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
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
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
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 !
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 ?
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
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
38.
39.
40.
41.
42.
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
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
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