Publications by authors named "Stéphanie Boisson-Dupuis"

118 Publications

Human ancient DNA analyses reveal the high burden of tuberculosis in Europeans over the last 2,000 years.

Am J Hum Genet 2021 03;108(3):517-524

Human Evolutionary Genetics Unit, Institut Pasteur, UMR2000, CNRS, 75015 Paris, France; Chair of Human Genomics and Evolution, Collège de France, 75005 Paris, France. Electronic address:

Tuberculosis (TB), usually caused by Mycobacterium tuberculosis bacteria, is the first cause of death from an infectious disease at the worldwide scale, yet the mode and tempo of TB pressure on humans remain unknown. The recent discovery that homozygotes for the P1104A polymorphism of TYK2 are at higher risk to develop clinical forms of TB provided the first evidence of a common, monogenic predisposition to TB, offering a unique opportunity to inform on human co-evolution with a deadly pathogen. Here, we investigate the history of human exposure to TB by determining the evolutionary trajectory of the TYK2 P1104A variant in Europe, where TB is considered to be the deadliest documented infectious disease. Leveraging a large dataset of 1,013 ancient human genomes and using an approximate Bayesian computation approach, we find that the P1104A variant originated in the common ancestors of West Eurasians ∼30,000 years ago. Furthermore, we show that, following large-scale population movements of Anatolian Neolithic farmers and Eurasian steppe herders into Europe, P1104A has markedly fluctuated in frequency over the last 10,000 years of European history, with a dramatic decrease in frequency after the Bronze Age. Our analyses indicate that such a frequency drop is attributable to strong negative selection starting ∼2,000 years ago, with a relative fitness reduction on homozygotes of 20%, among the highest in the human genome. Together, our results provide genetic evidence that TB has imposed a heavy burden on European health over the last two millennia.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008489PMC
March 2021

Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations.

PLoS Genet 2021 Mar 4;17(3):e1009392. Epub 2021 Mar 4.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.

The natural history of tuberculosis (TB) is characterized by a large inter-individual outcome variability after exposure to Mycobacterium tuberculosis. Specifically, some highly exposed individuals remain resistant to M. tuberculosis infection, as inferred by tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). We performed a genome-wide association study of resistance to M. tuberculosis infection in an endemic region of Southern Vietnam. We enrolled household contacts (HHC) of pulmonary TB cases and compared subjects who were negative for both TST and IGRA (n = 185) with infected individuals (n = 353) who were either positive for both TST and IGRA or had a diagnosis of TB. We found a genome-wide significant locus on chromosome 10q26.2 with a cluster of variants associated with strong protection against M. tuberculosis infection (OR = 0.42, 95%CI 0.35-0.49, P = 3.71×10-8, for the genotyped variant rs17155120). The locus was replicated in a French multi-ethnic HHC cohort and a familial admixed cohort from a hyper-endemic area of South Africa, with an overall OR for rs17155120 estimated at 0.50 (95%CI 0.45-0.55, P = 1.26×10-9). The variants are located in intronic regions and upstream of C10orf90, a tumor suppressor gene which encodes an ubiquitin ligase activating the transcription factor p53. In silico analysis showed that the protective alleles were associated with a decreased expression in monocytes of the nearby gene ADAM12 which could lead to an enhanced response of Th17 lymphocytes. Our results reveal a novel locus controlling resistance to M. tuberculosis infection across different populations.
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http://dx.doi.org/10.1371/journal.pgen.1009392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963100PMC
March 2021

Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance.

J Clin Immunol 2021 Apr 8;41(3):639-657. Epub 2021 Jan 8.

Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, 24 Boulevard du Montparnasse, Paris, France.

Purpose: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown.

Methods: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives.

Results: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic.

Conclusion: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.
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http://dx.doi.org/10.1007/s10875-020-00930-3DOI Listing
April 2021

Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance.

Proc Natl Acad Sci U S A 2021 Jan;118(3)

Human Evolutionary Genetics Unit, Institut Pasteur, UMR 2000, CNRS, 75015 Paris, France.

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.
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http://dx.doi.org/10.1073/pnas.2001248118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826345PMC
January 2021

Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria.

Cell 2020 Dec 8;183(7):1826-1847.e31. Epub 2020 Dec 8.

St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University of Paris, Imagine Institute, 75015 Paris, France; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France; Howard Hughes Medical Institute, New York, NY, USA. Electronic address:

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2 γδ T lymphocytes, and of Mycobacterium-non reactive classic T1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8 αβ T and non-classic CD4 αβ T1 lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2 γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8 αβ T, and CD4 αβ T1 cells unable to compensate for this deficit.
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http://dx.doi.org/10.1016/j.cell.2020.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770098PMC
December 2020

Multibatch Cytometry Data Integration for Optimal Immunophenotyping.

J Immunol 2021 Jan 23;206(1):206-213. Epub 2020 Nov 23.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065.

High-dimensional cytometry is a powerful technique for deciphering the immunopathological factors common to multiple individuals. However, rational comparisons of multiple batches of experiments performed on different occasions or at different sites are challenging because of batch effects. In this study, we describe the integration of multibatch cytometry datasets (iMUBAC), a flexible, scalable, and robust computational framework for unsupervised cell-type identification across multiple batches of high-dimensional cytometry datasets, even without technical replicates. After overlaying cells from multiple healthy controls across batches, iMUBAC learns batch-specific cell-type classification boundaries and identifies aberrant immunophenotypes in patient samples from multiple batches in a unified manner. We illustrate unbiased and streamlined immunophenotyping using both public and in-house mass cytometry and spectral flow cytometry datasets. The method is available as the R package iMUBAC (https://github.com/casanova-lab/iMUBAC).
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http://dx.doi.org/10.4049/jimmunol.2000854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855665PMC
January 2021

Autoantibodies against type I IFNs in patients with life-threatening COVID-19.

Authors:
Paul Bastard Lindsey B Rosen Qian Zhang Eleftherios Michailidis Hans-Heinrich Hoffmann Yu Zhang Karim Dorgham Quentin Philippot Jérémie Rosain Vivien Béziat Jérémy Manry Elana Shaw Liis Haljasmägi Pärt Peterson Lazaro Lorenzo Lucy Bizien Sophie Trouillet-Assant Kerry Dobbs Adriana Almeida de Jesus Alexandre Belot Anne Kallaste Emilie Catherinot Yacine Tandjaoui-Lambiotte Jeremie Le Pen Gaspard Kerner Benedetta Bigio Yoann Seeleuthner Rui Yang Alexandre Bolze András N Spaan Ottavia M Delmonte Michael S Abers Alessandro Aiuti Giorgio Casari Vito Lampasona Lorenzo Piemonti Fabio Ciceri Kaya Bilguvar Richard P Lifton Marc Vasse David M Smadja Mélanie Migaud Jérome Hadjadj Benjamin Terrier Darragh Duffy Lluis Quintana-Murci Diederik van de Beek Lucie Roussel Donald C Vinh Stuart G Tangye Filomeen Haerynck David Dalmau Javier Martinez-Picado Petter Brodin Michel C Nussenzweig Stéphanie Boisson-Dupuis Carlos Rodríguez-Gallego Guillaume Vogt Trine H Mogensen Andrew J Oler Jingwen Gu Peter D Burbelo Jeffrey I Cohen Andrea Biondi Laura Rachele Bettini Mariella D'Angio Paolo Bonfanti Patrick Rossignol Julien Mayaux Frédéric Rieux-Laucat Eystein S Husebye Francesca Fusco Matilde Valeria Ursini Luisa Imberti Alessandra Sottini Simone Paghera Eugenia Quiros-Roldan Camillo Rossi Riccardo Castagnoli Daniela Montagna Amelia Licari Gian Luigi Marseglia Xavier Duval Jade Ghosn John S Tsang Raphaela Goldbach-Mansky Kai Kisand Michail S Lionakis Anne Puel Shen-Ying Zhang Steven M Holland Guy Gorochov Emmanuelle Jouanguy Charles M Rice Aurélie Cobat Luigi D Notarangelo Laurent Abel Helen C Su Jean-Laurent Casanova

Science 2020 10 24;370(6515). Epub 2020 Sep 24.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
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http://dx.doi.org/10.1126/science.abd4585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857397PMC
October 2020

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Authors:
Qian Zhang Paul Bastard Zhiyong Liu Jérémie Le Pen Marcela Moncada-Velez Jie Chen Masato Ogishi Ira K D Sabli Stephanie Hodeib Cecilia Korol Jérémie Rosain Kaya Bilguvar Junqiang Ye Alexandre Bolze Benedetta Bigio Rui Yang Andrés Augusto Arias Qinhua Zhou Yu Zhang Fanny Onodi Sarantis Korniotis Léa Karpf Quentin Philippot Marwa Chbihi Lucie Bonnet-Madin Karim Dorgham Nikaïa Smith William M Schneider Brandon S Razooky Hans-Heinrich Hoffmann Eleftherios Michailidis Leen Moens Ji Eun Han Lazaro Lorenzo Lucy Bizien Philip Meade Anna-Lena Neehus Aileen Camille Ugurbil Aurélien Corneau Gaspard Kerner Peng Zhang Franck Rapaport Yoann Seeleuthner Jeremy Manry Cecile Masson Yohann Schmitt Agatha Schlüter Tom Le Voyer Taushif Khan Juan Li Jacques Fellay Lucie Roussel Mohammad Shahrooei Mohammed F Alosaimi Davood Mansouri Haya Al-Saud Fahd Al-Mulla Feras Almourfi Saleh Zaid Al-Muhsen Fahad Alsohime Saeed Al Turki Rana Hasanato Diederik van de Beek Andrea Biondi Laura Rachele Bettini Mariella D'Angio' Paolo Bonfanti Luisa Imberti Alessandra Sottini Simone Paghera Eugenia Quiros-Roldan Camillo Rossi Andrew J Oler Miranda F Tompkins Camille Alba Isabelle Vandernoot Jean-Christophe Goffard Guillaume Smits Isabelle Migeotte Filomeen Haerynck Pere Soler-Palacin Andrea Martin-Nalda Roger Colobran Pierre-Emmanuel Morange Sevgi Keles Fatma Çölkesen Tayfun Ozcelik Kadriye Kart Yasar Sevtap Senoglu Şemsi Nur Karabela Carlos Rodríguez-Gallego Giuseppe Novelli Sami Hraiech Yacine Tandjaoui-Lambiotte Xavier Duval Cédric Laouénan Andrew L Snow Clifton L Dalgard Joshua D Milner Donald C Vinh Trine H Mogensen Nico Marr András N Spaan Bertrand Boisson Stéphanie Boisson-Dupuis Jacinta Bustamante Anne Puel Michael J Ciancanelli Isabelle Meyts Tom Maniatis Vassili Soumelis Ali Amara Michel Nussenzweig Adolfo García-Sastre Florian Krammer Aurora Pujol Darragh Duffy Richard P Lifton Shen-Ying Zhang Guy Gorochov Vivien Béziat Emmanuelle Jouanguy Vanessa Sancho-Shimizu Charles M Rice Laurent Abel Luigi D Notarangelo Aurélie Cobat Helen C Su Jean-Laurent Casanova

Science 2020 10 24;370(6515). Epub 2020 Sep 24.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
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http://dx.doi.org/10.1126/science.abd4570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857407PMC
October 2020

Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy.

J Clin Immunol 2020 11 27;40(8):1065-1081. Epub 2020 Aug 27.

St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1-dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.
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http://dx.doi.org/10.1007/s10875-020-00847-xDOI Listing
November 2020

Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical and Genetic Features of 32 Iranian Patients.

J Clin Immunol 2020 08 30;40(6):872-882. Epub 2020 Jun 30.

Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFNγ) immunity, including interleukin IL-12 receptor-β1 (IL-12Rβ1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFNγ receptor 1 (IFNγR1) deficiency, IFNγ receptor 2 (IFNγR2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.
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http://dx.doi.org/10.1007/s10875-020-00813-7DOI Listing
August 2020

Three Copies of Four Interferon Receptor Genes Underlie a Mild Type I Interferonopathy in Down Syndrome.

J Clin Immunol 2020 08 22;40(6):807-819. Epub 2020 Jun 22.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Hospital for Sick Children, Paris, France.

Down syndrome (DS) is characterized by the occurrence of three copies of human chromosome 21 (HSA21). HSA21 contains a cluster of four interferon receptor (IFN-R) genes: IFNAR1, IFNAR2, IFNGR2, and IL10RB. DS patients often develop mucocutaneous infections and autoimmune diseases, mimicking patients with heterozygous gain-of-function (GOF) STAT1 mutations, which enhance cellular responses to three types of interferon (IFN). A gene dosage effect at these four loci may contribute to the infectious and autoimmune manifestations observed in individuals with DS. We report high levels of IFN-αR1, IFN-αR2, and IFN-γR2 expression on the surface of monocytes and EBV-transformed-B (EBV-B) cells from studying 45 DS patients. Total and phosphorylated STAT1 (STAT1 and pSTAT1) levels were constitutively high in unstimulated and IFN-α- and IFN-γ-stimulated monocytes from DS patients but lower than those in patients with GOF STAT1 mutations. Following stimulation with IFN-α or -γ, but not with IL-6 or IL-21, pSTAT1 and IFN-γ activation factor (GAF) DNA-binding activities were significantly higher in the EBV-B cells of DS patients than in controls. These responses resemble the dysregulated responses observed in patients with STAT1 GOF mutations. Concentrations of plasma type I IFNs were high in 12% of the DS patients tested (1.8% in the healthy controls). Levels of type I IFNs, IFN-Rs, and STAT1 were similar in DS patients with and without recurrent skin infections. We performed a genome-wide transcriptomic analysis based on principal component analysis and interferon modules on circulating monocytes. We found that DS monocytes had levels of both IFN-α- and IFN-γ-inducible ISGs intermediate to those of monocytes from healthy controls and from patients with GOF STAT1 mutations. Unlike patients with GOF STAT1 mutations, patients with DS had normal circulating Th17 counts and a high proportion of terminally differentiated CD8 T cells with low levels of STAT1 expression. We conclude a mild interferonopathy in Down syndrome leads to an incomplete penetrance at both cellular and clinical level, which is not correlate with recurrent skin bacterial or fungal infections. The constitutive upregulation of type I and type II IFN-R, at least in monocytes of DS patients, may contribute to the autoimmune diseases observed in these individuals.
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http://dx.doi.org/10.1007/s10875-020-00803-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418179PMC
August 2020

Inherited human IFN-γ deficiency underlies mycobacterial disease.

J Clin Invest 2020 06;130(6):3158-3171

INSERM U1163, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM 1163, Paris, France.

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to clinical disease caused by the Bacille Calmette-Guérin (BCG) vaccine and environmental mycobacteria. The known genetic etiologies of MSMD are inborn errors of IFN-γ immunity due to mutations of 15 genes controlling the production of or response to IFN-γ. Since the first MSMD-causing mutations were reported in 1996, biallelic mutations in the genes encoding IFN-γ receptor 1 (IFN-γR1) and IFN-γR2 have been reported in many patients of diverse ancestries. Surprisingly, mutations of the gene encoding the IFN-γ cytokine itself have not been reported, raising the remote possibility that there might be other agonists of the IFN-γ receptor. We describe 2 Lebanese cousins with MSMD, living in Kuwait, who are both homozygous for a small deletion within the IFNG gene (c.354_357del), causing a frameshift that generates a premature stop codon (p.T119Ifs4*). The mutant allele is loss of expression and loss of function. We also show that the patients' herpesvirus Saimiri-immortalized T lymphocytes did not produce IFN-γ, a phenotype that can be rescued by retrotransduction with WT IFNG cDNA. The blood T and NK lymphocytes from these patients also failed to produce and secrete detectable amounts of IFN-γ. Finally, we show that human IFNG has evolved under stronger negative selection than IFNGR1 or IFNGR2, suggesting that it is less tolerant to heterozygous deleterious mutations than IFNGR1 or IFNGR2. This may account for the rarity of patients with autosomal-recessive, complete IFN-γ deficiency relative to patients with complete IFN-γR1 and IFN-γR2 deficiencies.
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http://dx.doi.org/10.1172/JCI135460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260033PMC
June 2020

Patient iPSC-Derived Macrophages to Study Inborn Errors of the IFN-γ Responsive Pathway.

Cells 2020 02 19;9(2). Epub 2020 Feb 19.

REBIRTH Cluster of Excellence, Institute of Experimental Hematology, Hannover Medical School (MHH), 30625 Hannover, Germany.

Interferon γ (IFN-γ) was shown to be a macrophage activating factor already in 1984. Consistently, inborn errors of IFN-γ immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD). MSMD is characterized by genetic predisposition to disease caused by weakly virulent mycobacterial species. Paradoxically, macrophages from patients with MSMD were little tested. Here, we report a disease modeling platform for studying IFN-γ related pathologies using macrophages derived from patient specific induced pluripotent stem cells (iPSCs). We used iPSCs from patients with autosomal recessive complete- and partial IFN-γR2 deficiency, partial IFN-γR1 deficiency and complete STAT1 deficiency. Macrophages from all patient iPSCs showed normal morphology and IFN-γ-independent functionality like phagocytic uptake of bioparticles and internalization of cytokines. For the IFN-γ-dependent functionalities, we observed that the deficiencies played out at various stages of the IFN-γ pathway, with the complete IFN-γR2 and complete STAT1 deficient cells showing the most severe phenotypes, in terms of upregulation of surface markers and induction of downstream targets. Although iPSC-derived macrophages with partial IFN-γR1 and IFN-γR2 deficiency still showed residual induction of downstream targets, they did not reduce the mycobacterial growth when challenged with Bacillus Calmette-Guérin. Taken together, we report a disease modeling platform to study the role of macrophages in patients with inborn errors of IFN-γ immunity.
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http://dx.doi.org/10.3390/cells9020483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072779PMC
February 2020

The monogenic basis of human tuberculosis.

Hum Genet 2020 Jun 13;139(6-7):1001-1009. Epub 2020 Feb 13.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France.

The pathogenesis of tuberculosis (TB) remains poorly understood, as no more than 5-10% of individuals infected with Mycobacterium tuberculosis go on developing clinical disease. The contribution of human genetics to TB pathogenesis has been amply documented by means of classic genetics since the turn of the twentieth century. Over the last 20 years, following-up on the study of Mendelian susceptibility to mycobacterial disease (MSMD), monogenic disorders have been found to underlie TB in some patients. Rare inborn errors of immunity, such as autosomal recessive, complete IL-12Rβ1 and TYK2 deficiencies, impairing the IL-12- and IL-23-dependent induction of IFN-γ, were initially identified in a few patients. More recently, homozygosity for a common variant of TYK2 (P1104A) that selectively disrupts cellular responses to IL-23 was found in two cohorts of TB patients. It shows high penetrance in areas endemic for TB and appears to be responsible for about 1% of TB cases in populations of European descent. Both rare and common genetic etiologies of TB affect IFN-γ immunity, providing a rationale for novel preventive and therapeutic approaches for TB control, including the use of recombinant IFN-γ.
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http://dx.doi.org/10.1007/s00439-020-02126-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275886PMC
June 2020

Genetic, Immunological, and Clinical Features of the First Mexican Cohort of Patients with Chronic Granulomatous Disease.

J Clin Immunol 2020 04 10;40(3):475-493. Epub 2020 Feb 10.

Imagine Institute, Paris University, Paris, France.

Purpose: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019.

Methods: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds.

Results: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations.

Conclusions: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.
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http://dx.doi.org/10.1007/s10875-020-00750-5DOI Listing
April 2020

Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency.

N Engl J Med 2020 01;382(5):437-445

From St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University (S.B.D., D.H., N.H., S.B., F.R., B.B., R.F., E.J., J.B., L.A., S.B.-D., J.-L.C.), the Department of Microbiology and Immunology, Weill Cornell Medicine (R.B., C.N.), and Howard Hughes Medical Institute (J.-L.C.) - all in New York; the Pediatric Respiratory Diseases Research Center (D.M., S.A.M.), the Department of Clinical Immunology and Infectious Diseases (D.M., N. Mansouri), and the Clinical Tuberculosis and Epidemiology Research Center (D.M., M.M.), National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; the Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM Unité 1163 (A.-L.N., L.L.-D., E.J., J.B., L.A., S.B.-D., V.B., J.-L.C.), Paris University, Imagine Institute (A.-L.N., L.L.-D., E.J., J.B., L.A., S.B.-D., V.B., J.-L.C.), and the Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP) (J.B.), and the Pediatric Immunology-Hematology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, and the Department of Pathology, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt (J.-F.E.) - all in France; the Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany (A.-L.N.); the Research Branch, Sidra Medicine (M.R., T.K., F.A.A., N. Marr), and the College of Health and Life Sciences, Hamad Bin Khalifa University (N. Marr), Doha, Qatar; and the Division of Pulmonary Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (N. Mansouri).

Background: Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 () are susceptible to the related murine CMV infection.

Methods: We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally.

Results: We found a homozygous frameshift mutation in encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all variants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001.

Conclusions: These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.).
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http://dx.doi.org/10.1056/NEJMoa1910640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063989PMC
January 2020

A New Patient with Inherited TYK2 Deficiency.

J Clin Immunol 2020 01 11;40(1):232-235. Epub 2019 Nov 11.

Immunology, Asthma and Allergy Research Institute (IAARI), Tehran University of Medical Sciences, 4th Floor, Building No.3, Children's Medical Center, Gharib St, Keshavarz Blvd, Tehran, 1419733154, Iran.

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http://dx.doi.org/10.1007/s10875-019-00713-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218688PMC
January 2020

Prevalence and risk factors for latent tuberculosis infection among healthcare workers in Morocco.

PLoS One 2019 15;14(8):e0221081. Epub 2019 Aug 15.

Genetics Unit, Military Hospital Mohamed V, Rabat, Morocco.

Increased prevalence of latent tuberculosis infection (LTBI) has been observed among high-risk populations such as healthcare workers (HCWs). The results may depend on the method of LTBI assessment, interferon-gamma release assay (IGRA) and/or tuberculin skin test (TST). Here, we investigated the prevalence and risk factors for LTBI assessed by both IGRAs and TST in HCWs living in Morocco, a country with intermediate tuberculosis (TB) endemicity and high BCG vaccination coverage. HCWs were recruited in two Moroccan hospitals, Rabat and Meknes. All the participants underwent testing for LTBI by both IGRA (QuantiFERON-TB Gold In-Tube, QFT-GIT) and TST. Different combinations of IGRA and TST results defined the LTBI status. Risk factors associated with LTBI were investigated using a mixed-effect logistic regression model. The prevalence of LTBI among 631 HCWs (age range 18-60 years) varied from 40.7% (95%CI 36.9-44.5%) with QFT-GIT to 52% (95%CI 48.2-56.0%) with TST using a 10 mm cut-off. The highest agreement between QFT-GIT and TST (κ = 0.50; 95%CI 0.43-0.56) was observed with the 10 mm cut-off for a positive TST. For a definition of LTBI status using a double positive result for both QFT-GIT and TST, significant associations were found with the following risk factors: being male (OR = 2.21; 95%CI 1.40-3.49; p = 0.0007), belonging to age groups 35-44 years (OR = 2.43; 95%CI 1.45-4.06; p = 0.0007) and even more 45-60 years (OR = 4.81; 95%CI 2.72-8.52; p = 7.10-8), having a family history of TB (OR = 6.62; 95%CI 2.59-16.94; p = 8.10-5), and working at a pulmonology unit (OR = 3.64; 95%CI 1.44-9.23; p = 0.006). Smoking was associated with LTBI status when defined by a positive QFT-GIT result (OR = 1.89; 95%CI 1.12-3.21; p = 0.02). A high prevalence of LTBI was observed among HCWs in two Moroccan hospitals. Male gender, increased age, family history of TB, and working at a pulmonology unit were consistent risk factors associated with LTBI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221081PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695119PMC
March 2020

A deep intronic splice mutation of underlies hyper IgE syndrome by negative dominance.

Proc Natl Acad Sci U S A 2019 08 25;116(33):16463-16472. Epub 2019 Jul 25.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, 75015 Paris, France;

Heterozygous in-frame mutations in coding regions of human underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients' primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical 3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.
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http://dx.doi.org/10.1073/pnas.1901409116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697804PMC
August 2019

A purely quantitative form of partial recessive IFN-γR2 deficiency caused by mutations of the initiation or second codon.

Hum Mol Genet 2018 11;27(22):3919-3935

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, Paris, France.

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by clinical disease caused by weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette-Guérin vaccines, in otherwise healthy individuals. All known genetic etiologies disrupt interferon (IFN)-γ immunity. Germline bi-allelic mutations of IFNGR2 can underlie partial or complete forms of IFN-γ receptor 2 (IFN-γR2) deficiency. Patients with partial IFN-γR2 deficiency express a dysfunctional molecule on the cell surface. We studied three patients with MSMD from two unrelated kindreds from Turkey (P1, P2) and India (P3), by whole-exome sequencing. P1 and P2 are homozygous for a mutation of the initiation codon(c.1A>G) of IFNGR2, whereas P3 is homozygous for a mutation of the second codon (c.4delC). Overexpressed mutant alleles produce small amounts of full-length IFN-γR2 resulting in an impaired, but not abolished, response to IFN-γ. Moreover, SV40-fibroblasts of P1 and P2 responded weakly to IFN-γ, and Epstein Barr virus-transformed B cells had a barely detectable response to IFN-γ. Studies in patients' primary T cells and monocyte-derived macrophages yielded similar results. The residual expression of IFN-γR2 protein of normal molecular weight and function is due to the initiation of translation between the second and ninth non-AUG codons. We thus describe mutations of the first and second codons of IFNGR2, which define a new form of partial recessive IFN-γR2 deficiency. Residual levels of IFN-γ signaling were very low, accounting for the more severe clinical phenotype of these patients with residual expression levels of normally functional surface receptors than of patients with partial recessive IFN-γR2 deficiency due to surface-expressed dysfunctional receptors, whose residual levels of IFN-γ signaling were higher.
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http://dx.doi.org/10.1093/hmg/ddy275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216222PMC
November 2018

Homozygosity for P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry.

Proc Natl Acad Sci U S A 2019 05 8;116(21):10430-10434. Epub 2019 May 8.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France.

The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96-10.31, = 2 × 10]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with , as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for P1104A may account for ∼1% of TB cases in Europeans.
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http://dx.doi.org/10.1073/pnas.1903561116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534977PMC
May 2019

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.

Sci Immunol 2018 12;3(30)

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 × 10; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
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http://dx.doi.org/10.1126/sciimmunol.aau8714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341984PMC
December 2018

Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23.

Sci Immunol 2018 12;3(30)

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αβ T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4 T cells, including, in particular, mycobacterium-specific T1* cells (CD45RACCR6), is dependent on both IL-12 and IL-23. Last, we show that , , and have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rβ2 or IL-23R deficiency, relative to IL-12Rβ1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rβ2-deficient than IL-12Rβ1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively.
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http://dx.doi.org/10.1126/sciimmunol.aau6759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380365PMC
December 2018

Mendelian susceptibility to mycobacterial disease: 2014-2018 update.

Immunol Cell Biol 2019 04 25;97(4):360-367. Epub 2018 Oct 25.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, UMR 1163, Necker Hospital for Sick Children, Paris, France.

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity. Since 1996, disease-causing mutations have been found in 11 genes, which, through allelic heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014. Highlights include the discoveries of (1) a new genetic etiology, autosomal recessive signal peptide peptidase-like 2 A deficiency, (2) TYK2-deficient patients with a clinical phenotype of MSMD, (3) an allelic form of partial recessive IFN-γR2 deficiency, and (4) two forms of syndromic MSMD: RORγ/RORγT and JAK1 deficiencies. These recent findings illustrate how genetic and immunological studies of MSMD can shed a unique light onto the mechanisms of protective immunity to mycobacteria in humans.
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http://dx.doi.org/10.1111/imcb.12210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438774PMC
April 2019

Impaired IL-12- and IL-23-Mediated Immunity Due to IL-12Rβ1 Deficiency in Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease.

J Clin Immunol 2018 10 25;38(7):787-793. Epub 2018 Sep 25.

Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.

Purpose: Inborn errors of IFN-γ-mediated immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD), which is characterized by an increased susceptibility to severe and recurrent infections caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccines and environmental, nontuberculous mycobacteria (NTM).

Methods: In this study, we investigated four patients from four unrelated consanguineous families from Isfahan, Iran, with disseminated BCG disease. We evaluated the patients' whole blood cell response to IL-12 and IFN-γ, IL-12Rβ1 expression on T cell blasts, and sequenced candidate genes.

Results: We report four patients from Isfahan, Iran, ranging from 3 months to 26 years old, with impaired IL-12 signaling. All patients suffered from BCG disease. One of them presented mycobacterial osteomyelitis. By Sanger sequencing, we identified three different types of homozygous mutations in IL12RB1. Expression of IL-12Rβ1 was completely abolished in the four patients with IL12RB1 mutations.

Conclusions: IL-12Rβ1 deficiency was found in the four MSMD Iranian families tested. It is the first report of an Iranian case with S321* mutant IL-12Rβ1 protein. Mycobacterial osteomyelitis is another type of location of BCG infection in an IL-12Rβ1-deficient patient, notified for the first time in this study.
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http://dx.doi.org/10.1007/s10875-018-0548-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469360PMC
October 2018

Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency.

J Exp Med 2018 10 24;215(10):2567-2585. Epub 2018 Aug 24.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY

Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient's cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.
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http://dx.doi.org/10.1084/jem.20180628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170168PMC
October 2018

Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.

Nat Immunol 2018 09 20;19(9):973-985. Epub 2018 Aug 20.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA.

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory T1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a mice lack cDC2s, have CD4 T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory T1* cells.
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http://dx.doi.org/10.1038/s41590-018-0178-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130844PMC
September 2018

A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency.

J Clin Immunol 2018 07 11;38(5):617-627. Epub 2018 Jul 11.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France.

Purpose: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs.

Methods: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variations by IL12RB1-targeted next-generation sequencing (NGS).

Results: We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on phytohemagglutinin-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, either in the homozygous state (n = 1) or in trans (n = 4) with a single-nucleotide variation (n = 3) or a small indel (n = 1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%).

Conclusion: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency.
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http://dx.doi.org/10.1007/s10875-018-0527-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329663PMC
July 2018

Autosomal Dominant IFN-γR1 Deficiency Presenting with both Atypical Mycobacteriosis and Tuberculosis in a BCG-Vaccinated South African Patient.

J Clin Immunol 2018 05 18;38(4):460-463. Epub 2018 May 18.

DST/NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, 8000, Francie van Zijl Drive, Tygerberg, Cape Town, 7505, South Africa.

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http://dx.doi.org/10.1007/s10875-018-0509-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478027PMC
May 2018