Medicine:Mendelian susceptibility to mycobacterial disease

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Mendelian susceptibility to mycobacterial disease
Other namesMendelian susceptibility to atypical mycobacteria[1]
SpecialtyImmunology

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.[2][3][4]

Symptoms and signs

Normally patients who suffer from this disease are young children under 3 years which have also lack of response to IFN-γ cytokine replacement therapy. This disease is very rare and have high index of mortality.[5][6] Following symptoms and signs are:

  • recurrent wheezing
  • dyspnea
  • asthma-like symptoms
  • recurring fever
  • productive cough
  • endobronchial mycobacterial infection[5]
  • low hemoglobin

Patients with IFNγR1 deficiency can also suffer of disorders of the lung, parenchymal lung diseases caused by mycobacterial infections, hylar lymphadenopathy, or endobronchial disease. If these patients have nontubercular mycobacterial infection[7] there should be suspicion for immunodeficiency.[8]

Transplantation of hematopoietic stem cell is the only one curative therapy for these patients. Children with partial MSMD usually have milder clinical phenotype, later onset, less severe infections, better response for IFNγ and antibiotic therapy, better survival rates and normally they don't need hematopoietic stem cell transplant.[6][5]

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.[9] 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.[10]

The phagocytes recognize mycobacteria and other pathogens by their pattern recognition receptors (PRR), which include Toll-like receptors (TLR) and NOD2.[9] 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.[10]

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.[2][10][11] Genetic defects impairing the IL12/IFNγ pathway increase the susceptibility to mycobacterial infections by impeding either the production or the response to IFNγ.[12]

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.[9][13][14][15] IFNγR1 deficiency was the first identified genetic disorder described as MSMD. Mutation in genes encoding IFNγR1 can be dominant or recessive and it can lead to partial or complete deficiency of this receptor.[16] IFNγR1 gene is located in to chromosome 6q23.3 and it is formed of 22 868 base pairs which are composed in 7 exons.[5][17][18][19]

Diagnosis

Mendelian susceptibility to mycobacterial disease may be suspected in people with disseminated infections caused by environmental mycobacteria or BCG. Children with a complete deficiency in the interferon-gamma receptor have significant elevations in plasma concentrations of interferon-gamma, which can be measured by ELISA.[20]

References

  1. ↑ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Mendelian susceptibility to mycobacterial diseases" (in en). https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=748. Retrieved 28 July 2019. 
  2. ↑ 2.0 2.1 Esser, Monika; Suchard, Melinda; Buldeo, Suvarna (2017). Rezaei, Nima; Aghamohammadi, Asghar; Notarangelo, Luigi D.. eds. Primary Immunodeficiency Diseases. doi:10.1007/978-3-662-52909-6. ISBN 978-3-662-52907-2. 
  3. ↑ "Mendelian susceptibility to mycobacterial disease". Clinical Genetics 79 (1): 17–22. January 2011. doi:10.1111/j.1399-0004.2010.01510.x. PMID 20718793. 
  4. ↑ "IMMUNODEFICIENCY 27A; IMD27A". OMIM. Johns Hopkins University. 8 September 2014. https://omim.org/entry/209950. 
  5. ↑ 5.0 5.1 5.2 5.3 Gutierrez, Maria J.; Kalra, Neelu; Horwitz, Alexandra; Nino, Gustavo (November 2016). "Novel Mutation of Interferon-γ Receptor 1 Gene Presenting as Early Life Mycobacterial Bronchial Disease". Journal of Investigative Medicine High Impact Case Reports 4 (4): 232470961667546. doi:10.1177/2324709616675463. ISSN 2324-7096. PMID 27868075. 
  6. ↑ 6.0 6.1 Holland, Steven M.; Casanova, Jean-Laurent; Kumararatne, Dinakantha; Roesler, Joachim; Levin, Michael; Newport, Melanie; Rosenzweig, Sergio D.; Baretto, Richard et al. (2004-12-11). "Clinical features of dominant and recessive interferon γ receptor 1 deficiencies" (in English). The Lancet 364 (9451): 2113–2121. doi:10.1016/S0140-6736(04)17552-1. ISSN 0140-6736. PMID 15589309. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)17552-1/abstract. 
  7. ↑ Wu, U. I.; Holland, S. M. (2015). "Host susceptibility to non-tuberculous mycobacterial infections.". The Lancet. Infectious Diseases 15 (8): 968–80. doi:10.1016/S1473-3099(15)00089-4. PMID 26049967. https://zenodo.org/record/1260254. 
  8. ↑ Jouanguy, E.; Dupuis, S.; Pallier, A.; Döffinger, R.; Fondanèche, M. C.; Fieschi, C.; Lamhamedi-Cherradi, S.; Altare, F. et al. (2000). "In a novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ". The Journal of Clinical Investigation 105 (10): 1429–1436. doi:10.1172/JCI9166. PMID 10811850. 
  9. ↑ 9.0 9.1 9.2 "The Child with Recurrent Mycobacterial Disease". Current Allergy and Asthma Reports 18 (8): 44. June 2018. doi:10.1007/s11882-018-0797-3. PMID 29936646. 
  10. ↑ 10.0 10.1 10.2 "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. May 2014. doi:10.1089/jir.2013.0050. PMID 24359575. 
  11. ↑ Rosenzweig, Sergio D.; Holland, Steven M. (2005). "Defects in the interferon-γ and interleukin-12 pathways". Immunological Reviews 203 (1): 38–47. doi:10.1111/j.0105-2896.2005.00227.x. ISSN 1600-065X. PMID 15661020. 
  12. ↑ "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity". Seminars in Immunology 26 (6): 454–70. December 2014. doi:10.1016/j.smim.2014.09.008. PMID 25453225. 
  13. ↑ "Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guérin infection". The New England Journal of Medicine 335 (26): 1956–61. December 1996. doi:10.1056/nejm199612263352604. PMID 8960475. 
  14. ↑ "A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection". The New England Journal of Medicine 335 (26): 1941–9. December 1996. doi:10.1056/nejm199612263352602. PMID 8960473. 
  15. ↑ "The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies". Journal of Clinical Immunology 38 (1): 129–143. January 2018. doi:10.1007/s10875-017-0465-8. PMID 29226301. 
  16. ↑ Seelow, Dominik; Markus Schuelke; Cooper, David N.; Schwarz, Jana Marie (April 2014). "MutationTaster2: mutation prediction for the deep-sequencing age". Nature Methods 11 (4): 361–362. doi:10.1038/nmeth.2890. ISSN 1548-7105. PMID 24681721. 
  17. ↑ Filipe-Santos, Orchidée; Bustamante, Jacinta; Chapgier, Ariane; Vogt, Guillaume; de Beaucoudrey, Ludovic; Feinberg, Jacqueline; Jouanguy, Emmanuelle; Boisson-Dupuis, Stéphanie et al. (2006-12-01). "Inborn errors of IL-12/23- and IFN-γ-mediated immunity: molecular, cellular, and clinical features". Seminars in Immunology. Human Genetics of Infectious Diseases: Immunological Implications 18 (6): 347–361. doi:10.1016/j.smim.2006.07.010. ISSN 1044-5323. PMID 16997570. 
  18. ↑ "IFNGR1 interferon gamma receptor 1 [ Homo sapiens (human) "]. https://www.ncbi.nlm.nih.gov/gene/3459. 
  19. ↑ Bryant, Stephen H.; Kans, Jonathan A.; Chappey, Colombe; Geer, Lewis Y.; Wang, Yanli; Bryant, Stephen H.; Kans, Jonathan A.; Chappey, Colombe et al. (2000-06-01). "Cn3D: sequence and structure views for Entrez" (in English). Trends in Biochemical Sciences 25 (6): 300–302. doi:10.1016/S0968-0004(00)01561-9. ISSN 0968-0004. PMID 10838572. https://www.cell.com/trends/biochemical-sciences/abstract/S0968-0004(00)01561-9. 
  20. ↑ Fieschi, Claire; Dupuis, Stéphanie; Picard, Capucine; Smith, C. I. Edvard; Holland, Steven M.; Casanova, Jean-Laurent (1 April 2001). "High Levels of Interferon Gamma in the Plasma of Children With Complete Interferon Gamma Receptor Deficiency". Pediatrics 107 (4): e48. doi:10.1542/peds.107.4.e48. PMID 11335769. 

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