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Combined Immunodeficiency


Combined Immunodeficiency and/or Severe Combined Immunodeficiency

Combined Immunodeficiency and/or Severe Combined Immunodeficiency

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  • 1. Combined Immunodeficiency A talk on the Pathogenesis & Therapies For CID
    Disorders of Blood & Immune System
    Lecturer: Dr. Sin Yoke Min
    Compiled and Presented by
    Su Htwe Cho, BBSF1 0707A
  • 2. CID
    • Lack of necessary immunity in the body
    • 3. Defects in production OR maturation of T cells &/or B cells of acquired immunity
    • 4. Susceptible to recurrent infections; esp. by Candida albicans, Steph. aureus, etc.
    • 5. Sterile-isolation, Immune Therapy, BM Therapy, Gene Therapy, Antibiotics.
  • CID - Pathogenesis
    • Directly related to production of T and B cells of the Adaptive Immunity
    • 6. Mutagenic defects
    • 7. Metabolic deficiencies
    • 8. Protein Defects (DNA-binding Proteins)
    • 9. Eight types of immunodeficiencys
    • 10. Six out of 8 – genetic defects
    • 11. The rest – metabolic deficiencies
    T cell
    Regulation of B Cell Development (2007)
  • 12.
  • 13. Mutagenic CID
    • Due to mutations in genes
    • 14. Autosomal Recessive
    • 15. ZAP-70 Deficiency
    • 16. Bare Lymphocyte Syndrome
    • 17. JAK3 Deficiency
    • 18. Omenn’s Syndrome
    • 19. X-linked
    • 20. XSCID
    • 21. X-linked Lymphoproliferative Disease
    • 22. Wiskott-Aldrich Syndrome
    Cavazzana & Fisher (2007)
    Pike-Overzet et al. (2007)
  • 23. Enzyme Deficient CID
    Due to the deficiency of enzymes
    Deficient enzymes cause accumulation of toxic metabolic intermediates that blocks immune cell maturation
    Two types of enzyme deficiencies are :
    ADA (Adenosine Deaminase) deficiency
    PNP (Purine Nucleoside Phosphorylase) deficiency
  • 24. Mutagenic CIDs -Autosomal Recessive
    X-linked SCID
    Genes encoding portions (gamma chains) of cytokine receptors of Interleukins IL2, IL4, IL7, IL9, IL15, IL21.
    Interleukin Receptor protein is encoded on X chromosome
    Mutations in X-chromosome => XSCID
    Males Descendents Affected, Females Descendents Carriers unless both parents carry mutagenic genes
    IL2R - Lymphocyte proliferation signaling absent
    IL4R - B cell class-switch defected
    IL7R - Loss of antiapoptotic signal, Loss of T cell selection in Thymus
    IL15R - Ablation of of NK cell Development
    Infectious mononucleosis, X-linked lymphoproliferative disease could happen secondary to XSCID
  • 25. Mutagenic CIDs – X Linked
    Wiskott-Aldrich Syndrome
    Absence of isohemagglutins & alteration of
    cell membrane glycoprotein sialophorin (CD43)
    Absence or Low IgM, Elevated IgA, Normal IgG
    Compromised T & B cell fuctions
    Fail to produce antibodies to polysaccharide antigens
    Smaller Lymphocytes with fewer microvilli
    Eczema, Bloody Diarrhea, Thrombocytopenia
    JAK3 Deficiency
    Cytokine receptors using gamma chains associate with JAK3 tyrosine kinase & major cytokine receptors transducing subunits bind to JAK1
    Expression of JAK3 gene is important for lymphoid development and function
    Defects in JAK3 gene could lead to defective production of lymphocytes
    This 1-year-old boy was noted to have eczema and petechiae
    His history was significant for a subdural hematoma for which trauma
    Was denied; at that time the platelet count was 212,000. His diagnosis of
    Wiskott-Aldrich Syndrome (WAS) was confirmed by the detection of a
    missense mutation (Phe 128 Ser).
        Fig.:  The organization of the Jak homology (JH) domains of the Jak3 protein (Notarangelo and Vihinen 1999).
  • 26. Mutagenic CIDs -Autosomal Recessive
    • Bare Lymphocyte Syndrome
    • 27. Severe defects in both cellular and humoral immune responses
    • 28. MHC Class I deficiency
    • 29. MHC class I molecules not expressed on lymphocyte membranes
    • 30. MHC Class II deficiency
    • 31. Lymphocytes and monocytes
    fail to express class II MHC antigens
    • Agammaglobulinemia,
    diminshed cell-mediated immunity
  • 32. Mutagenic CIDs -Autosomal Recessive
    • ZAP70 Deficiency
    • 33. Absence of CD8+T cells
    • 34. Abundant CD3+/CD4+T lymphocytes
    that don’t respond to TCR mediated
    stimuli, in peripheral blood
    • ZAP70 is a non-src family protein
    tyrosine kinase necessary in T cell
    • ZAP70 needed for physiologic
    development & function of T cells
    • Marked by CD8 lymphocytopenia
  • 35. Omenn’s Syndrome
    Immunoglobulin & TCR recombination genes : RAG (Recombination activation gene) 1 & 2 mutations
    Artemis Defect (VDJ rearrangement)
    Th2 mediated condition; Depleted B cells
    Elevated Serum IgE, Circulating and tissue-infiltrating
    T lymphocytes increased
    Lymph node architecture grossly abnormal
    Characterized by protracted diarrhea, hepatosplenomegaly, hypereosinophilia
    Mutagenic CIDs -Autosomal Recessive
  • 36. Enzyme Deficient CIDs
    Adenosine Deaminase (ADA) Deficiency
    Abnormal ADA or lack of ADA couldn’t
    bind to deoxyadenosine
    Deoxy-adenosine levels rise up
    Kill T and B cells > No Adaptive Immunity
    PNP deficiency
    Purine Nucleoside Phosphorylase Deficiency
    PNP >> involved in purine degradation
    T & B cell development
    Underdeveloped thymus in infants
    Autosomal Recessive
    ADA Deficiency (2010)
  • 37. Treatments
    • Bone Marrow Transplantation OR Hemopoietic Stem Cell Transplantation
    • 38. Somatic Gene Therapy (Retrovirus gene therapy)
    • 39. Passive Administration &/or transfusion of Deficient Antibodies
    • 40. Introduction of Deficient Enzymes (Adenosine Deaminase, Purine Nucleoside Phosphatase)
    Plus, Antibiotics for the recurrent infections!
  • 41. Treatments
    • Various Experiments – Murine Models
    Introduction of Foreign T & B cells
    Steps :
    Radiation Therapy – kill all lymphoid cells
    Introduction of Immune Cells into
    Peripheral blood (transfusion)
    (3) No graft Vs. Host disease <- No Immunity
    • Result – Successful expression of
    immune responses after Therapy
    Currently a treatment option
  • 42. Treatments
    Bone Marrow & Xenogenic
    (1) Radiation Therapy
    (2) Bone Marrow & Thymus
    Fragments Introduced
    (3) No Rejection of Foreign
    Tissue/ Stem Cells
    • Result – Successful !
    Currently a treatment option
  • 43. Somatic Gene Therapy
    (1) Transfection of stem cells
    with normal copy of the genes
    (2) Reinfusion of transfected
    cells into circulation
    • Result - Successful expression of immune responses after the Therapy
    A Potential treatment option
  • 44. References
    • Jeff M. Milunsky, Stephen I. Pelton; Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders.
    • 45. A. Villa, Cristina Sobacchi, Francesca Rucci, Veronica Marella, Jessica Galleani (2009); Genetics of Primary Immunodeficiency's; Institute of Biomedical Technologies, National Research Council
    • 46. Marina Cavazzana-Calvo and Alain Fischer (Jun 2007); Gene therapy for severe combined immunodeficiency: are we there yet? ; J. Clin. Invest. 117:6 doi:10.1172/JCI30953
    Karin Pike-Overzet, Mirjam van der Burg, Gerard Wagemaker, Jacques JM van Dongen and Frank JT Staal (2007); New Insights and Unresolved Issues Regarding Insertional Mutagenesis in X-linked SCID Gene Therapy; Molecular Therapy; 15 11, 1910–1916. doi:10.1038/
    Adenosine Deaminase Deficiency (2010); Genetics Sci Learning Center; University of Utah. <>
    Regulation of B cell development (2006); <>
    Notarangelo LD, Vihinen M.  1999.  JAK3base: Mutation registry for autosomal recessive severe combined JAK3 deficiency.  <> 
    • ZAP 70;
    • 47. The Case of the Missing Enzyme:
    • 48. JAK3:
    • 49. Chapter 21 Immunodeficiency Diseases; The Immune System in Health and Disease – Part IV.
    • 50. Chapter 7 Organization of Expression of Immunoglobulin Genes; Part II - Generation of B-Cell & T-Cell Responses.
    • 51. Chapter 9 Failures of the Body’s Defenses; Inherited Immunodeficiency Diseases.
    • 52. Atlas of Immunology; Immunodeficiences: Congenital & Acquired.
    • 53. Chapter 3 Antigen Recognition by T Lymphocytes; T-cell Receptor Diversity & Antigen Processing and Presentation.
  • Any Questions?
  • 54. Thanks