1、Immunodeficiency diseases,Wang, XiaochuanDepartment of Clinical Immunology, Childrens Hospital of Fudan University,Pathogens,Environment Material,Immunity,Infectious Immunity,Allergy,Tumor Immunity,Autoimmune Disease,PID,Immunologic disorders,Human,Immunocompromised Host,Individual who has one or mo
2、re 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 barriersSecondary - infection, tumor, drug, othersPhysiology- Infants
3、, aged,Characteristics of Immunoglobulines,Development of Immunoglobulin,6M,birth,100%,IgG level of Infant,Age dependent changes of serum Igs levels(g/L),Schematic diagram of the exposure of microorganism during early life,fetus,Full tern,6M,Day care,pathogens,probiotics,Period of susceptible childr
4、en,premature,Full term,6M,Day care,Management,Exclusion of PIDClinical featuresFrequency of infectionSeverityComplicationsFollow up,Management,General medical care (prevention、nutrition、exercise)Complication TreatmentMedication AntibioticsImmune regulatorImmunizations,(Primary Immunodeficiency Disea
5、se, ),Primary Immunodeficiency Disease,A group of 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 inf
6、ection, high risk of autoimmune diseases, allergy and malignancy,50%,20%,10%,18%,2%,Antibody,Complement,Phagocyte,Cell mediated,Combined,Predictive patients number of PID in Shanghai,X-Linked Agammaglobulinemia (XLA) 1/ 100,000Selective IgA Deficiency 1/10000 Severe Combined Immunodeficiency (SCID)
7、1/1,000,000Chronic Granulomatous Disease (CGD) 1/1,000,000,1005001010,Classification (old),Antibody(B cell) deficiencyT cell deficiencyCombined immunodeficiencyPhagocyte deficiencyComplement deficiency,Classification(new),Combined Immunodeficiency Predominantly antibody deficiencyPredominantly T-cel
8、l deficiencyImmunodeficiency syndromesPhagocyte deficiencyComplement deficiencyOthers,Up to 2007 more then 200 kinds of PID reported,1. 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(
9、PNP)缺陷(7)MHC 类缺陷(8)CD3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
10、合征(DiGeorge anomaly)(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
11、细胞减少症(4)白细胞粘附缺损1(5)白细胞粘附缺损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
12、缺陷(2)IL-2缺陷(3)多种细胞因子缺陷(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,Case,7-year-old Male，with 6 years history of recurrent coughing, fever, joints swollen and painful for 5 years.The first onset of fever and coughing was at 10 months of age. Fever, coughing and left knee painful with move obstruction
13、 at 1 years and half age. After then on, the recurrent high fever, coughing and processing left knee functional obstruction exhibited every 2-3 months. Sometimes the symptoms were released by penicillin. The JRA, ankylosing spondylitis, rheumatic pneumonia were diagnosed successively and treatment w
14、ith a series medicines. A mothers brother died as reccurent pnumonia and septicemia in infancy.,Case (continue),Physical examination：T 39-40C，malnutrition, small lymph nodes, absent tonsilHe had pneumonia and hepatosplenomegaly. Bilateral elbows, wrists, knees and ankle were swelling with tender, mu
15、scular atrophy.,Case (continue)Lab investigation,RF negative , ESR：19mm/h, CRP：positive ANA negative，ENA negative, blood culture：negativeCD3: 83.77%, CD4: 31.89%, CD8: 46.98%, CD19: 0%. IgG: 0.1g/L; IgA: 0.02g/L; IgM: 0.03g/L; IgE: 32IU/ml。CH50：90U/ml; C3: 189mg/dlX-ray：periarticular soft-tissue swe
16、lling, periarticular osteopenia, and erosions with subluxation of the joint. Knees were deformation.,Characteristics,Male, onset at 10 monthsRecurrent infectionRecurrent arthritisDeceased serum IgsAbsence of circulating B cell,Case continue (Diagnosis),Primary Immunodeficiency disease(X-linked agamm
17、aglobulinemia)Juvenal Idiopathic ArthritisPneumoniaDiarrheaMalnutrition,Antibody (B cell) Immunodeficiency,Hypogammaglobulinemia X-linked agammaglobulinemia (XLA) Transient Hypogammaglobulinemia Common variable immunodeficiency disease (CVID) Selective Ig deficiency selective Ig A deficiency selecti
18、ve Ig M deficiency selective Ig G subclass deficiency,Clinical features of antibody immunodeficiency,Onset during 612 months of ageRecurrent Pyogenic bacterial infection (encapsulated invasive bacteria)Pneumonia, media otitis, sinusitis, skin infection, meningitis, sepsisRare fungal, viral infection
19、 (but entericvirus)High risk of allergy and autoimmune diseases,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 impaired,Clinical manifestations of XLA(1),Onset at 6-12 m
20、onth of age, male Recurrent bacterial infectionPyogenic encapsulated bacteria: Streptococcus, Pneumoniae, Haemophilus influenzae, Staphylococcus aureus Recurrent upper and lower respiratory infections, Pneumonia, media otitis, sinusitis, skin infection, meningitis, sepsis1/3 untreated patients with
21、arthritis,Clinical 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
22、expression,Common variable immunodeficiency disease(CVID),Pathogenesis: unclear,Clinical manifestations,Onset at any age, male and female Recurrent Pyogenic bacterial infectionHigher risk for autoimmune diseases Physical examination:Part of patients tonsil and lymph node enlarge Lab investigation: I
23、gGG mutation,Intron 15 (+2) T/G carrier,Intron 15 (+2) T/G carrier,IFNg/IL-12 pathway,Macrophage,IL-12 R,IL-12,IFN-g,p40p35,T/NK cell,b1b2,IFN-g R,Other factors, e.g., TNF-a,IFN-g R,STAT4,STAT1,It is now clear that most, if not all individuals, suffer from at least one PID, the clinical expression o
24、f which depends on exposure to ad hoc environmental factors, infectious or otherwise.,Casanova JL, Abel L. SCIENCE 2007(317): 617-619,Treatment,General management ImmunoglobulinReplacement therapy Transplantation, others,General management,DietAvoidance of pathogens (“germ-free” care)AntibioticsUse
25、in acute illnessProphylactic Avoid whole blood transfusion in combined immunodeficiency disorderAvoid live virus vaccines and BCG,Immunoglobulin replacement,Treatment of severe antibody disordersIntramuscular 0.1g/kg/m Intravenous0.4-0.6g/kg/m,Immunoglobulin replacement adverse effects,Local reactio
26、ns: intramuscular gammaglobulin, tenderness, abscesses, fibrosisSystemic reaction: Fever, chills, nausea, vomiting; anaphylactic reaction are unusual,Specific treatment for cellular deficiency,Bone marrow transplantationReplacement therapyEnzyme replacementGene therapyThymic hormonesCytokinesFetal thymus transplantation,Specific treatment of phagocytic disorders,Interferon gamma for CGDGranulocyte transfusion,Thank you for your attention,
