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
“ MSMD”
 “Medelian susceptibility to mycobacterial diseases”
 Defect in IL-12/23-IFN-γ circuit
 Compose of 6 syndromes

1.24

MOST COMMON

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

Main 1

Main 1

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

 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

Main 1

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

Main 1

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 !

Main 1

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 ?

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 phenotype less severe than other type
- good prognosis
- not require HSCT

Main 1

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

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

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 intracellular mycobacteria

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 ; 1715-24)
(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 !

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)

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 innate immunity can increase
susceptibility to mycobacterial infection
 In adult mycobacterial infection may caused
by autoantibodies to IFN-γ

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-12 B

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

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

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

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

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

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

THANK YOU
FOR
YOUR ATTENTION

1.28

taiwan

Main 2