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  1. p. 463 Ch. 20

  2. Ch. 20. AIDS and Other Immunodeficiencies Primary: affects either adaptive or innate immunity inherited developmental Secondary: exposure to viruses and other agents Consequence: infection, life-threatening Ch. 20

  3. p. 494 Ch. 20

  4. Severity depends on the number and type of immune system aspects involved Earlier developmental defects are more severe Reticular dysgenesis- cells do not differentiate during hematopoiesis No lymphocytes No phagocytes Ch. 20

  5. p. 495 Ch. 20

  6. SCID: Severe Combined Immunodeficiency Lymphoid cells are depleted Thymus does not develop Usually fatal without intervention Ch. 20

  7. Several causes of SCID Lack of  chain of IL-2 receptor also affects signaling through IL-4,-7,-9,-15 ADA (adenosine deaminase) deficiency Defects in signal transduction or transcription Deficiencies in MHC Class I or Class II synthesis Ch. 20

  8. p. 497 Ch. 20

  9. Ch. 20

  10. p. 496 Ch. 20

  11. Specialized immunodeficiencies Phagocytic fewer phagocytes or reduction in function (chemotaxis, extravasation, killing) Increased susceptibility to infections S. aureus, S. pneumoniae, E. coli, Pseudomonas, Candida, Aspergillus Ch. 20

  12. Neutrophil reduction Neutropenia and worse congenital or acquired radiation or drugs autoimmune syndromes (e.g., SLE) can be temporary neonatal neutropenia – Ab’s from mother Ch. 20

  13. Loss of function LAD (leukocyte adhesion deficiency) cells cannot adhere to endothelial cells killer cells (CTL, NK) can’t adhere to targets Th and B cells can’t form conjugates Defect in synthesis of beta-chain of integrin adhesion molecules Lazy-leukocyte syndrome Ch. 20

  14. Killing defects Chronic granulomatous disease (X-linked) (CGD) Neutrophils can phagocytose bacteria but can’t kill them Defect in oxygen metabolism; can’t produce H2O2 Ch. 20

  15. Humoral deficiencies X-linked agammaglobulinemia (XLA) first immunodeficiency defined Pre-B cells do not progress to mature B cells all isotypes affected Defect in Bruton’s tyrosine kinase heavy-chain genes are rearranged but light chain genes are not Ch. 20

  16. Diagnosed by serum electrophoresis (gamma-globulin is severely reduced) Treated with gamma-globulin Still susceptible to pulmonary infections; lack of secretory IgA Ch. 20

  17. X-linked hyper-IgM Lack of CD40L on their Th cells CD40-CD40L interaction required for B cell response to T-dependent antigens no class switching no memory cells no germinal centers in lymphoid organs Ch. 20

  18. Late-onset problems: various possible causes Inability to switch from membrane-bound to secreted form Structural defect in antibody B cells do not respond to cytokines Ch. 20

  19. p. 499 Ch. 20

  20. Selective IgA deficiency very common (1:600-800) Asymptomatic or Recurrent GI and respiratory infections Tend to have more allergic reactions Complement deficiencies result in either: Immunodeficiency (infections) and/or immune complex disease Ch. 20

  21. Cell-mediated deficiencies Increased susceptibility to viral, protozoan, fungal diseases Usually innocuous microbes can become life-threatening Tend to affect humoral responses, too Ch. 20

  22. DiGeorge syndrome Lack of thymus (also defects in parathyroid and aortic arches) Diagnosis: low T cell count, no DTH, decreased T cell activity Treatment: fetal thymus grafts Ch. 20

  23. p. 500 Ch. 20

  24. p. 503 Ch. 20

  25. Nude mice: no CMI Little antibody response Death within 6 months Can tolerate grafts Thymus transplants can restore immune competence Ch. 20

  26. To summarize, treatments for immunodeficiencies: replacement of defective element: * missing protein * missing cell type or lineage * missing or defective gene Ch. 20

  27. Thus, pooled human gamma-globulin (Ab’s) for agammaglobulinemia Recombinant gamma-interferon for CGD Recombinant IL-2 for AIDS patients Recombinant ADA for ADA-deficient SCID patients Gene therapy for ADA-deficiency and CGD, p67phox-deficiency: CD34+ stem cells from pt. transfected with normal copy of defective gene) Cell replacement: bone marrow transplantation CD34+ stem cells from HLA-matched donor Ch. 20

  28. SCID mice- autosomal recessive mutation no B or T cells, other cells functional can be cured with bone marrow transplant RAG knockout mice have also been developed Knockout mice can be “designed” with specific immune deficiencies SCID-hu mouse is engrafted with human fetal liver, adult thymus and lymph nodes Ch. 20

  29. SCID-hu Mice – discussed on p. 504 Ch. 20

  30. Secondary immunodeficiencies Acquired hypogammaglobulinemia Immune suppression Agent-induced immunodeficiency AIDS, caused by HIV-1 retrovirus Ch. 20

  31. p. 505 Ch. 20

  32. p. 506 Ch. 20

  33. p. 508 Ch. 20

  34. Ch. 20

  35. p. 509 Ch. 20

  36. p. 510 Ch. 20

  37. Ch. 20

  38. p. 511 Ch. 20

  39. Ch. 20

  40. Ch. 20

  41. p. 512 Ch. 20

  42. p. 513 Ch. 20

  43. Ch. 20 p. 516

  44. Ch. 20

  45. p. 515 Ch. 20

  46. p. 516 Ch. 20

  47. Categories of drugs – p. 517 Reverse transcriptase inhibitors nucleoside analogs nonnucleoside analogs Protease inhibitors Fusion inhibitor Lots of drugs, lots of side effects Combinations lower viral load Ch. 20

  48. p. 517 Ch. 20

  49. p. 519 Ch. 20

  50. Summary Immune deficiencies are either primary (genetic, developmental) Or acquired (infection, radiation, HIV, immunosuppressive treatment) Classified by type of cell(s) compromised Treatments: replacement: bone marrow, gene therapy less extreme: antibody therapy, drugs Ch. 20