People with certain primary immunodeficiencies (PIDs) are at higher risk for mycobacterial infections. One type of PID that specifically increases risk is called Mendelian susceptibility to mycobacterial disease (MSMD). MSMD involves defects in the IL-12/IFN-γ pathway that are important for controlling mycobacterial infections. The most common forms of MSMD involve mutations affecting IFN-γ receptor 1 (IFNGR1), IFNGR2, IL-12p40, or IL-12Rβ1. Acquired IFN-γ deficiency from neutralizing autoantibodies can also increase risk for mycobacterial infections. Defects in innate immunity components like

1. WHO ARE AT RISK
FOR
MYCOBACTERIAL
INFECTION ?
w.pongsak

2. scope
 MSMD
 Acquired IFN-γ deficiency
 Innate immunity defects
 Quiz

4. Main 1

5. T / NK cell DC

6. 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

7. 1.24

8. MOST COMMON

11.  IFNGR1 deficiency
 IFNGR2 deficiency
 IL-12p40 deficiency
 IL-12Rβ1 deficiency
 STAT-1 deficiency
 NEMO defect

13. Main 1

14. Main 1

15. 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

16.  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

22. Main 1

23. 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

24. Main 1

25. 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 !

28. Main 1

30. 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 ?

31. Impaired IFNα/β , IL-6, IL-10 pathway
Main 1

33. Main 1

34. = GAF

35. 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

36. Main 1

37. 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

43. 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

49. J immuno

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

52. Innate immunity & Mycobacterium

53. Toll Like Receptors
Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007

54. Toll Like Receptors
 TLR2 detect mycobacterial p19 lipoprotein
 TLR4 detect heat sensitive ligand
 TLR9 detect intracellular mycobacteria

55. Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007

56.  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 !

57. 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)

58. MyD 88
Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007

61. IL-18

65. 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

66. QUIZ
1. What is the most frequent type of MSMD ?
a. XR
b. AR
c. AD
d. polygenic

67. 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

68. 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

69. 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

70. 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

71. 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

72. 7.Which type of PID that not increase risk for
mycobacterial dis ?
a. HIEs
b. HIGM
c. SCID
d. Artemis deficiency
e. LAD

73. 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

74. THANK YOU
FOR
YOUR ATTENTION

75. 1.28

76. taiwan

77. Main 2