WHO ARE AT RISK
      FOR
MYCOBACTERIAL
  INFECTION ?



          w.pongsak
scope
   MSMD
   Acquired IFN-γ deficiency
   Innate immunity defects
   Quiz
Main 1
T / NK cell   DC
MSMD
 Many types of PID predispose to mycobacterial
  infection
 One type that specific for mycobacterial infection is

...
1.24
MOST COMMON
   IFNGR1 deficiency
   IFNGR2 deficiency
   IL-12p40 deficiency
   IL-12Rβ1 deficiency
   STAT-1 deficiency
   NEMO...
Main 1
Main 1
IFNγR1 deficiency
 Complete IFNγR1 deficiency
 - loss of expression of receptor at cell surface
 - BCG infection and envi...
 Partial IFNγR1 deficiency
 - Mixed of wild-type and mutant type in cell surface
 - impair recycling of impaired receptor...
Main 1
IFNγR2 deficiency
 Complete deficiency
 - signal transducing chain of the IFNγ receptor
 - tightly regulate than IFNγR1 c...
Main 1
IL12p40 deficiency
- homozygous frameshift mutation
- Mortality 38 %
- cause of infection same as other phenotype
- severe...
Main 1
IL12Rβ1 deficiency
- most common in MSMD
- loss of surface expression of IL12Rβ1 on activated T cell
- complete absence re...
Impaired IFNα/β , IL-6, IL-10 pathway




            Main 1
Main 1
= GAF
Stat 1 deficiency
- Stat 1 is required for both type I/II IFN
- in pathway of type II IFN the product is GAF
- clinical ph...
Main 1
NEMO defects

- NEMO is critical and non redundant component of
   NF-кB
- itself no catalytic activity
- hypomorphic muta...
Acquired IFN-γ Deficiency

   Case report in world-wild
   Neutralizing Auto-antibodies to IFN-γ
   Demonstrate Auto-an...
J immuno
Innate immunity & Mycobacterium

   Neutrophils
   Natural Killer cells
   Toll Like receptors
   MyD 88
   IL-18
Innate immunity & Mycobacterium
Toll Like Receptors




  Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
Toll Like Receptors
 TLR2 detect mycobacterial p19 lipoprotein
 TLR4 detect heat sensitive ligand
 TLR9 detect intracel...
Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
 In animal model
 - TLR 2/4/9 KO mice enhance mortality


                          (A Bafica et al. J.Exp Med 202 ; 1715...
MyD 88
   Adaptor molecule
   Also liking receptor for IL-1β and IL-18
   IL-1β => protective role in TB
   In animal ...
MyD 88




         Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
IL-18
Take home message
 Mycobacterial infection can occur in multiple
  type of PID
 MSMD “ what did you know?”
 Defect in i...
QUIZ
1. What is the most frequent type of MSMD ?
   a. XR
   b. AR
   c. AD
   d. polygenic
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...
3. A defect in the gene for which of the following
   cytokines is associated with MSMD ?
   a. IFN-γ
   b. IL-12
   c. IL...
4.Patients with an impaired IL-12/23 pathway
  have high incidence of infection with …
  a. Streptococcus pneumoniae
  b. ...
5. Which of the following mechanisms
  stimulates the STAT-1 pathway infection
  with mycobacteria species
  a. IFN-α/β ac...
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 ...
7.Which type of PID that not increase risk for
  mycobacterial dis ?
  a. HIEs
  b. HIGM
  c. SCID
  d. Artemis deficiency...
8. What type of MSMD is X-link disease ?
   a. IFNγR1 deficiency
   b. IFNγR2 deficiency
   c. STAT1 defect
   d. NEMO def...
THANK YOU
     FOR
YOUR ATTENTION
1.28
taiwan
Main 2
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
Who are at risk for mycobacterial infections
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Who are at risk for mycobacterial infections

  1. 1. WHO ARE AT RISK FOR MYCOBACTERIAL INFECTION ? w.pongsak
  2. 2. scope  MSMD  Acquired IFN-γ deficiency  Innate immunity defects  Quiz
  3. 3. Main 1
  4. 4. T / NK cell DC
  5. 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. 6. 1.24
  7. 7. MOST COMMON
  8. 8.  IFNGR1 deficiency  IFNGR2 deficiency  IL-12p40 deficiency  IL-12Rβ1 deficiency  STAT-1 deficiency  NEMO defect
  9. 9. Main 1
  10. 10. Main 1
  11. 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. 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. 13. Main 1
  14. 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. 15. Main 1
  16. 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. 17. Main 1
  18. 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. 19. Impaired IFNα/β , IL-6, IL-10 pathway Main 1
  20. 20. Main 1
  21. 21. = GAF
  22. 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. 23. Main 1
  24. 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. 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. 26. J immuno
  27. 27. Innate immunity & Mycobacterium  Neutrophils  Natural Killer cells  Toll Like receptors  MyD 88  IL-18
  28. 28. Innate immunity & Mycobacterium
  29. 29. Toll Like Receptors Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
  30. 30. Toll Like Receptors  TLR2 detect mycobacterial p19 lipoprotein  TLR4 detect heat sensitive ligand  TLR9 detect intracellular mycobacteria
  31. 31. Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
  32. 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. 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. 34. MyD 88 Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
  35. 35. IL-18
  36. 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. 37. QUIZ 1. What is the most frequent type of MSMD ? a. XR b. AR c. AD d. polygenic
  38. 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. 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. 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. 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. 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. 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. 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. 45. THANK YOU FOR YOUR ATTENTION
  46. 46. 1.28
  47. 47. taiwan
  48. 48. Main 2

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