【儿科学】161原发性免疫缺陷病课件

1、【儿科学】161原发性免疫缺陷病【儿科学】161原发性免疫缺陷病【儿科学】161原发性免疫缺陷病中性粒细胞总数：300个/ul中性粒细胞总数：Semin Respir Infect 9(3):140-52，1994mortality (per10 000)Mortality Trends with Pneumonia from 1900 to 1990 in USA0204060801001201401601802001900191019201930194019501960197019801990penicillinsulfonamideAntibiotic renovationPublic

2、health improvmentSemin Respir Infect 9(3):140-5Medicinal “The Long Tail”Common infections80%Rare infections20%Developing regionDeveloped regionRecurrent Severe Multi、specific pathogensInefficacy with routine treatmentMedicinal “The Long Tail”CommoPathogen virulence X Amount Host resistanceInfection

3、=Pathogen virulence X Amount HBasic function of immunityDefenceHemeostasis,toleranceSurveillance InfectionAutoimmunity, AllergyCancer Basic function of immunityDefePathogens Environment MaterialImmunityInfectious ImmunityAllergyTumor ImmunityAutoimmune DiseasePIDImmunologic disordersHumanPathogens E

4、nvironment MaterialImmunocompromised HostIndividual who has one or more defects in the bodys natural defense mechanisms which are sufficiently severe to predispose the host to life- threatening infection and high risk of autoimmune diseases, allergy and malignancyPrimary - PID, damage to anatomical

5、barriersSecondary - infection, tumor, drug, othersPhysiology- Infants, agedImmunocompromised HostIndividuCharacteristics of ImmunoglobulinesIgGIgMIgAIgDIgESerum Con. (mg/dl)120012020030.01Percentage 70-805-1010-1510.01Half life(days)21572.82.3Distribution (%)4580457550Quantity (mg/kg)1150492301.50.0

6、4Synthesis(mg/kg/D)357250.40.02Transport through placenta +-Characteristics of ImmunoglobuDevelopment of Immunoglobulin IgG from motherIgG of infant6Mbirth100%IgG level of InfantDevelopment of Immunoglobulin Age dependent changes of serum Igs levels(g/L)AgesIgGIgAIgMNeonate6.46-17.740.004-0.0170.05-

7、0.271m-2.75-7.500.05-0.600.10-0.704m-3.70-8.300.14-0.500.33-1.257m-3.50-8.900.06-0.540.36-1.201y-5.52-11.460.06-0.740.60-2.123y-4.95-12.740.33-0.890.65-2.017y-6.09-12.850.52-2.160.67-2.4612y-6.98-14.260.92-2.500.56-2.1815-18y7.54-16.020.89-3.240.72-2.28Age dependent changes of serumPeriod of suscept

8、ible childrenprematureFull term6MDay carePeriod of susceptible childrenManagementExclusion of PIDClinical featuresFrequency of infectionSeverityComplicationsFollow upManagementExclusion of PID(Primary Immunodeficiency Disease, )(Primary Immunodeficiency DisePrimary Immunodeficiency DiseaseA group of

9、 disorders characterized by an impaired ability to produce normal immune response. Most of these disorders are cased by mutations in genes involved in the development and function of immune organs, cells, and molecules. Clinical features：Recurrent infection, high risk of autoimmune diseases, allergy

10、 and malignancyPrimary Immunodeficiency DiseaClassification (old)Antibody(B cell) deficiencyT cell deficiencyCombined immunodeficiencyPhagocyte deficiencyComplement deficiency Classification (old)Antibody(Classification(new)Combined Immunodeficiency Predominantly antibody deficiencyPredominantly T-c

11、ell deficiencyImmunodeficiency syndromesPhagocyte deficiencyComplement deficiencyOthers Classification(new)Combined ImDistribution of PID from Childrens Hospital of Fudan University (to 2007)From JMF (2004-2006)18973 casesTotal 137 cases我国PID现状Distribution of PID from Child50%20%10%18%2%AntibodyComp

12、lementPhagocyteCell mediatedCombined50%20%10%18%2%AntibodyComplemeUp to 2007 more then 200 kinds of PID reported1. 联合免疫缺陷(1) 无T有B (a)X-连锁(c缺陷)(b)常染色体隐性(Jak3缺陷)(c)IL7R缺陷(d)CD45缺陷(2)无T无B(a)RAG1/2缺陷(b)Artemis缺陷(c)腺苷脱氨酶(ADA)缺陷(d)网状组织发育不良(3)Omenn综合征(4)X-连锁高IgM综合征(5)CD40缺陷(6)嘌呤核苷磷酸化酶(PNP)缺陷(7)MHC 类缺陷(8)CD

13、3或CD3缺陷(9)CD8缺陷(10)ZAP-70缺陷(11)TAP-1缺陷(12)TAP-2缺陷(13)WHN缺陷2.抗体缺损为主的免疫缺陷(1)X-连锁无丙种球蛋白血症(2)常染色体隐性无丙种球蛋白血症(3)Ig重链基因缺失(4)链缺陷(5)选择性Ig缺陷(a) IgG亚类缺陷(b) IgA缺陷(6)Ig水平正常的抗体缺陷(7)常见变异型免疫缺陷(8)婴儿暂时性低丙种球蛋白血症(9)AID缺陷3.其它确认的免疫缺陷综合征(1)Wiskott-Aldrich综合征(2)共济失调毛细血管扩张(3)Nijmegen breakage (4)第3、4咽囊综合征(DiGeorge anomaly)(

14、5)伴有白化病的免疫缺陷(a) Chediak Higashi 综合征(b) Griscelli综合征(6)x-连锁淋巴增殖综合征(7)家族嗜血细胞性淋巴组织病(8)X-连锁免疫调节异常、多种内分泌病、肠病综合征(9)自身免疫性多种内分泌病和外胚层发育不良(10) X-连锁免疫缺陷和外胚层发育不良4.补体缺陷C1q,C1r,C4,C2,C3,C5,C6,C7,C8，C8，C9，C1抑制物，I因子，H因子，D因子，备解素等16种成分各自的缺陷5.吞噬细胞数量和/或功能缺陷(1)严重先天性嗜中性粒细胞减少症(2)循环嗜中性粒细胞减少症(3)X-连锁嗜中性粒细胞减少症(4)白细胞粘附缺损1(5)白细

15、胞粘附缺损2(6) Rac-2GTP酶缺陷(7) 幼年型局限性牙周炎(8) 特异性颗粒缺陷(9) Schwachman-Diamond综合征(10)慢性肉芽肿病(CGD)(a)X-连锁CGD(细胞色素b的91kD链缺陷)(b)常染色体隐性遗传(细胞色素b的22kD链缺陷或胞液因子的p47或p67缺陷)(11) 嗜中性粒细胞葡萄糖-6-磷酸脱氢酶(G6PD)缺陷(12) 髓过氧化酶缺陷(13)白细胞分枝杆菌缺陷(a) IFN-受体缺陷(b) STAT-1缺陷(c) IL-12受体缺陷(d) IL-12缺陷 6.其它原发性免疫缺陷病(1)原发性CD4T细胞缺陷(2)IL-2缺陷(3)多种细胞因子缺

16、陷(4)伴有或不伴有肌病的信号转导(transduction)缺陷(5)伴肌病的钙流通缺陷Up to 2007 more then 200 kindsCase 7-year-old Male，with 6 years history of recurrent coughing, fever, joints swollen and painful for 5 years.The onset was at 10 months of ageThe JRA, ankylosing spondylitis, rheumatic pneumonia were diagnosed successively

17、and treatment with a series medicines. A mothers brother died as reccurent pnumonia and septicemia in infancy.Case 7-year-old Male，with 6 yeCase (continue)Physical examination：T 39-40C，malnutrition, small lymph nodes, absent tonsilHe had pneumonia and hepatosplenomegaly. Bilateral elbows, wrists, kn

18、ees and ankle were swelling with tender, muscular atrophy.Case (continue)Physical examinCase (continue)Lab investigationCD3: 83.77%, CD4: 31.89%, CD8: 46.98%, CD19: 0%. IgG: 0.1g/L; IgA: 0.02g/L; IgM: 0.03g/L; Case (continue)Lab investigatCharacteristics Male, onset at 10 monthsRecurrent infectionRe

19、current arthritisDeceased serum IgsAbsence of circulating B cellCharacteristics Male, onset atCase continue (Diagnosis)Primary Immunodeficiency disease(X-linked agammaglobulinemia)ArthritisPneumoniaDiarrheaMalnutritionCase continue (Diagnosis)Prima【儿科学】161原发性免疫缺陷病【儿科学】161原发性免疫缺陷病【儿科学】161原发性免疫缺陷病Anti

20、body (B cell) Immunodeficiency Hypogammaglobulinemia X-linked agammaglobulinemia (XLA) Transient Hypogammaglobulinemia Common variable immunodeficiency disease (CVID) Selective Ig deficiency selective Ig A deficiency selective Ig M deficiency selective Ig G subclass deficiencyAntibody (B cell) Immun

21、odeficiClinical features of antibody immunodeficiencyOnset during 612 months of ageRecurrent Pyogenic bacterial infection (encapsulated invasive bacteria)Pneumonia, media otitis, sinusitis, skin infection, meningitis, sepsisRare fungal, viral infection (but entericvirus)High risk of allergy and auto

22、immune diseasesClinical features of antibody X-linked agammaglobulinemia (XLA; Bruton syndrom)Gene defect：Xq22 coded B cell tyrosin kinase ( Btk ) defect, XLMechanism:B cell signal pass way disorder, development of B cell impairedX-linked agammaglobulinemia BTK gene/protein structure and mutationsid

23、entified by gene analysis71015123456891112131416171819PHTHSH3SH2Kinase13812152803776591kb1128114138197234281355525590591594598Mutation types: L11P,R28C,F114delX115,W588delX589,L138ins140X,I197ins207X,Q234X,W281X,I355N,R525Q , I590F, Y591S、G594E、Y598X588http:/bioinf.uta.fi/BTKbase/)ChinesePatients(06

24、)Wang Journal of clinical immunology 2008;王晓川 等 X连锁无丙种球蛋白血症的基因诊断 中华儿科杂志 2005；43：449-452经典PID-抗体缺陷病BTK gene/protein structure andClinical manifestations of XLA(1)Onset at 6-12 month of age, male Recurrent bacterial infectionPyogenic encapsulated bacteria: Streptococcus, Pneumoniae, Haemophilus influe

25、nzae, Staphylococcus aureus Recurrent upper and lower respiratory infections, Pneumonia, media otitis, sinusitis, skin infection, meningitis, sepsis1/3 untreated patients with arthritisClinical manifestations of XLAArthritis in XLA王晓川 中华儿科杂志 2004；42：564-567经典PID-抗体缺陷病Arthritis in XLA王晓川 中华儿科杂志 200Cl

26、inical features of XLA(2)Physical examination：Failure to thrive, small or absent tonsil, peripheral lymph nodesLab investigation： IgG2g/L, IgM、IgA、IgE reduced Peripheral B cells absence, presence of pre or pro B cells in bone marrowNormal T cell counts and function Reduced monocyte BTK expressionCli

27、nical features of XLA(2)PhyCommon variable immunodeficiency disease(CVID)Pathogenesis: unclearCommon variable immunodeficienClinical manifestationsOnset at any age, male and female Recurrent Pyogenic bacterial infectionHigher risk for autoimmune diseases Physical examination:Part of patients tonsil and lym