mendelian susceptibility to mycobacterial diseases

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  • Mendelian susceptibility to mycobacterial diseases

    (MSMD)

    Kanlada wongworapat, MD.

    9th September 2016

    Topic review

  • INTRODUCTION

    first reported in 1964 in families with disseminated NTM

    rare congenital syndrome

    named Mendelian susceptibility to mycobacterial diseases

    (MSMD, Picard and others 2006)

    disease caused by weakly virulent mycobacteria such as BCG

    vaccines (disseminated BCG infection), non-tuberculous

    environmental mycobacteria (NTM infection) and recurrent or

    disseminated TB infection

    in otherwise healthy individuals with no overt abnormalities in

    routine hematological and immunological tests

    J. Bustamante et al. Seminars in Immunology 26. 2014; 454470

  • Geographical distribution

    44 countries Asia (China, India,

    Indonesia, Japan, Malaysia, Taiwan, Lebanon, Iran, Israel, Pakistan, Qatar, Saudi Arabia, Sri Lanka, Turkey)

    Saleh Al-Muhsen, et al. J ALLERGY CLIN IMMUNOL. Dec 2008; 1043-51.

  • PATHOGENESIS

    Genetic defects in the IL-12/IFN- pathway

    Saleh Al-Muhsen, et al. J ALLERGY CLIN IMMUNOL. Dec 2008; 1043-51.

  • IL-12/IFN- pathway

    connecting myeloid cells (monocytes, macrophages, and dendritic cells) to lymphoid cells (T cells and natural killer cells)

    Host defense against

    M. tuberculosis (TB)

    Nontuberculous mycobacteria (NTM)

    (M. fortuitum, M. chelonae, M. abscessus, M. avium complex, M. kansasii, M. simiae, and M. marinum)

    Salmonellae

    Saleh Al-Muhsen, et al. J ALLERGY CLIN IMMUNOL. Dec 2008; 1043-51.

  • Macrophage Monocyte

    Dendritic cell

    T-cell NK-cell IFN-

    IL-12

    IL-12

    IL-12/IFN- pathway

  • Macrophage Monocyte

    Dendritic cell

    T-cell NK-cell IFN-

    IL-12

    IL-12

    IL-12/IFN- pathway defect

  • AR IFN- R1 IFN- R2 IL-12R-1 IL-12 p40 (IL12B) STAT1 interferon regulatory factor 8 (IRF8) interferon-stimulated gene 15 (ISG15) tyrosine kinase 2 (TYK2) the zinc-finger transcription factor GATA2 (GATA2)

    XR IKBKG (encodes nuclear factor kappa B essential modulator

    [NEMO]) CYBB (encodes gp91phox)

    IL-12/IFN- pathway defect

    J. Bustamante et al. Seminars in Immunology 26. 2014; 454470

  • Gulbu Uzel, et al. UTD. Aug 2016

  • Gulbu Uzel, et al. UTD. Aug 2016

  • Macrophage Monocyte

    Dendritic cell

    T-cell NK-cell IFN-

    IL-12

    IL-12

    IL-12/IFN- pathway defect

  • Autosomal IFN- R1 IFN- R2 IL-12R-1 IL-12 p40 (IL12B) STAT1 interferon regulatory factor 8 (IRF8) interferon-stimulated gene 15 (ISG15) tyrosine kinase 2 (TYK2) the zinc-finger transcription factor GATA2 (GATA2)

    XR IKBKG (encodes nuclear factor kappa B essential modulator

    [NEMO]) CYBB (encodes gp91phox)

    IL-12/IFN- pathway defect

    J. Bustamante et al. Seminars in Immunology 26. 2014; 454470

  • Weakly pathogenic mycobacteria

    Environmental non-tuberculous mycobacteria (NTM)

    Bacillus Calmette-Gurin (BCG vaccine: M. bovis)

    disseminated BCG infection

    Invasive salmonellosis/ Extraintestinal infection with nontyphoid Salmonella

    Mycobacterium tuberculosis

    Severe viral infection (CMV, HHV8, PRV-3, RSV and VZV)

    Diseases cause by these organisms

    Dorman SE, et al. Lancet 2004; 364:2113.

  • (Rare)

    Intramacrophagic bacteria (listeriosis, nocar-diosis, klebsiellosis)

    Fungi (candidiasis, histoplasmosis, paracoccidioidomycosis, coccidioidomycosis)

    Parasites (leishmaniasis, toxoplasmosis)

    Diseases cause by these organisms

    Dorman SE, et al. Lancet 2004; 364:2113.

  • Organisms

    115 IFN- R1 deficiencies (C and P) 21 IFN- R2deficiencies (C and P) 17 partial STAT1 deficiency

    J. Bustamante et al. Seminars in Immunology 26. 2014; 454470

  • Organisms

    J. Bustamante et al. Seminars in Immunology 26. 2014; 454470

    180 complete IL-12R 1 deficiency 50 completeIL-12p40 deficiency

  • MSMD is misleading name due to other types of intracellular pathogens(eg, Nocardia and Paracoccidioidomyces

    inborn defects of the IL-12/IFN- axis

  • CLINICAL FEATURES

    Complete defects

    onset early childhood

    disseminated disease

    Partial defects or less severe defects

    (IRF8 or IL12RB1 mutations )

    adolescence

    milder recurrent infections

    Dorman SE, et al. Lancet 2004; 364:2113.

  • M.H. Haverkamp et al. Journal of Infection (2014) 68, 134-150

  • M.H. Haverkamp et al. Journal of Infection (2014) 68, 134-150

  • M.H. Haverkamp et al. Journal of Infection (2014) 68, 134-150

  • CLINICAL FEATURES

    Infected strain depend on location

    Routine BCG vaccine: infection with vaccine strain

    Not routine BCG vaccine: infection with M. avium, M. fortuitum, M. chelonae, or M. smegmatis ensues (via environmental exposure)

    Dorman SE, et al. Lancet 2004; 364:2113.

  • Disseminated BCG infection

    within weeks to months of immunization similar to environmental NTM infection few exceptions Draining lymph nodes: enlarge and fistulize to

    skin and surrounding tissues, causing skin and soft tissue infection with direct spread or hematogenous spread to distant sites. Meningitis and osteomyelitis

    Multifocal osteomyelitis: not isolated (difference from environmental atypical mycobacteria

    Dorman SE, et al. Lancet 2004; 364:2113.

  • PID with BCG complications.

  • PID with BCG complications.

    S.Norouzi, et al. Journal of Infection (2012) 64, 543e554

  • Disseminated NTM infection

    nonspecific (fever, weight loss, sweating, diarrhea, generalized lymphadenopathy, generalized cutaneous lesions, diffuse abdominal tenderness, and hepatosplenomegaly)

    Depend on major sites of involvement (eg, bone marrow, lymphoreticular system, gastrointestinal tract, lungs)

    Skin lesions

    Dorman SE, et al. Lancet 2004; 364:2113.

  • Diffuse nodular skin lesions caused by Mycobacterium avium intracellulare complex in a 39-year-old white man with GATA2 deficiency

    Un-In Wu, Steven M Holland. Lancet Infect Dis 2015;15: 96880

  • Multiple erythematous papules on the left leg

  • (C) An unhealed BCG vaccination

    wound on the left arm

    (D) Diffuse bilateral pulmonary nodular

    infiltrates

    (E) Improvement in CXR findings after 2 months of anti-BCG treatment

    (F) Multiple vertebral osteomyelitis over L1e2 and L5 (shown by arrows) in MRI (G) A large and difficult-to-heal wound on the right knee

    (H) The wound improved after 2

    months of antibiotic treatment against Mycobacterial abscessus.

    Li-Hui Wang. Journal of Microbiology, Immunology and Infection (2012) 45, 411e417

  • DIAGNOSIS

    Un-In Wu, Steven M Holland. Lancet Infect Dis 2015;15: 96880

  • DIAGNOSIS 1st step testing for presence or absence of proteins involved in

    IFN- pathway

    cytokine secretion after leukocyte stimulation

    cell-surface receptor on monocytes and lymphocytes analysis by flow cytometry

    examination of signaling by intracellular staining (eg, lack of STAT1 phosphorylation in response to IFN-gamma or STAT4 phosphorylation in response to IL-12) or western blot

    Wang LH, et al. J Microbiol Immunol Infect 2012; 45:411.

  • DIAGNOSIS

    2nd step Identification of the genetic defect

    cDNA sequencing of the gene

    next-generation sequencing techniques (in cases which cannot identify specific defect)

    50% patients with disseminated non-tuberculous mycobacterial diseases: no identified defects in the interleukin 12interferon axis

    Wang LH, et al. J Microbiol Immunol Infect 2012; 45:411.

  • Known genetic defect

    J. Bustamante et al. Seminars in Immunology 26. 2014; 454470

  • Known genetic defect

    J. Bustamante et al. Seminars in Immunology 26. 2014; 454470

  • 406 MSMD patients

    J. Bustamante et al. Seminars in Immunology 26. 2014; 454470

  • J. Bustamante et al. Seminars in Immunology 26. 2014; 454470

  • DIFFERENTIAL DIAGNOSIS

    HIV Other T cell immunodeficiencies

    SCID

    ectodermal dysplasia with immunodeficiency (EDID) due to mutations in NF-kappa B

    essential modifier (NEMO)

    CGD

    Hairy cell leukaemia

  • DIFFERENTIAL DIAGNOSIS

    autoantibodies to IFN- adult-onset disseminated mycobacterial

    infection

    Asian, no familial clustering

    INV: high titers of anti-IFN-gamma antibodies with neutralizing activity

    Additional treatment: IVIG, plasmapheresis, or anti-B cell targeted therapy

    Browne SK,et al. N Engl J Med 2012; 367:725.

  • Browne SK, et al. N Engl J Med. August, 2012; 367:725-734

  • Browne SK, et al. N Engl J Med. August, 2012; 367:725-734

  • group 1: disseminated NTM

    group 2: other opportunistic infections w or w/o NTM

    group 3: disseminated tuberculosis

    group 4: pulmonary tuberculosis

    Group 5: healthy controls Browne SK, et al. N Engl J Med. August, 2012; 367:725-734

  • Browne SK, et al. N Engl J Med. August, 2012; 367:725-734

  • Browne SK, et al. N Engl J Med. August, 2012; 367:725-734

  • Lee WI, et al. Immunobiology 2013; 218:762.

  • Lee WI, et al. Immu