This document discusses a case presentation of a 2-year-old boy named D. George who has been brought in by his parents due to concerns about recurrent infections. The boy has a history of frequent upper respiratory infections and ear infections, and has been hospitalized twice for infections. The document provides background on primary immunodeficiency diseases and different aspects of the immune system to help evaluate the child's condition and determine if he has an immunodeficiency.

1. Primary Immunodeficiency Diseases （ PID ） MBBS.weebly.com

2. Objectives What will I learn? Characteristics of immune development in children classification and clinical manifestation Diagnosis Treatment

3. D.Deorge Wiskott Aldrich

4. Case Presentation D. George is a 2 year old male brought in by his parents Wiskott and Aldrich because of concerns about recurrent infections . They state he has been sick many times over the last two years. He has been in the hospital twice with some sort of infection. He has also had frequent upper respiratory infections and has had Otitis Media 7 times in the last two years.

7. Immunology review (development and features of IM)

8. Organs of the Immune System

9. Immune system Specific Nospecific ILs IFNγ TNFα IgM IgG1 ～ 4 IgA1 、 2 IgD 、 IgE phagocytic cells Macrophages (MC/MΦ) Neutrophils T cells B cells （ organs, cells and molecules ） complement system

11. SL SC ProB CFU MØ PMN Plet RBC PreB PT T THYRUM Epi. BM CD3 + IFN- γ 、 IL-2 IL-4 、 5 、 8 、 9 、 10 、 13 Development of Immune cell B Plasma IgM B Plasma IgA IgA IgM B Plasma IgG IgG B Plasma IgE IgE CD19 + CD20 + CD8 + CD4 + TH1 TH2 CTL

15. Development of Immunoglobulin 6M birth 100% IgG level of Infant IgG from mother IgG of infant

16. Age dependent changes of serum Igs levels(g/L ) Ages IgG IgA IgM Neonate 6.46-17.74 0.004-0.017 0.05-0.27 1m- 2.75-7.50 0.05-0.60 0.10-0.70 4m- 3.70-8.30 0.14-0.50 0.33-1.25 7m- 3.50-8.90 0.06-0.54 0.36-1.20 1y- 5.52-11.46 0.06-0.74 0.60-2.12 3y- 4.95-12.74 0.33-0.89 0.65-2.01 7y- 6.09-12.85 0.52-2.16 0.67-2.46 12y- 6.98-14.26 0.92-2.50 0.56-2.18 15-18y 7.54-16.02 0.89-3.24 0.72-2.28

17. Schematic diagram of the exposure of microorganism during early life fetus Full tern 6M Day care pathogens probiotics

18. Period of susceptible children premature Full term 6M Day care

23. 50% 20% 10% 18% 2% Antibody Complement Phagocyte Cell medi ated Combined Distribution of PID Up to 2007 more then 200 kinds of PID reported

26. Combined immunodeficiencies （ 1 ） 1. Severe combined immunodeficiency （ SCID ） X-linked (γc deficiency) Autosomal recessive (Jak3 deficiency) RAG1/RAG2 deficiency Adenosine deaminase (ADA) deficiency Reticular dysgenesis T – B + T - B -

27. Severe Combined Immunodeficiency ， SCID (Bubble boy)

28. Combined immunodeficiencies （ 2 ） 2. Hyper-IgM syndrome 3. Purine nucleoside phosphorylase (PNP) deficiency 4. MHC class Ⅱ deficiency

30. Humoral / B-cell Defects

31. Predominantly antibody defects ● Panhypogammaglobulinemia X-linked agammaglobulinaemia （ Bruton disease ） Common variable immunodeficiency （ CVID ） Transient hypogammaglobulinaemia of infancy (ITHG) ● Selective Ig deficiency Ig heavy chain deficiency IgA deficiency Selective IgG subclass deficiency

32. — Bruton disease — mutations in btk — maturation disorder of pre-B cell

33. CVID—variable ( lack of signals from T cells ) ITHG—delayed maturation of T H function

34. Predominantly antibody defects Common clinical manifestations: ● Recurrent bacterial infections (sepsis and meningitis) ● Viral ,fungal or protozoan infections rare ● Lymphatic system hypoplasia- tonsils, lymph node （ except CVID ） ● Autoimmune disease

36. . Cell-Mediated/T cell Immunity

37. Predominantly T-cell defects 1. CD 4 + deficiency 2. CD 7 + deficiency 3. IL-2 deficiency 4. multiple cytokines deficiency （ IL-2 、 -4 、 -5 ） Not completely understood ？？

38. Destination serum Ig B-cells T-cells genetic defect clinical findings ● Wiskott- IgM↓ Normal Progressive ↓ XL Thrombocytopenia Aldrich Syn Mutation in WAS eczema lymphoma ● Ataxia- IgA, E, G↓ Normal ↓ ATM Ataxia, Telangiectasia IgM ↑ telangiectasia ● DiGeorge Normal or ↓ Normal ↓or normal Deletion of Hypoparathyroidism Syn chromosome conotruncal defect 22q11.2-pter abnormal facies Immunodeficiency syndrome deficiencies

40. （ eczema ）

42. Ataxia

43. telangiectasi a

44. DiGeorge Syndrome

47. DiGeorge anormaly

48. Hypertelorism hooded eyelids short philtrum with fish-mouth appearance , micrognathia Low set ears telecanthus with short palpebral fissures Facial features of children with DiGeorge syndrome

49. DiGeorge syndrome

50. Phagocytic Disorders

51. Congenital defects of phagocytic number and/or function ● Sever congenital neutropenia （ SCN ， Kostmann syndrome ） ● Chronic granulomatous disease ● Chediak-Hiashi syndrome

52. Bacteria phagosome Bacteria Phagosome Neutrophil NADPH H + NADPH H + e - +O 2 O 2 - H + H 2 O 2 Normsal phagocyte Dysfunction of phagocyte Chronic granulomatous disease

55. Complement Disorders

56. Complement deficiency Defects Inheritance Clinical findings ● Classical pathway Infections ， (C1q 、 r 、 s 、 C 2 、 C 4 ) AR Autoimmune disease C 1 inhibitor AD Hereditary angioedema ● Alternaive pathway Recurrent pyogenic infection (C 3 、 FactorⅠ 、 FactorH) AR ● Others Neisseria infection (C 5 ～ 8 、 properdin 、 factor D) AR Lupus-link syndrome C 9 AR Asymptomatic

58. Table 1. Characteristic infections of the primary immunodeficiencies component primary pathogen primary site clinical example T-cells intracellular, bacteria viruses, protozoa, fungi, non-specific SCID, DiGeorge B-cells pneumococcus, streptococcus, haemophilus lung, skin, CNS IgG, IgM deficiency IgG, IgM deficiency enteric bacteria and viruses GI, nasal, eye IgA deficiency phagocytes Staphylococcal, Klebsiella Pseudomonas, lung, skin, regional lymph node Chronic granulomatous disease (CGD) complement neisseria, Haemophilus, pneumococcus, streptococcus CNS lung skin C3, Factors I and H, late C omponents

59. Approach to the patients with suspected immunodeficiency ● The medical history in immunodeficiency ● Physical examination ● Laboratory investigation

61. From INFO4PI.ORG

64. Initial and advanced laboratory tests for immunodeficiency

65. From INFO4PI.ORG

66. Management of PID ● General treatment ● Replacement therapy ● Immune reconstruction ● Gene therapy

68. Bubble Boy

70. How to get out of the bubble ?

72. A new hope for gene therapy of immunodeficency how to get out of the bubble?

73. Specific treatment of phagocytic disorders ● Interferon gamma for CGD ● Granulocyte transfusion

74. Case Presentation D. George is a 2 year old male brought in by his parents Wiskott and Aldrich because of concerns about recurrent infections . They state he has been sick many times over the last two years. He has been in the hospital twice with some sort of infection. He has also had frequent upper respiratory infections and has had Otitis Media 7 times in the last two years.

78. Related website http://www.info4pi.org/aboutPIin/ http://elearning.sysu.edu.cn/webapps/login/

79. Thanks you for your attention

80. Mini case discussion