA u chainAR11IL-12R1deficiencyIL
29、-12R1AR2212WASWASXR4111868101748CGDCYBBXR10222248NCF1AR112LAD-ITGB2AR211132HIESSTAT3AD441ALPSFASLAD111IPEXFOXP3XR2222Total1223034111722146145Summary of genetically defined PID patients over the past 10 years Review of basic ImmunologyReview of basic ImmunologyPhysiological features of immune functio
30、n in Physiological features of immune function in childhoodchildhoodDefinition of immunodeficiency diseaseDefinition of immunodeficiency diseaseClassification of PIDClassification of PIDCommon clinical presentationsCommon clinical presentationsScreening laboratory testsScreening laboratory testsPrin
31、ciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immunodeficiency OUTLINE -反复感染反复感染 -反复性呼吸道感染反复性呼吸道感染 -严重细菌性感染严重细菌性感染(肺炎肺炎,败血症败血症,脑膜炎脑膜炎,骨髓炎和其它骨髓炎和其它 -感染难以控制感染难以控制 -严重病毒性感染严重病毒性感染 -机会感染机会感染(卡氏肺囊虫卡氏肺囊虫,隐孢子菌，支原体）隐孢子菌，支原体）-自身免疫性疾病自身免疫性疾病:关节痛关节痛,关节炎关节炎,狼疮等狼疮等 -淋巴系统
32、肿瘤淋巴系统肿瘤 -其它其它:家族史家族史,生长发育迟缓生长发育迟缓,肝脾淋巴结肿大或扁桃体肝脾淋巴结肿大或扁桃体/淋巴结淋巴结 缺如缺如 Review of basic ImmunologyReview of basic ImmunologyPhysiological features of immune function in Physiological features of immune function in childhoodchildhoodDefinition of immunodeficiency diseaseDefinition of immunodeficiency d
33、iseaseClassification of PIDClassification of PIDCommon clinical presentationsCommon clinical presentationsScreening laboratory testsScreening laboratory testsPrinciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immunodeficiency OUTLINE实验室过筛检查实验室过筛检查(1)B细胞缺陷细胞缺陷
34、 -血清血清IgG,IgM,IgA水平水平 -ASO，血型抗体，血型抗体 -疫苗抗体反应疫苗抗体反应 -IgG 亚类亚类 -外周血外周血B 细胞计数细胞计数(CD19 or CD20)-X-线了解增殖体影线了解增殖体影 T细胞缺陷细胞缺陷 -外周血白细胞计数和形态学观察外周血白细胞计数和形态学观察 -迟发皮肤过敏反应迟发皮肤过敏反应(毛霉菌毛霉菌,腮腺炎病毒腮腺炎病毒,念珠菌念珠菌,破伤风类毒素破伤风类毒素)-外周血外周血T细胞亚群细胞亚群(CD3,CD4,CD8)-抗原或丝裂原增殖反应抗原或丝裂原增殖反应实验室过筛检查实验室过筛检查(2)吞噬细胞缺陷吞噬细胞缺陷 -外周血白细胞计数和形态学观
35、察外周血白细胞计数和形态学观察 -NBT 染料试验染料试验 -血清血清IgE水平水平 -趋化功能趋化功能 -吞噬和杀菌功能吞噬和杀菌功能 补体缺陷补体缺陷 -CH50 活性活性 -C3、C4 水平和其它补体成分测定水平和其它补体成分测定 无刺激无刺激 患儿患儿 正常正常 对照对照 四唑氮蓝试验（四唑氮蓝试验（NBTNBT）PMAPMA刺激刺激慢性肉芽肿病(CYBB)备解素缺陷（PFC）湿疹血小板减少综合征(WASP)严重联合免疫缺陷病（IL-2RG）X-连锁无丙种球蛋白血症（btk）X-连锁 淋巴增生性疾病.(XLP）X-连锁高IgM血症（CD40L）22.322.221.1 2111.411
36、.311.211.2 12 13 21 22 23 24 25 26 27 28pq基因诊断基因诊断DOCK8DOCK8缺陷：新型基因诊断方法缺陷：新型基因诊断方法流式细胞术快速诊断流式细胞术快速诊断DOCK8DOCK8缺陷缺陷 Review of basic ImmunologyReview of basic ImmunologyPhysiological features of immune function in Physiological features of immune function in childhoodchildhoodDefinition of immunodefic
37、iency diseaseDefinition of immunodeficiency diseaseClassification of PIDClassification of PIDCommon clinical presentationsCommon clinical presentationsScreening laboratory testsScreening laboratory testsPrinciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immun
38、odeficiency OUTLINE 一般处理一般处理 预防和治疗感染预防和治疗感染 心理学支持心理学支持 鼓励正常的学习和生活鼓励正常的学习和生活 可接种灭活疫苗可接种灭活疫苗 防止移植物抗宿主反应防止移植物抗宿主反应 脾切除为禁忌症脾切除为禁忌症 替代治疗替代治疗 静脉丙种球蛋白滴注静脉丙种球蛋白滴注(0.20.4g/kg/m)特异性免疫血清特异性免疫血清(VZIG,RIG,TIG,HBIG,RSV-IG)血浆血浆(20ml/kg)中性粒细胞输注（仅用于严重感染者）中性粒细胞输注（仅用于严重感染者）其它其它(酶，酶，IFN-,IL-2,胸腺素胸腺素,转移因子转移因子)免疫重建免疫重建 胎
39、儿胸腺移植及胸腺上皮移植胎儿胸腺移植及胸腺上皮移植/胎儿肝脏移植胎儿肝脏移植 骨髓移植骨髓移植 -HLA-同型移植同型移植 -HLA-半半 合子移植合子移植 -无关配型移植无关配型移植 脐血干细胞移植脐血干细胞移植 外周血干细胞移植外周血干细胞移植 基因治疗基因治疗(ADA 缺陷缺陷,LAD-1,CGD)造血干细胞移植造血干细胞移植干细胞移植干细胞移植原发性免疫缺陷病免疫重建原发性免疫缺陷病免疫重建造血干细胞移植是根治疗某些原发性免疫缺陷病的最佳方案，造血干细胞移植是根治疗某些原发性免疫缺陷病的最佳方案，全球已有近万例病儿接受该治疗，成功率全球已有近万例病儿接受该治疗，成功率40-80%40-
40、80%，我国上海和重庆已成功进行我国上海和重庆已成功进行3 3例造血干细胞移植治疗。例造血干细胞移植治疗。2岁岁6 6个月个月WiskottWiskott-Aldrich syndrome(WAS)Aldrich syndrome(WAS)患儿在重庆医科大学儿患儿在重庆医科大学儿童医院经同胞（姐）供童医院经同胞（姐）供体同型骨髓移植后无病体同型骨髓移植后无病健康存活。图为患者母健康存活。图为患者母亲、患者和供髓的姐姐亲、患者和供髓的姐姐在一起。在一起。WAS免疫重建效果免疫重建效果Pre-SCTPre-SCTPost-SCTPost-SCT成功植入成功植入完全的造血重建和免疫重建完全的造血重建
41、和免疫重建Immune reconstitutionCase#DiseaseAge of SCTDonorFollow-up durationStatus1WAS3+yMatched sibling2y 4mHealthy2WAS3+y5/6 cord bloodDied of CMV infection+40d3WAS2+y5/6 cord blood1y2mHealthy4WAS2+y5/6 cord blood5mHealthy 5WAS3+y4/6 cord blood3mGvHD grade 26WAS4+yMatched sibling1m100%engraftment7HIM2+
42、yMatched cord blood2+m100%engraftment8SCID(IL-7Ra)8+m5/6 cord blood1y1mAlive with BCG problemPIDPID基因治疗现状基因治疗现状病毒载体疾病(致病基因)临床试验单位(病例数)预处理临床效果/副作用逆转录病毒X-SCID(IL2RG)英国（11）法国（11）美国（3）无临床效果明显，但年长者稍差/其中5例发生T细胞白血病，1例死亡ADA-SCID(ADA)意大利（18）美国（14）英国（8）白消安白消安或马法兰15/18、10/14、可脱离ADA酶替代治疗4/8可脱离替代治疗CGD(NCF1/CYBB)
43、美国（5+3）德国和瑞士（4）英国（4）韩国（2）无或白消安白消安马法兰白消安+氟达拉宾无效长期纠正但在随访的1035个月内4/4病例均出现MDS短暂纠正/未见MDS短暂纠正WAS（WAS）德国（10）白消安长期纠正，但4/10例发生T细胞白血病自身灭活载体X-SCID(IL2RG)法国、英国和美国（8）无纠正T细胞ADA-SCID(ADA)美国和英国（4）白消安目前随访不足1年，免疫功能纠正CGD(NCF1/CYBB)瑞士、德国、法国和英国（共2例）白消安临床试验已启动WAS（WAS）英国、美国、法国和意大利（10）白消安+氟达拉宾ATG/利妥昔单抗临床试验已启动，湿疹及血管炎有所改善 Re
44、view of basic ImmunologyReview of basic ImmunologyPhysiological features of immune function in Physiological features of immune function in childhoodchildhoodDefinition of immunodeficiency diseaseDefinition of immunodeficiency diseaseClassification of PIDClassification of PIDCommon clinical presenta
45、tionsCommon clinical presentationsScreening laboratory testsScreening laboratory testsPrinciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immunodeficiency OUTLINE 由于环境因素所致（感染、药物、营养不良、由于环境因素所致（感染、药物、营养不良、外科、年龄等）外科、年龄等）发病率很高，是儿童时期的常见病发病率很高，是儿童时期的常见病 免疫系统免疫系统广泛受累
46、广泛受累(T,B,NK,PMN,M)，但明显不如原发性免疫缺陷病严重但明显不如原发性免疫缺陷病严重 清除原发疾病或诱因后，免疫功能即能恢复清除原发疾病或诱因后，免疫功能即能恢复 正常正常继发性原发性继发性免疫缺陷病的诱因继发性免疫缺陷病的诱因(1)早产儿和未成熟儿早产儿和未成熟儿 遗传代谢性疾病遗传代谢性疾病 染色体异常染色体异常(21-三体综合征），尿毒症，糖尿病，蛋白质丧失三体综合征），尿毒症，糖尿病，蛋白质丧失 性肠病，肾病综合征，张力性肌萎缩，镰状细胞贫血性肠病，肾病综合征，张力性肌萎缩，镰状细胞贫血 营养不良营养不良 -维生素和微量元素缺乏维生素和微量元素缺乏 -蛋白质蛋白质-热能营
47、养不良热能营养不良 营养紊乱营养紊乱 免疫功能低下免疫功能低下反复感染反复感染 肿瘤肿瘤 自身免疫性疾病自身免疫性疾病 继发性免疫缺陷病的诱因继发性免疫缺陷病的诱因(2)免疫抑制剂：免疫抑制剂：放射线、放射线、免疫抑制药物、免疫抑制药物、糖皮质激素、抗淋巴细胞糖皮质激素、抗淋巴细胞 抗体、抗抗体、抗T细胞单抗细胞单抗 感染：感染：先天性风疹，出疹性病毒感染（麻疹、水痘），先天性风疹，出疹性病毒感染（麻疹、水痘），HIV 感染，巨细胞病毒感染，传染性单核细胞增多症，细感染，巨细胞病毒感染，传染性单核细胞增多症，细 菌性感染，分支杆菌、霉菌或寄生虫感染菌性感染，分支杆菌、霉菌或寄生虫感染(3)继发
48、性免疫缺陷病的诱因继发性免疫缺陷病的诱因(3)肿瘤肿瘤 组织细胞增生症、内肉瘤病、何杰金病和淋巴瘤、组织细胞增生症、内肉瘤病、何杰金病和淋巴瘤、白血病、骨髓瘤、粒细胞减少症和再生障碍性贫血、白血病、骨髓瘤、粒细胞减少症和再生障碍性贫血、骨髓移植后发生的淋巴瘤骨髓移植后发生的淋巴瘤 外科及损伤外科及损伤 烧伤、脾切除、麻醉、脑外伤烧伤、脾切除、麻醉、脑外伤 其它其它 红斑狼疮、慢性活动性肝炎、肝硬化红斑狼疮、慢性活动性肝炎、肝硬化 -免疫缺陷病的最常见的临床表现是反复和慢性感染-确诊免疫缺陷病必须进行免疫学检查-原发性免疫缺陷病是单基因遗传病，治疗原则是替 代、干细胞移植和基因治疗-继发性免疫缺陷病是最常见的免疫缺陷病，去除病 因后免疫功能即可恢复结 论关爱关爱PID患儿，关注我们的网站！患儿，关注我们的网站！www.pidchina.orgSaipan Island 2003Thank you for your attention!
