(儿科学英文课件）14 Immunodeficiency

1、( (儿科学英文课件）儿科学英文课件）14 14 ImmunodeficiencyImmunodeficiencyImmune functionsImmune functionsBy effecter functionBy effecter function Cellular immunity: hosted by cells Humoral immunity: carry out by fluid-borne moleculesBy antigen specificityBy antigen specificity Innate immunity: Non-antigen-specific,

2、 such as skin and mucosal barriers, interferons, NK cells, phagocytes, etc. Adaptive immunity: Antigen-specific, mediated only by lymphocytes Immune organsImmune organs Immune cellsImmune cells Immune moleculesImmune molecules Cytokines: secreted by immune cells Membrane bound molecules - Adherence

3、molecules - Receptors - Other surface markers Soluble molecules: antibody, complement Immune systemImmune systemSLSCProBCFUMPMNPletRBCPreBPTTBCD8+PlasmaCD4+TH1TH2IgMBPlasmaIgAIgAIgMBPlasmaIgGIgGBPlasmaIgEIgETHYRUM Epi. Cytokines（IL-118，INF，IFN，IGF -1） Membrane markers（CD28-B7，CD40-CD40L，MHCI, ，cytok

4、ine receptors） Adhesion molecules（ICAM-1，LFA-1，SELECTIN, and so on） ComplementsBMCD3+CD19/20Pluripotent stem cellsPOSITIVE SELECTION Self MHC restricted: (1) Rescue of double-positive thymocytes from programmed cell death, and (2) determine the expression of CD4 or CD8 coreceptor on mature T cells.b

5、ind to MHC class ICD8 T cell Bind to self MHC alivebind to MHC class IICD4 T cellDo not bind self MHCApoptosis NEGATIVE SELECTION Self tolerant: Thymocytes recognizing self peptide:self MHC complexes too well are induced to undergo apoptosis.Bind to self MHC-self antigenApoptosisDo not bind to self

6、MHC-self antigenAliveThymic cortical epithelial cellsBone marrow derived dendritic cells and macrophages 1st phase: Antigen presenting2nd phase: proliferation of lymphocytes3rd phase: Effecter function4th phase: Apoptosis of activated lymphocytesImmune responseImmune responseAgMTH1CTLNKADCCBPMNIL-4，

7、5，6，7，8，9，10，11，13，14，16，17AbImmune complexActivate complementEndothelialsOsteoblasts Osteoclasts Fibroblasts Mast cells Eosinophils TH2Ag CKs & mediators InflammationTH0 IL-12,IL-18IL-1IL-10IL-4IL-2IFNIL-1，IL-6，TNFTr1TH3IL-10MHCIICD4TCR CD3 Antigen presenting Antigen presentingAPCT cellAgPI3-Kinase

8、PLCr1VavSH2SH2 JNKB cellB cellT cellIgAIgMIgGIgET CD40L TCR CD28 Ag I L-6 I L-5 I L-4B CD40 MHCB7ReceptorsT and B cell interactionT and B cell interactionAgMTH1CTLNKADCCBPMNIL-4，5，6，7，8，9，10，11，13，14，16，17AbImmune complexActivate complementEndothelialsOsteoblasts Osteoclasts Fibroblasts Mast cells E

9、osinophils TH2Ag CKs & mediators InflammationTH0 IL-12,IL-18IL-1IL-10IL-4IL-2IFNIL-1，IL-6，TNFTr1TH3IL-10 Immune response is always accompanied by inflammation Ensure an appropriate immune response to clear the antigen, Prevent excessive inflammatory response Summary Review of basic ImmunologyReview

10、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 clinical presentati

11、onsScreening laboratory testsScreening laboratory testsPrinciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immunodeficiency OUTLINE Phagocytosis - macrophages , dentritic cells (APC) - neutraphil T lymphocyte: - CD40L , CD28 expression - TH1/TH2 B lymphocyte:

12、- 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 1.8-0.6 4 8 12ms 2 4 8 10 12 yrsIgGIgMIgAImmunoglobulin development in infants and children

13、summary Nearly all branches of immune function are maturely developed at birth Transient dysfunction or immunocomprimise condition is mainly due to insufficient exposure to antigens Review of basic ImmunologyReview of basic ImmunologyPhysiological features of immune function in Physiological feature

14、s of immune function in childhoodchildhoodDefinition of immunodeficiency diseaseDefinition of immunodeficiency diseaseClassification of PIDClassification of PIDCommon clinical presentationsCommon clinical presentationsScreening laboratory testsScreening laboratory testsPrinciples of PID managementPr

15、inciples of PID managementSecondary immunodeficiencySecondary immunodeficiency OUTLINEA diverse group of illnesses that, as a result of one or more abnormalities of the immune system, increased susceptibility to infection.Definition of immunodeficiencyDefinition of immunodeficiency -Gene mutation as

16、sociated: primary immunodeficiency, PID) -Environment-associated: Secondary immunodeficiency ，SID or immunocompromise -HIV infection: Acquired immunodeficiency syndrome，AIDSThree types of immunodeficiencyMilestones of PIDSyllaba & Henner：1926年描述毛细血管扩张、共济失调（ataxia-telangiectasia）Thorpe & Handley：1929

17、年描述皮肤粘膜念珠菌病（mucocutaneous candidiasis）Wiskott：1937年描述湿疹、血小板减少伴免疫缺陷综合征（Wiskott-Aldrich syndrome）Glanzmann & Riniker：1950年描述细胞免疫缺陷Bruton：报道了1952年首例先天性无丙种球蛋白血症，从此免疫缺陷病这一名词才被广泛应用和受到重视Hitzig：1958年则发现抗体缺陷和细胞免疫缺陷在一个病人同时存在，称为瑞士型无丙种球蛋白血症 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

18、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. 2002Total GDP: 10.88 trillion do

19、llarsGDP per capita: 8000 dollarsOpportunitiesRare diseases including PIDs：more and more attention from the government and society亚太免疫缺陷学会（亚太免疫缺陷学会（APSID）成立）成立2016.4 香港 Nomenclature - by name or place - by underlying genetic defects or immunological mechanisms Bruton disease (Bruton, 1952) X linked

20、agammaglobulinemia，XLA Swiss type agammaglobulinemia (Hitziget al,1958) Severe combined ID Review of basic ImmunologyReview of basic ImmunologyPhysiological features of immune function in Physiological features of immune function in childhoodchildhoodDefinition of immunodeficiency diseaseDefinition

21、of immunodeficiency diseaseClassification of PIDClassification of PIDCommon clinical presentationsCommon clinical presentationsScreening laboratory testsScreening laboratory testsPrinciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immunodeficiency OUTLINENewes

22、t classification of PIDJackson Hole, Wyo: 8 categories（J Allergy Clin Immunol 2007） Combined T-cell and B-cell deficiencies Predominantly antibody deficiencies Other well defined immunodeficiency syndromes Diseases of immune dysregulaton Congenital defects of phagocyte number, function, or both Defe

23、cts in innate immunity Autoinflammatory disorders Complement deficiencies Different features of infections in PIDDifferent features of infections in PIDJCAI 2009X-linked agammaglobulinemia (XLA)X-linked agammaglobulinemia (XLA) Brutons disease Due to btk gene mutation, causing blockade of Pre-B to m

24、ature B cell Predominantly antibody deficiency Male Recurrent bacterial infections of respiratory tract or other 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 SLSCProB

25、CFUMPMNPletRBCPreBPTTBCD8+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+Hyper IgM symdrome Combined immunodefic

26、iency X-linked or autosomal recessive Recurrent bacterial, fungal, protozoan infections Autoimmune: autoimmune hemolytic anemia, hepatosplenomegaly, neutrapenia Normal number of peripheral B cells Decreased IgG, IgA; normal or increased IgM Need stem cell transplantation (SCT) to reconstitute the im

27、mune functionIgAIgMIgGIgET CD40L TCR CD28 Ag I L-6 I L-5 I L-4B CD40 MHCB7ReceptorsSevere combined immunodeficiency (SCID) Combined immunodeficiency X-linked or autosomal recessive Onset in early months of life Life-threatening infection of almost all kinds of pathogens, disseminated infection of va

28、ccine 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-linked severe combined immunodeficiencyX-linked severe combined immunodeficiency（IL-2 receptor common chain defect）Wiskott Aldrich syndrome Well defined immunodefici

29、ency syndrome X-linked Triad: thrombocytopenia, eczema, increased susceptibility to infection Mild cases may present solely thrombocytopenia, 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WAS patients CQ13319195/122

30、/84/82/115/163/211/4XLT patientWAS patientYearsTotal 152 WAS/XLT cases diagnosed in the past 12 years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 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Distribution of PID cases in CMU Review of basic ImmunologyReview of basic ImmunologyPhysiological features of

31、immune function in Physiological features of immune function in childhoodchildhoodDefinition of immunodeficiency diseaseDefinition of immunodeficiency diseaseClassification of PIDClassification of PIDCommon clinical presentationsCommon clinical presentationsScreening laboratory testsScreening labora

32、tory testsPrinciples 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

33、病: 关节痛关节痛, 关节炎关节炎, 狼疮等狼疮等 - 淋巴系统肿瘤淋巴系统肿瘤 - 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 dis

34、easeDefinition of immunodeficiency diseaseClassification of PIDClassification of PIDCommon clinical presentationsCommon clinical presentationsScreening laboratory testsScreening laboratory testsPrinciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immunodeficien

35、cy 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 - 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

36、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

37、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 2111.411.311.211.2 12 13 21 22 23 24 25 26 27 28pq基因诊断基因诊断Assays established to define PIDsSyndromeDNA-based assaysProtein-based assaysCIDIL2RG, RAG1/2, CD40L, TCR spectratypingCD40LAb deficiencyBTK, chain, Ig/, ,5, 5, CD40, AID, Ung, Nemo,

38、Taci, WHIMBtk, CD40Well definedWASP, ATWASPPhagocyte deficiencyCYBB, NCF1NBT, DHRImmune dysregulationFOXP3, SAP, FAS, FASL, Caspase 8 and 10FoxP3, FAS, FASL, SAP, Perforin, DNTInnate defectMyD88, IRAK-4Autoinflammatory diseasebkd（HID）、）、TRAPS、 CARD15（NOD2） Review of basic ImmunologyReview of basic I

39、mmunologyPhysiological features of immune function in Physiological features of immune function in childhoodchildhoodDefinition of immunodeficiency diseaseDefinition of immunodeficiency diseaseClassification of PIDClassification of PIDCommon clinical presentationsCommon clinical presentationsScreeni

40、ng laboratory testsScreening laboratory testsPrinciples of PID managementPrinciples of PID managementSecondary immunodeficiencySecondary immunodeficiency 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(0.2

41、0.4g/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

42、 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%40-80%， 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Wiskott-Wiskott-Aldrich syndrome(WAS)Aldrich syndrome(WAS)患儿在重庆医科大学儿患儿在重庆

43、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和免疫重建PID patients treated with transplantationChallenges1362554818YearsDisease NumberAliveDeadWAS41356CGD413SCID211X-HigM33XLA22Gene th

44、erapy ChallengesFuture of PIDGene therapy Gene therapy plan with CRISPR-cas9 strategy and AAV-6 initiates this year Clinical trial for XSCID is expected to be open as early as 2018 ChallengesFuture of PIDWAS gene mutation selectively influence TCR repertoire development or expansion in memory CD4 T

45、cells. This may reflect relatively less efficiency of T cell memory establishment as compared to normal individuals. Skewed TCR diversity in memory populations of T cells in WASPID research Wu et al. J Allerg Clin Immunol, 2015WASp plays an critical role in Tfh development and function WASp deficien

46、cy leads to impaired Tfh development and function in patients, knock-out mice, chimeric mice and CD4 transfered mice, which is T cell intrinsic.Accepted by BLOODPID research Human samples, DOCK8 KO mouse DOCK8 ko mice were prone to be induced to produce IgE. Essential role of Tfh-produced IL-21 in hypersensitivity of B cells to allergen and development of allergic diseases. Allergic phenotype can be fully rescued by nasally administered IL-21. IL-21 is the dominate regulator in DOCK8 deficiencyPID research MS under preparation Review of basic ImmunologyReview of basic ImmunologyPhysiologica