Mendelian susceptibility to mycobacterial disease

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.{{Cite journal|last1=Holland|first1=Steven M.|last2=Casanova|first2=Jean-Laurent|last3=Kumararatne|first3=Dinakantha|last4=Roesler|first4=Joachim|last5=Levin|first5=Michael|last6=Newport|first6=Melanie|last7=Rosenzweig|first7=Sergio D.|last8=Baretto|first8=Richard|last9=Dissel|first9=Jaap T. van|date=2004-12-11|title=Clinical features of dominant and recessive interferon γ receptor 1 deficiencies|url=https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)17552-1/abstract|journal=The Lancet|language=English|volume=364|issue=9451|pages=2113–2121|doi=10.1016/S0140-6736(04)17552-1|issn=0140-6736|pmid=15589309|s2cid=54388577|url-access=subscription}} Following symptoms and signs are:

• recurrent wheezing
• dyspnea
• asthma-like symptoms
• recurring fever
• productive cough
• endobronchial mycobacterial infection{{Cite journal|last1=Gutierrez|first1=Maria J.|last2=Kalra|first2=Neelu|last3=Horwitz|first3=Alexandra|last4=Nino|first4=Gustavo|date=November 2016|title=Novel Mutation of Interferon-γ Receptor 1 Gene Presenting as Early Life Mycobacterial Bronchial Disease|journal=Journal of Investigative Medicine High Impact Case Reports|volume=4|issue=4|pages=232470961667546|doi=10.1177/2324709616675463|pmid=27868075|issn=2324-7096|pmc=5103323}}
• 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{{Cite journal|title=Host susceptibility to non-tuberculous mycobacterial infections.|journal = The Lancet. Infectious Diseases|volume = 15|issue = 8|pages = 968–80|pmid = 26049967|year = 2015|last1 = Wu|first1 = U. I.|last2 = Holland|first2 = S. M.|doi = 10.1016/S1473-3099(15)00089-4|url = https://zenodo.org/record/1260254}} there should be suspicion for immunodeficiency.{{Cite journal|title=In a novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ|journal = The Journal of Clinical Investigation|volume = 105|issue = 10|pages = 1429–1436|pmc = 315467|year = 2000|last1 = Jouanguy|first1 = E.|last2 = Dupuis|first2 = S.|last3 = Pallier|first3 = A.|last4 = Döffinger|first4 = R.|last5 = Fondanèche|first5 = M. C.|last6 = Fieschi|first6 = C.|last7 = Lamhamedi-Cherradi|first7 = S.|last8 = Altare|first8 = F.|last9 = Emile|first9 = J. F.|last10 = Lutz|first10 = P.|last11 = Bordigoni|first11 = P.|last12 = Cokugras|first12 = H.|last13 = Akcakaya|first13 = N.|last14 = Landman-Parker|first14 = J.|last15 = Donnadieu|first15 = J.|last16 = Camcioglu|first16 = Y.|last17 = Casanova|first17 = J. L.|pmid = 10811850|doi = 10.1172/JCI9166}}

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.

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.{{cite journal | vauthors = Reed B, Dolen WK | title = The Child with Recurrent Mycobacterial Disease | journal = Current Allergy and Asthma Reports | volume = 18 | issue = 8 | pages = 44 | date = June 2018 | pmid = 29936646 | doi = 10.1007/s11882-018-0797-3 | s2cid = 207324525 }} 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.{{cite journal | vauthors = Ramirez-Alejo N, Santos-Argumedo L | title = Innate defects of the IL-12/IFN-γ axis in susceptibility to infections by mycobacteria and salmonella | journal = Journal of Interferon & Cytokine Research | volume = 34 | issue = 5 | pages = 307–17 | date = May 2014 | pmid = 24359575 | pmc = 4015507 | doi = 10.1089/jir.2013.0050 }}

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

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.{{Cite journal|last1=Rosenzweig|first1=Sergio D.|last2=Holland|first2=Steven M.|date=2005|title=Defects in the interferon-γ and interleukin-12 pathways|journal=Immunological Reviews|volume=203|issue=1|pages=38–47|doi=10.1111/j.0105-2896.2005.00227.x|pmid=15661020|s2cid=20865469|issn=1600-065X}} Genetic defects impairing the IL12/IFNγ pathway increase the susceptibility to mycobacterial infections by impeding either the production or the response to IFNγ.{{cite journal | vauthors = Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL | title = Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity | journal = Seminars in Immunology | volume = 26 | issue = 6 | pages = 454–70 | date = December 2014 | pmid = 25453225 | pmc = 4357480 | doi = 10.1016/j.smim.2014.09.008 }}

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.{{cite journal | vauthors = Jouanguy E, Altare F, Lamhamedi S, Revy P, Emile JF, Newport M, Levin M, Blanche S, Seboun E, Fischer A, Casanova JL | title = Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guérin infection | journal = The New England Journal of Medicine | volume = 335 | issue = 26 | pages = 1956–61 | date = December 1996 | pmid = 8960475 | doi = 10.1056/nejm199612263352604 | doi-access = free }}{{cite journal | vauthors = Newport MJ, Huxley CM, Huston S, Hawrylowicz CM, Oostra BA, Williamson R, Levin M | title = A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection | journal = The New England Journal of Medicine | volume = 335 | issue = 26 | pages = 1941–9 | date = December 1996 | pmid = 8960473 | doi = 10.1056/nejm199612263352602 | doi-access = free }}{{cite journal | vauthors = Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, Chatila T, Crow YJ, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, Ochs HD, Oksenhendler E, Puck J, Tang ML, Tangye SG, Torgerson TR, Casanova JL, Sullivan KE | display-authors = 6 | title = The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies | journal = Journal of Clinical Immunology | volume = 38 | issue = 1 | pages = 129–143 | date = January 2018 | pmid = 29226301 | pmc = 5742599 | doi = 10.1007/s10875-017-0465-8 }} 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.{{Cite journal|last1=Seelow|first1=Dominik|last2=Markus Schuelke|last3=Cooper|first3=David N.|last4=Schwarz|first4=Jana Marie|date=April 2014|title=MutationTaster2: mutation prediction for the deep-sequencing age|journal=Nature Methods|volume=11|issue=4|pages=361–362|doi=10.1038/nmeth.2890|pmid=24681721|s2cid=19382079|issn=1548-7105}} IFNγR1 gene is located in to chromosome 6q23.3 and it is formed of 22 868 base pairs which are composed in 7 exons.{{Cite journal|last1=Filipe-Santos|first1=Orchidée|last2=Bustamante|first2=Jacinta|last3=Chapgier|first3=Ariane|last4=Vogt|first4=Guillaume|last5=de Beaucoudrey|first5=Ludovic|last6=Feinberg|first6=Jacqueline|last7=Jouanguy|first7=Emmanuelle|last8=Boisson-Dupuis|first8=Stéphanie|last9=Fieschi|first9=Claire|date=2006-12-01|title=Inborn errors of IL-12/23- and IFN-γ-mediated immunity: molecular, cellular, and clinical features|journal=Seminars in Immunology|series=Human Genetics of Infectious Diseases: Immunological Implications|volume=18|issue=6|pages=347–361|doi=10.1016/j.smim.2006.07.010|pmid=16997570|issn=1044-5323}}{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/3459|title=IFNGR1 interferon gamma receptor 1 [ Homo sapiens (human) ]}}{{Cite journal|last1=Bryant|first1=Stephen H.|last2=Kans|first2=Jonathan A.|last3=Chappey|first3=Colombe|last4=Geer|first4=Lewis Y.|last5=Wang|first5=Yanli|last6=Bryant|first6=Stephen H.|last7=Kans|first7=Jonathan A.|last8=Chappey|first8=Colombe|last9=Geer|first9=Lewis Y.|date=2000-06-01|title=Cn3D: sequence and structure views for Entrez|url=https://www.cell.com/trends/biochemical-sciences/abstract/S0968-0004(00)01561-9|journal=Trends in Biochemical Sciences|language=English|volume=25|issue=6|pages=300–302|doi=10.1016/S0968-0004(00)01561-9|issn=0968-0004|pmid=10838572|url-access=subscription}}

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.{{cite journal |last1=Fieschi |first1=Claire |last2=Dupuis |first2=Stéphanie |last3=Picard |first3=Capucine |last4=Smith |first4=C. I. Edvard |last5=Holland |first5=Steven M. |last6=Casanova |first6=Jean-Laurent |title=High Levels of Interferon Gamma in the Plasma of Children With Complete Interferon Gamma Receptor Deficiency |journal=Pediatrics |date=1 April 2001 |volume=107 |issue=4 |pages=e48 |doi=10.1542/peds.107.4.e48|pmid=11335769 |doi-access= }}

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Category:Immune system disorders

Category:Genetic diseases and disorders

Category:Rare diseases