Mendelian susceptibility to mycobacterial disease
| Mendelian susceptibility to mycobacterial disease |
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Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disease. It is a primary immunodeficiency featured by molecular defects in IL12/IFNγ dependent signalling pathway, leading to increased susceptibility to local or disseminated infections by environmental mycobacteria, Mycobacterium bovis Bacille Calmette-Guerin strain, nontyphoidal and typhoidal Salmonella serotypes.[1][2][3]
Cause and Pathophysiology
Phagocytes are important components of the innate immune system for the body defence against infections by mycobacteria and other intracellular pathogens. The professional phagocytes include neutrophils, dendritic cells, macrophages and monocytes.[4] These cells engulf the pathogens by phagocytosis and activate the adaptive immune system to facilitate the elimination of the infection. Cytokine signalling is the key for the interplay between the innate and adaptive limbs of the immune system, the most important of which is the IL12-dependent, IFNγ-mediated pathway.[5]
The phagocytes recognize mycobacteria and other pathogens by their pattern recognition receptors (PRR), which include Toll-like receptors (TLR) and NOD2.[4] Once the pathogen is phagocytosed, the macrophages secrete IL12, which is a heterodimer formed by IL12p40 and IL12p35. IL12 receptors, composed of IL12Rβ1 and IL12Rβ2 subunits, are expressed on T lymphocytes and NK cells. It is associated with the signalling cascade formed by TYK and JAK2 kinases, eventually leading to STAT4 phosphorylation and nuclear translocation. The final response to IL12 stimulation is IFNγ production and secretion.[5]
The IFNγ receptor is expressed on the macrophages and other cells and consists of IFNγR1 and IFNγR2 subunits. It is associated with the signalling pathway of JAK1 and JAK2, leading to the homodimerization of STAT1 molecule. It is the common pathway for enhancing expression of a variety of IFNγ-inducible genes, accounting for the confinement and killing of intracellular pathogens.[1][5] Genetic defects impairing the IL12/IFNγ pathway increase the susceptibility to mycobacterial infections by impeding either the production or the response to IFNγ.[6]
Since the discovery of MSMD in 1996, multiple autosomal and two X-linked genes are identified in MSMD phenotypes, classified under the category of defects in intrinsic and innate immunity in the 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies.[4][7][8][9]
References
- ^ a b Rezaei, Nima; Aghamohammadi, Asghar; Notarangelo, Luigi D., eds. (2017). "Primary Immunodeficiency Diseases". doi:10.1007/978-3-662-52909-6.
{{cite journal}}: Cite journal requires|journal=(help) - ^ Cottle LE (January 2011). "Mendelian susceptibility to mycobacterial disease". Clinical Genetics. 79 (1): 17–22. doi:10.1111/j.1399-0004.2010.01510.x. PMID 20718793.
- ^ "IMMUNODEFICIENCY 27A; IMD27A". OMIM. Johns Hopkins University. 8 September 2014.
- ^ a b c Reed B, Dolen WK (June 2018). "The Child with Recurrent Mycobacterial Disease". Current Allergy and Asthma Reports. 18 (8): 44. doi:10.1007/s11882-018-0797-3. PMID 29936646.
- ^ a b c Ramirez-Alejo N, Santos-Argumedo L (May 2014). "Innate defects of the IL-12/IFN-γ axis in susceptibility to infections by mycobacteria and salmonella". Journal of Interferon & Cytokine Research. 34 (5): 307–17. doi:10.1089/jir.2013.0050. PMC 4015507. PMID 24359575.
- ^ Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL (December 2014). "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity". Seminars in Immunology. 26 (6): 454–70. doi:10.1016/j.smim.2014.09.008. PMC 4357480. PMID 25453225.
- ^ Jouanguy E, Altare F, Lamhamedi S, Revy P, Emile JF, Newport M, Levin M, Blanche S, Seboun E, Fischer A, Casanova JL (December 1996). "Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guérin infection". The New England Journal of Medicine. 335 (26): 1956–61. doi:10.1056/nejm199612263352604. PMID 8960475.
- ^ Newport MJ, Huxley CM, Huston S, Hawrylowicz CM, Oostra BA, Williamson R, Levin M (December 1996). "A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection". The New England Journal of Medicine. 335 (26): 1941–9. doi:10.1056/nejm199612263352602. PMID 8960473.
- ^ Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, et al. (January 2018). "The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies". Journal of Clinical Immunology. 38 (1): 129–143. doi:10.1007/s10875-017-0465-8. PMC 5742599. PMID 29226301.