Who are at risk for mycobacterial infections
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Transcript of Who are at risk for mycobacterial infections
WHO ARE AT RISK WHO ARE AT RISK FOR MYCOBACTERIAL FOR MYCOBACTERIAL
INFECTION ?INFECTION ?
w.pongsakw.pongsak
scopescope
MSMDMSMD Acquired IFN-Acquired IFN-γγ deficiency deficiency Innate immunity defectsInnate immunity defects QuizQuiz
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T / NK cell DC
MSMDMSMD
Many types ofMany types of PID predispose to mycobacterial PID predispose to mycobacterial infectioninfection
One type that specific for mycobacterial infection is One type that specific for mycobacterial infection is
““ MSMD”MSMD” ““Medelian susceptibility to mycobacterial diseases”Medelian susceptibility to mycobacterial diseases” Defect in IL-12/23-IFN-Defect in IL-12/23-IFN-γγ circuit circuit Compose of 6 syndromesCompose of 6 syndromes
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MOST COMMON
IFNGR1 deficiencyIFNGR1 deficiency IFNGR2 deficiencyIFNGR2 deficiency IL-12p40 deficiencyIL-12p40 deficiency IL-12RIL-12Rββ1 1 deficiencydeficiency STAT-1 STAT-1 deficiencydeficiency NEMO NEMO defectdefect
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IFNIFNγγR1 deficiencyR1 deficiency
Complete IFNComplete IFNγγR1 deficiencyR1 deficiency
- loss of expression of receptor at- loss of expression of receptor at cell surface cell surface
- BCG infection and environmental mycobacteria- BCG infection and environmental mycobacteria
- majority of patients death before 3 yrs old- majority of patients death before 3 yrs old
- other infection => non-typhoidal salmonella ,Listeria, some - other infection => non-typhoidal salmonella ,Listeria, some
viral infection ( rare, individual pts.)viral infection ( rare, individual pts.)
- pathology => multibacillary,poorly organized granuloma- pathology => multibacillary,poorly organized granuloma
- prognosis is poor- prognosis is poor
- Therapeutic option is BMT - Therapeutic option is BMT
Partial IFNPartial IFNγγR1 deficiencyR1 deficiency
- Mixed of wild-type and mutant type in cell surface- Mixed of wild-type and mutant type in cell surface
- impair recycling of impaired receptor- impair recycling of impaired receptor
- less severe disease and curable with prolong antibiotic - less severe disease and curable with prolong antibiotic
- BCG and NTM infection, non typhoidal infection- BCG and NTM infection, non typhoidal infection
- can control dis with IFN- can control dis with IFNγγ Rx Rx
- several patients had clinical liked histiocytosis X- several patients had clinical liked histiocytosis X
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IFNIFNγγR2 deficiencyR2 deficiency Complete deficiencyComplete deficiency
- signal- signal transducing chain of the IFNtransducing chain of the IFNγγ receptor receptor
- tightly regulate than IFN- tightly regulate than IFNγγR1 chainR1 chain
- accumulation of abnormal protein in cytoplasm- accumulation of abnormal protein in cytoplasm
- clinical phenotype severe as in IFN- clinical phenotype severe as in IFNγγR1 ( splenomegaly)R1 ( splenomegaly)
Partial deficiencyPartial deficiency
- missense mutation- missense mutation
- impaired response to IFN- impaired response to IFNγγ
- molecular mechanism is unclear- molecular mechanism is unclear
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IL12p40 deficiencyIL12p40 deficiency
- homozygous- homozygous frameshift mutationframeshift mutation
- Mortality 38 %- Mortality 38 %
- cause of infection same as other phenotype- cause of infection same as other phenotype
- severe than IL-12 R- severe than IL-12 Rββ1 deficiency1 deficiency
- higher incidence of Salmonella infection- higher incidence of Salmonella infection
- can correct defect with rec.IL-12- can correct defect with rec.IL-12
- good prognosis- good prognosis
- treatment with antimicrobial and recombinant IFN-- treatment with antimicrobial and recombinant IFN-γγ
Also defect in IL23/17 circuit ! Also defect in IL23/17 circuit !
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IL12RIL12Rββ1 deficiency1 deficiency
- most common in MSMD- most common in MSMD - loss of surface expression of IL12R- loss of surface expression of IL12Rββ1 on activated T cell1 on activated T cell - complete absence response to IL12/23- complete absence response to IL12/23 - - milder clinical phenotype than IFNmilder clinical phenotype than IFNγγ dependent dependent - IL-12 independent pathway- IL-12 independent pathway - 45% develop infection to mycobacterium and salmonella- 45% develop infection to mycobacterium and salmonella - mortality 11% ,good prognosis- mortality 11% ,good prognosis ( J Exp Med 2003;197:527-35) ( J Exp Med 2003;197:527-35)
- Rx antmicrobial agent and rec.IFN-- Rx antmicrobial agent and rec.IFN-γγ as need as need
TyK2 deficiencyTyK2 deficiency ??
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Impaired IFNα/β , IL-6, IL-10 pathway
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= GAF
Stat 1 deficiencyStat 1 deficiency
- Stat 1 is required for both type I/II IFN- Stat 1 is required for both type I/II IFN
- in pathway of type II IFN the product is GAF- in pathway of type II IFN the product is GAF
- clinical phenotype less severe than other type- clinical phenotype less severe than other type
- good prognosis- good prognosis
- not require HSCT- not require HSCT
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NEMO defectsNEMO defects
- NEMO is critical and non redundant component of - NEMO is critical and non redundant component of
NF-NF-ккBB
- itself no catalytic activity- itself no catalytic activity
- hypomorphic mutation - hypomorphic mutation
- - X link recessive diseaseX link recessive disease
- EDA-ID susceptibility to many type of infection- EDA-ID susceptibility to many type of infection
- recently, NEMO mutation susceptibility to - recently, NEMO mutation susceptibility to mycobacterial infection without EDA-ID mycobacterial infection without EDA-ID
Acquired IFN-Acquired IFN-γγ Deficiency Deficiency
Case report in world-wildCase report in world-wild Neutralizing Auto-antibodies to IFN-Neutralizing Auto-antibodies to IFN-γγ Demonstrate Auto-antibodies in serumDemonstrate Auto-antibodies in serum The patients experienced disseminated The patients experienced disseminated
tuberculosis as well as NTM infectionstuberculosis as well as NTM infections
J immuno
Innate immunity & MycobacteriumInnate immunity & Mycobacterium
NeutrophilsNeutrophils Natural Killer cellsNatural Killer cells Toll Like receptorsToll Like receptors MyD 88MyD 88 IL-18IL-18
Innate immunity & MycobacteriumInnate immunity & Mycobacterium
Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
Toll Like ReceptorsToll Like Receptors
Toll Like ReceptorsToll Like Receptors
TLR2 detect mycobacterial p19 lipoproteinTLR2 detect mycobacterial p19 lipoprotein TLR4 detect heat sensitive ligandTLR4 detect heat sensitive ligand TLR9 detect intracellular mycobacteriaTLR9 detect intracellular mycobacteria
Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
In animal modelIn animal model
- TLR 2/4/9 KO mice enhance mortality- TLR 2/4/9 KO mice enhance mortality
(A Bafica et al. J.Exp Med 202 ; 1715-24)(A Bafica et al. J.Exp Med 202 ; 1715-24)
(J.M.Blander et al. Science 304 1014-18)(J.M.Blander et al. Science 304 1014-18)
(R.M Yates et al. Immunity 23 409-17)(R.M Yates et al. Immunity 23 409-17)
-- TLR 2/4/9 deficient mice keep infection of TLR 2/4/9 deficient mice keep infection of
mycobacterium similar as wild type mycobacterium similar as wild type
(Hoelscher et al. Eur J Immuno 28;2008:680-94)(Hoelscher et al. Eur J Immuno 28;2008:680-94)
Role of TLRs in innate and adaptive response to Mycobacterium is still controversial !
MyD 88MyD 88 Adaptor molecule Adaptor molecule Also liking receptor for IL-1Also liking receptor for IL-1ββ and IL-18 and IL-18 IL-1IL-1ββ => protective role in TB => protective role in TB In animal model MyD 88 Ko mice slightly increase In animal model MyD 88 Ko mice slightly increase
susceptibility to mycobacterium susceptibility to mycobacterium
(Hoelscher et al. Eur J Immuno 28;2008:680-94)
Some experimental result was different from Some experimental result was different from above data above data
( Suragawa. Microbio Immuno 47;84:2003)( Suragawa. Microbio Immuno 47;84:2003)
Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007
MyD 88
IL-18 IL-18
Take home messageTake home message
Mycobacterial infection can occur in multiple Mycobacterial infection can occur in multiple type of PIDtype of PID
MSMD “ what did you know?”MSMD “ what did you know?” Defect in innate immunity can increase Defect in innate immunity can increase
susceptibility to mycobacterial infectionsusceptibility to mycobacterial infection In adult mycobacterial infection may caused In adult mycobacterial infection may caused
by autoantibodies to IFN-by autoantibodies to IFN-γγ
QUIZQUIZ
1.1. What is the most frequentWhat is the most frequent type of MSMD ?type of MSMD ?
a. XRa. XR
b. ARb. AR
c. ADc. AD
d. polygenicd. polygenic
2.Which of the following genes has not been 2.Which of the following genes has not been identified as a cause for MSMD ?identified as a cause for MSMD ?
a. IFNGR2a. IFNGR2
b. stat 1b. stat 1
c. stat 3c. stat 3
d. IL-12 Bd. IL-12 B
3. A defect in the gene for which of the following 3. A defect in the gene for which of the following
cytokines is associated with MSMDcytokines is associated with MSMD ??
a. IFN-a. IFN-γγ
b. IL-12b. IL-12
c. IL-2c. IL-2
d. IL-10 d. IL-10
4.Patients with an impaired IL-12/23 pathway 4.Patients with an impaired IL-12/23 pathway have high incidence of infection with …have high incidence of infection with …
a. Streptococcus pneumoniaea. Streptococcus pneumoniae
b. Pneumocystisb. Pneumocystis
c. Salmonellac. Salmonella
d. Staphylococcusd. Staphylococcus
e. Klebsella e. Klebsella
5. Which of the following mechanisms 5. Which of the following mechanisms stimulates the STAT-1 pathway infection stimulates the STAT-1 pathway infection with mycobacteria specieswith mycobacteria species
a. IFN-a. IFN-αα//ββ activate GAF activate GAF
b. IFN-b. IFN-γγ activate GAF activate GAF
c. IFN-c. IFN-δδ activate ISGF 3 activate ISGF 3
d. IFN- d. IFN- γγ activate ISGF 3 activate ISGF 3
6. Which type of Ab that neutralized IFN- 6. Which type of Ab that neutralized IFN- γγ in in Acquired IFN- Acquired IFN- γγ Deficiency? Deficiency? a. Ig Aa. Ig A b. Ig G1b. Ig G1 c. Ig G2c. Ig G2 d. Ig G3d. Ig G3 e. Ig G4e. Ig G4
7.Which type of PID that not increase risk for 7.Which type of PID that not increase risk for mycobacterial dis ?mycobacterial dis ?
a. HIEsa. HIEs b. HIGMb. HIGM c. SCID c. SCID d. Artemis deficiencyd. Artemis deficiency e. LAD e. LAD
8. What type of MSMD is X-link disease ?8. What type of MSMD is X-link disease ?
a. IFNa. IFNγγR1 deficiencyR1 deficiency
b. b. IFNIFNγγR2 deficiencyR2 deficiency
c. c. STAT1STAT1 defect defect
d. d. NEMONEMO defect defect
e. IL-12 deficiencye. IL-12 deficiency
THANK YOUTHANK YOU FOR FOR
YOUR ATTENTIONYOUR ATTENTION
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