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Mendelian susceptibility to mycobacterial diseases: An overview

Gulbu Uzel, MD
Section Editor
Jennifer M Puck, MD
Deputy Editor
Elizabeth TePas, MD, MS


Mendelian susceptibility to mycobacterial diseases (MSMD, MIM #209950) is caused by genetic defects in the mononuclear phagocyte/T helper cell type 1 (Th1) pathway [1]. Even though the name MSMD implies infections with mycobacteria only, infections with other pathogens have been described with this disorder. Typically, patients with MSMD have increased susceptibility to systemic infections caused by pathogens with varying degrees of virulence, from weakly virulent environmental nontuberculous mycobacteria (NTM), to Bacillus Calmette-Guérin (BCG), to disseminated infection with Mycobacterium bovis or Mycobacterium tuberculosis (TB). Other infections encountered in these genetically determined defects of host defense include intracellular pathogens other than mycobacteria, such as Salmonella species, Listeria, Leishmania, Candida (chronic mucocutaneous candidiasis), fungi (histoplasmosis, paracoccidioidomycosis, coccidioidomycosis), and viruses (cytomegalovirus virus [CMV], human herpesvirus 8 (HHV8), pseudorabies virus 3 [PRV3], respiratory syncytial virus [RSV], and varicella-zoster virus [VZV]). Common to all the infections seen in MSMD are defects in the interferon gamma (IFN-gamma)-interleukin 12 (IL-12) pathway and/or supporting accessory pathways (figure 1). This topic reviews the pathogenesis, typical presentation, diagnosis, and general management of MSMD. Specific forms of MSMD are reviewed separately. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)


Host defense against pathogenic (M. tuberculosis [TB]) and nontuberculous (atypical) mycobacteria (M. fortuitum, M. chelonae, M. abscessus, M. avium complex, M. kansasii, M. simiae, and M. marinum), as well as salmonellae, depends heavily upon the functional integrity of mononuclear phagocytes and their interaction with T cells. Interferon gamma (IFN-gamma), a pleiotropic T helper cell type 1 (Th1)-type cytokine, is a principal factor in the elimination of both TB and the nontuberculous group of mycobacteria (NTM) [2]. It is also essential in the control of certain bacterial, parasitic, and viral infections [3-9]. (See "Pathogenesis of nontuberculous mycobacterial infections".)

Macrophages infected with mycobacteria produce the cytokine interleukin 12 (IL-12, which is a heterodimer of IL-12 p40 plus IL-12 p35) [10]. IL-12 stimulates T cells and natural killer (NK) cells via its heterodimeric receptor (IL-12Rbeta1 plus IL-12Rbeta2). In response to stimulation with IL-12, activated T cells and NK cells produce IFN-gamma (figure 1). IFN-gamma binds to its receptor, IFN-gamma-R1, with high affinity, leading to receptor dimerization. This is followed by aggregation of two accessory chains (IFN-gamma-R2) with the receptor complex. IFN-gamma-R2 is required for signal transduction.

Transphosphorylation of Janus kinase 1 and 2 (JAK1 and JAK2), the Janus kinases that are constitutively associated with IFN-gamma-R1 and IFN-gamma-R2 respectively, occurs next [11]. The subsequent signaling event is the tyrosine phosphorylation of the latent cytosolic transcription factor signal transducer and activator of transcription 1 (STAT1), which is followed by homodimerization and translocation of STAT1 to the nucleus as a complex (figure 2).

This initiates the transcription of IFN-gamma-regulated genes [12,13]. One of the results of IFN-gamma activation on phagocytes is the production of tumor necrosis factor alpha (TNF-alpha). In addition, there is further upregulation of IL-12 production. At this point, IFN-gamma also promotes mycobacterial killing, for which the mechanism remains unknown.

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Literature review current through: Nov 2017. | This topic last updated: Sep 27, 2017.
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