Mendelian susceptibility to mycobacterial disease: recent discoveries

Bustamante, Jacinta

doi:10.1007/s00439-020-02120-y

Cited by 149 publications

(169 citation statements)

References 67 publications

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“…In other words, physiological homogeneity can be identified for many genotypes underlying a given phenotype. Classic examples of this are Mendelian susceptibility to mycobacterial disease (MSMD), which results from impaired IFNγ-mediated immunity following exposure to mycobacterial species [ 58 ], and herpes simplex virus encephalitis (HSE) resulting from impaired TLR3-mediated anti-HSV1 immunity [ 59 , 60 ]. Thus, variants in genes affecting the production of IFNγ (e.g., IL12RB1 , IL12RB2 , IL23R, TYK2, IKBKG , SPPL2A , IRF8 ) or cellular responses to IFNγ (e.g., IFNGR1 , IFNGR2 , STAT1 , JAK1 ) result in MSMD in otherwise healthy individuals [ 58 ].…”

Section: Joining the Dots With Discoveries Of Novel Inborn Errors Ofmentioning

confidence: 99%

“…Classic examples of this are Mendelian susceptibility to mycobacterial disease (MSMD), which results from impaired IFNγ-mediated immunity following exposure to mycobacterial species [ 58 ], and herpes simplex virus encephalitis (HSE) resulting from impaired TLR3-mediated anti-HSV1 immunity [ 59 , 60 ]. Thus, variants in genes affecting the production of IFNγ (e.g., IL12RB1 , IL12RB2 , IL23R, TYK2, IKBKG , SPPL2A , IRF8 ) or cellular responses to IFNγ (e.g., IFNGR1 , IFNGR2 , STAT1 , JAK1 ) result in MSMD in otherwise healthy individuals [ 58 ]. Similarly, inactivating mutations in signaling components of the TLR3 signaling pathway ( TLR3 , UNC93B , TRIF , TRAF3 , TBK1 , IRF3 ) underlie HSE due to impaired type 1 IFN-mediated central nervous system (CNS) intrinsic immunity against HSV1 [ 59 , 60 ].…”

Section: Joining the Dots With Discoveries Of Novel Inborn Errors Ofmentioning

confidence: 99%

“…Recent discoveries have further linked common clinical phenotypes with unique genotypes that converge in a shared pathway. Thus, the non-redundant role of IFNγ-mediated immunity in host defense against mycobacterial infection [ 58 ] has been definitively established by the identification of individuals with inactivating bi-allelic mutations in not only IFNG itself [ 26 ] but also TBX21 [ 25 ], the transcription factor that regulates expression and production of IFNγ.…”

Section: Joining the Dots With Discoveries Of Novel Inborn Errors Ofmentioning

confidence: 99%

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The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

et al. 2021

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The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.

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Section: Joining the Dots With Discoveries Of Novel Inborn Errors Ofmentioning

confidence: 99%

Section: Joining the Dots With Discoveries Of Novel Inborn Errors Ofmentioning

confidence: 99%

Section: Joining the Dots With Discoveries Of Novel Inborn Errors Ofmentioning

confidence: 99%

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The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

et al. 2021

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“…Finally, a child with an X-linked hemizygous NEMO mutation impairing IFN-a/b, -g, and -l production, and another child with AR complete STAT1 deficiency impairing cellular responses to IFN-a/b,g, and -l both developed HSE and mycobacterial disease (24,21). Impaired IFN-g immunity accounted for their mycobacterial disease, as all genetic etiologies of Mendelian susceptibility to mycobacterial disease disrupt the production of, or the response to IFN-g (25,26). Together, these findings suggest that TLR3-dependent, IFN-a/b-and/or IFN-l-mediated immunity is crucial for the control of HSV-1 infection in the forebrain (27,28).…”

Section: Germline Mutations Of Unc93b1 Tlr3 Trif Traf3 Tbk1 Irf3mentioning

confidence: 99%

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

Bastard¹,

Manry²,

Chen³

et al. 2021

Journal of Clinical Investigation

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Inborn errors of TLR3-dependent IFN-a/b-and-l-mediated immunity in the central nervous system (CNS) can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-a/b and-l are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3'UTR of the last exon of IFNAR1, who died from HSE at the age of two years. An older cousin died following vaccination against measles, mumps and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient's fibroblasts and EBV-B cells did not respond to IFN-a2b or IFN-b, in terms of STAT1, STAT2 and STAT3 phosphorylation, or the genome-wide induction of IFN-stimulated genes. The patient's fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-a2b or IFN-b. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of Nature indicates that IFN-a/b are essential for anti-HSV-1 immunity in the CNS.

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“…We entertained the diagnosis of a naturally evolving and relapsing M chelonae infection for many months, because the patient adhered reliably to therapy, endured adverse effects, presented with a seemingly sporotrichoid pattern of progression well described for M chelonae infections [ 7 ], and experienced apparently treatment-related emergence of a rrl gene mutation conferring clarithromycin resistance ( Supplementary Data ). Because difficult-to-treat M chelonae infections are primarily encountered in immunocompromised patients [ 8 ], we even planned a diagnostic work-up for genetic Mendelian susceptibility to mycobacterial disease [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

Recurrent Mycobacterium chelonae Skin Infection Unmasked as Factitious Disorder Using Bacterial Whole Genome Sequence Analysis

Flohr

Ramette

Agyeman

et al. 2020

Open Forum Infectious Diseases

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Mendelian susceptibility to mycobacterial disease: recent discoveries

Cited by 149 publications

References 67 publications

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

Recurrent Mycobacterium chelonae Skin Infection Unmasked as Factitious Disorder Using Bacterial Whole Genome Sequence Analysis

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