Combined Immunodeficiency and/or Severe Combined Immunodeficiency

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

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.

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 deficienciesT cell (www.lbl.gov/Publications/Currents/Archive/Oct-03-2003.html#head0) Regulation of B Cell Development (2007) (www.tmd.ac.jp/med/mbch/projects_English.htm)

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 SyndromeCavazzana & 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).

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

33. Absence of CD8+T cells

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 www.itb.cnr.it/flex/images/D.f910a9dcfd7a58b35d44/infant_omenn_syndrome.jpg

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 wikipedia/commons/c/c6/Adenosine_deaminase_1VFL.png http://necat.chem.cornell.edu/Structures2/Struct_Pic2/3GGS.jpg ADA Deficiency (2010)

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!

45. A. Villa, Cristina Sobacchi, Francesca Rucci, Veronica Marella, Jessica Galleani (2009); Genetics of Primary Immunodeficiency's; Institute of Biomedical Technologies, National Research Council

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.

54. Thanks