Inherited human IFN-γ deficiency underlies mycobacterial disease

Kerner, Gaspard; Rosain, Jérémie; Guérin, Antoine; Al-Khabaz, Ahmad; Oleaga-Quintas, Carmen; Rapaport, Franck; Massaad, Michel J.; Ding, Jing-Ya; Khan, Taushif; Ali, Fatima; Rahman, Mahbuba; Deswarte, Caroline; Martı́nez-Barricarte, Rubén; Geha, Raif S.; Jeanne-Julien, Valentine; Garcia, Diane S. T.; Chi, Chih-Yu; Yang, Rui; Roynard, Manon; Fleckenstein, Bernhard; Rozenberg, Flore; Boisson–Dupuis, Stéphanie; Ku, Cheng-Lung; Seeleuthner, Yoann; Béziat, Vivien; Marr, Nico; Abel, Laurent; Al‐Herz, Waleed; Casanova, Jean‐Laurent; Bustamante, Jacinta

doi:10.1172/jci135460

Cited by 95 publications

(77 citation statements)

References 89 publications

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“…Recently-reported gene defects have been found for most categories of inborn errors of immunity, including novel causes of: SCID ( PAX1 [ 5 , 6 ], SLP76 [ 7 ]); CID ( MCM10 [ 8 ], IL6ST [ 9 – 11 ]); Predominantly antibody deficiencies ( FNIP1 [ 14 , 15 ], PIK3CG [ 16 , 17 ], CTNNBL1 [ 18 ], TNFSF13 [ 19 ]); Autoinflammatory diseases ( SOCS1 [ 20 – 22 ], TET2 [ 23 ], CEBPE [ 24 ], CDC42 [ 33 – 39 ], LSM11 , RNU7–1 [ 32 ], STAT2 [ 40 , 41 ], RIPK1 [ 42 , 43 ], NCKAP1L [ 44 – 46 ]), UBA1 (somatic mutations) [ 47 ]; and Susceptibility to infection with specific pathogens ( MAPK8 [ 31 ]; TBX21 [ 25 ], IFNG [ 26 ], NOS2 [ 28 ], SNORA31 [ 29 ], ATG4A , MAP1LC3B2 [ 30 ]) (Table 1 ). …”

Section: Novel Causes Of Inborn Errors Of Immunitymentioning

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 Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity.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: Novel Causes Of Inborn Errors Of Immunitymentioning

confidence: 99%

“…Susceptibility to infection with specific pathogens ( MAPK8 [ 31 ]; TBX21 [ 25 ], IFNG [ 26 ], NOS2 [ 28 ], SNORA31 [ 29 ], ATG4A , MAP1LC3B2 [ 30 ]) (Table 1 ).…”

Section: Novel Causes Of Inborn Errors Of Immunitymentioning

confidence: 99%

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

et al. 2021

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“…VirScan assay was used to assess antibody responses to microbial species on the basis of stringent cutoff values, as previously described (108).…”

Section: Virscanmentioning

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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“…number of available peptides in the input library. To mitigate this effect, we evaluated an adjusted virus threshold score with a generalized linear model (GLM), in which we regressed the virus library size and number of enriched peptides to model virus specific cutoff from known in-house cases as described earlier (25). In brief, specimens with known IgG titers for CMV, EBV, HSV, Varicella Zoster, Mumps, Measles, Rubella, Hepatitis A, Hepatitis B, and Parvovirus B19 viruses were used.…”

Section: Discussionmentioning

confidence: 99%

Virome-wide serological profiling reveals association of herpesviruses with obesity

Hasan

Rahman

Khan

et al. 2020

Preprint

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The relationship between viral infection and obesity has been known for several decades but epidemiological data related to obesity is limited to only a few viral pathogens. To identify associations between viral infections and obesity, a high-throughput virome-wide serological profiling tool, VirScan, was used to measure antibody responses to a wide range of viruses. Serum specimens from 457 Qatari adults (lean=184;obese=273) and 231 Qatari children (lean=111;obese=120) were assessed by VirScan. Pediatric specimens were simultaneously tested by conventional serology for several herpesviruses to validate VirScan results. Viral association with obesity was determined by calculation of odds ratio (OR) and p-values from Fisher test, and by multivariate regression analysis to adjust for age and gender, with Bonferroni correction for multiple testing. Comprehensive serological profiling of Qatari adult population with VirScan revealed positive and negative associations (p<0.05) of antibody responses to members of Herpesviridae and Picornaviridae families, respectively, with obesity. After adjusting p-values for multiple comparisons, only herpes simplex virus 1 (HSV-1) and Rhinovirus A were positively (OR=3.3; 95%CI 2.15-4.99; p=2.787E-08) and negatively (OR=0.4; 95%CI 0.26-0.65; p=1.175E-03) associated with obesity. At the peptide level, higher prevalence of antibodies against several peptide epitopes of HSV-1/2 was positively (OR=2.35-3.82; p≤3.981E-05) associated with obesity. No such associations were seen at the species or peptide levels in the pediatric population. By multivariate regression analysis, HSV-1 was independently associated with obesity irrespective of age and gender. These findings are in agreement with limited data on the adipogenic properties of HSV-1 observed in vitro.ImportanceThe state of Qatar has one of the highest rates of obesity and associated morbidities in the world. Although obesity is predominantly caused by the intake of high calorie diet and reduced physical activities, other factors including infections with certain viruses have been reported. Among these viruses, human adenoviruses were widely studied but epidemiological data for other viruses in relation to human obesity are limited. Here, we studied the association of obesity in Qatari adults and children with a wide range of viral pathogens using VirScan, a virome-wide serological profiling tool. Our results indicate significant association HSV-1 with obesity in the adult population only. Furthermore, we have identified a set of HSV peptides as candidate obesogenic factors for future studies.

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Inherited human IFN-γ deficiency underlies mycobacterial disease

Cited by 95 publications

References 89 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

Virome-wide serological profiling reveals association of herpesviruses with obesity

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