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  • 1. WHO ARE AT RISK FOR MYCOBACTERIAL INFECTION ? w.pongsak
  • 2. scope  MSMD  Acquired IFN-γ deficiency  Innate immunity defects  Quiz
  • 3. Main 1
  • 4. T / NK cell DC
  • 5. MSMD  Many types of PID predispose to mycobacterial infection  One type that specific for mycobacterial infection is “ MSMD”  “Medelian susceptibility to mycobacterial diseases”  Defect in IL-12/23-IFN-γ circuit  Compose of 6 syndromes
  • 6. 1.24
  • 7. MOST COMMON
  • 8.  IFNGR1 deficiency  IFNGR2 deficiency  IL-12p40 deficiency  IL-12Rβ1 deficiency  STAT-1 deficiency  NEMO defect
  • 9. Main 1
  • 10. Main 1
  • 11. IFNγR1 deficiency  Complete IFNγR1 deficiency - loss of expression of receptor at cell surface - BCG infection and environmental mycobacteria - majority of patients death before 3 yrs old - other infection => non-typhoidal salmonella ,Listeria, some viral infection ( rare, individual pts.) - pathology => multibacillary,poorly organized granuloma - prognosis is poor - Therapeutic option is BMT
  • 12.  Partial IFNγR1 deficiency - Mixed of wild-type and mutant type in cell surface - impair recycling of impaired receptor - less severe disease and curable with prolong antibiotic - BCG and NTM infection, non typhoidal infection - can control dis with IFNγ Rx - several patients had clinical liked histiocytosis X
  • 13. Main 1
  • 14. IFNγR2 deficiency  Complete deficiency - signal transducing chain of the IFNγ receptor - tightly regulate than IFNγR1 chain - accumulation of abnormal protein in cytoplasm - clinical phenotype severe as in IFNγR1 ( splenomegaly)  Partial deficiency - missense mutation - impaired response to IFNγ - molecular mechanism is unclear
  • 15. Main 1
  • 16. IL12p40 deficiency - homozygous frameshift mutation - Mortality 38 % - cause of infection same as other phenotype - severe than IL-12 Rβ1 deficiency - higher incidence of Salmonella infection - can correct defect with rec.IL-12 - good prognosis - treatment with antimicrobial and recombinant IFN-γ Also defect in IL23/17 circuit !
  • 17. Main 1
  • 18. IL12Rβ1 deficiency - most common in MSMD - loss of surface expression of IL12Rβ1 on activated T cell - complete absence response to IL12/23 - milder clinical phenotype than IFNγ dependent - IL-12 independent pathway - 45% develop infection to mycobacterium and salmonella - mortality 11% ,good prognosis ( J Exp Med 2003;197:527-35) - Rx antmicrobial agent and rec.IFN-γ as need TyK2 deficiency ?
  • 19. Impaired IFNα/β , IL-6, IL-10 pathway Main 1
  • 20. Main 1
  • 21. = GAF
  • 22. Stat 1 deficiency - Stat 1 is required for both type I/II IFN - in pathway of type II IFN the product is GAF - clinical phenotype less severe than other type - good prognosis - not require HSCT
  • 23. Main 1
  • 24. NEMO defects - NEMO is critical and non redundant component of NF-кB - itself no catalytic activity - hypomorphic mutation - X link recessive disease - EDA-ID susceptibility to many type of infection - recently, NEMO mutation susceptibility to mycobacterial infection without EDA-ID
  • 25. Acquired IFN-γ Deficiency  Case report in world-wild  Neutralizing Auto-antibodies to IFN-γ  Demonstrate Auto-antibodies in serum  The patients experienced disseminated tuberculosis as well as NTM infections
  • 26. J immuno
  • 27. Innate immunity & Mycobacterium  Neutrophils  Natural Killer cells  Toll Like receptors  MyD 88  IL-18
  • 28. Innate immunity & Mycobacterium
  • 29. Toll Like Receptors Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
  • 30. Toll Like Receptors  TLR2 detect mycobacterial p19 lipoprotein  TLR4 detect heat sensitive ligand  TLR9 detect intracellular mycobacteria
  • 31. Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
  • 32.  In animal model - TLR 2/4/9 KO mice enhance mortality (A Bafica et al. J.Exp Med 202 ; 1715-24) (J.M.Blander et al. Science 304 1014-18) (R.M Yates et al. Immunity 23 409-17) - TLR 2/4/9 deficient mice keep infection of mycobacterium similar as wild type Role of TLRs in innate and adaptive response to MycobacteriumJ is still28;2008:680-94) (Hoelscher et al. Eur Immuno controversial !
  • 33. MyD 88  Adaptor molecule  Also liking receptor for IL-1β and IL-18  IL-1β => protective role in TB  In animal model MyD 88 Ko mice slightly increase susceptibility to mycobacterium (Hoelscher et al. Eur J Immuno 28;2008:680-94)  Some experimental result was different from above data ( Suragawa. Microbio Immuno 47;84:2003)
  • 34. MyD 88 Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
  • 35. IL-18
  • 36. Take home message  Mycobacterial infection can occur in multiple type of PID  MSMD “ what did you know?”  Defect in innate immunity can increase susceptibility to mycobacterial infection  In adult mycobacterial infection may caused by autoantibodies to IFN-γ
  • 37. QUIZ 1. What is the most frequent type of MSMD ? a. XR b. AR c. AD d. polygenic
  • 38. 2.Which of the following genes has not been identified as a cause for MSMD ? a. IFNGR2 b. stat 1 c. stat 3 d. IL-12 B
  • 39. 3. A defect in the gene for which of the following cytokines is associated with MSMD ? a. IFN-γ b. IL-12 c. IL-2 d. IL-10
  • 40. 4.Patients with an impaired IL-12/23 pathway have high incidence of infection with … a. Streptococcus pneumoniae b. Pneumocystis c. Salmonella d. Staphylococcus e. Klebsella
  • 41. 5. Which of the following mechanisms stimulates the STAT-1 pathway infection with mycobacteria species a. IFN-α/β activate GAF b. IFN-γ activate GAF c. IFN-δ activate ISGF 3 d. IFN- γ activate ISGF 3
  • 42. 6. Which type of Ab that neutralized IFN- γ in Acquired IFN- γ Deficiency? a. Ig A b. Ig G1 c. Ig G2 d. Ig G3 e. Ig G4
  • 43. 7.Which type of PID that not increase risk for mycobacterial dis ? a. HIEs b. HIGM c. SCID d. Artemis deficiency e. LAD
  • 44. 8. What type of MSMD is X-link disease ? a. IFNγR1 deficiency b. IFNγR2 deficiency c. STAT1 defect d. NEMO defect e. IL-12 deficiency
  • 45. THANK YOU FOR YOUR ATTENTION
  • 46. 1.28
  • 47. taiwan
  • 48. Main 2