Author
Gaspard Kerner
Other affiliations: Paris Descartes University, Pasteur Institute
Bio: Gaspard Kerner is an academic researcher from French Institute of Health and Medical Research. The author has contributed to research in topics: Natural killer T cell & Tuberculosis. The author has an hindex of 7, co-authored 11 publications receiving 434 citations. Previous affiliations of Gaspard Kerner include Paris Descartes University & Pasteur Institute.
Papers
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Rockefeller University1, Garvan Institute of Medical Research2, Shahid Beheshti University of Medical Sciences and Health Services3, University of Melbourne4, Walter and Eliza Hall Institute of Medical Research5, Royal Melbourne Hospital6, French Institute of Health and Medical Research7, Paris Descartes University8, Pasteur Institute9, Icahn School of Medicine at Mount Sinai10, Centre national de la recherche scientifique11, Hiroshima University12, University of Erlangen-Nuremberg13, Ankara University14, Memorial Sloan Kettering Cancer Center15, Cornell University16, King's College London17, La Jolla Institute for Allergy and Immunology18, University of California, San Diego19, Versailles Saint-Quentin-en-Yvelines University20, Leiden University Medical Center21, ETH Zurich22
TL;DR: 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.
Abstract: 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 TH1* cells (CD45RA-CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R 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.
139 citations
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Rockefeller University1, Paris Descartes University2, French Institute of Health and Medical Research3, Pasteur Institute4, Centre national de la recherche scientifique5, Garvan Institute of Medical Research6, Karolinska University Hospital7, Singapore General Hospital8, University of Vermont9, University of New South Wales10, Qatar Airways11, Université de Montréal12, University of Ottawa13, Memorial Sloan Kettering Cancer Center14, University of Chile15, Pontifical Catholic University of Chile16, Icahn School of Medicine at Mount Sinai17, University of La Frontera18, Federal University of São Paulo19, University of São Paulo20, Bilkent University21, University of Erlangen-Nuremberg22, Tehran University of Medical Sciences23, San Sebastián University24, Seattle Children's Research Institute25, Beijing Genomics Institute26
TL;DR: Homozygosity for the catalytically inactive P1104A missense variant of the TYK2 Janus kinase selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
Abstract: 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 TYK2 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 (P = 8.37 × 10-8; 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 TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
127 citations
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Paris Descartes University1, Rockefeller University2, French Institute of Health and Medical Research3, Columbia University Medical Center4, University of Texas Health Science Center at San Antonio5, Shanghai Jiao Tong University6, National Institutes of Health7, Icahn School of Medicine at Mount Sinai8, Baylor College of Medicine9, Katholieke Universiteit Leuven10
TL;DR: The authors report three unrelated children with inheritedTLR3 deficiency, impaired TLR3-dependent, IFN-α/β– and/or -λ–mediated, pulmonary epithelial cell–intrinsic immunity to influenza A virus, and life-threatening influenza pneumonitis.
Abstract: Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN-mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.
121 citations
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Paris Descartes University1, French Institute of Health and Medical Research2, Garvan Institute of Medical Research3, University of New South Wales4, Boston Children's Hospital5, Istanbul University6, Centre national de la recherche scientifique7, Pasteur Institute8, University of Erlangen-Nuremberg9, Rockefeller University10, Harvard University11
TL;DR: In two complementary papers, Casanova, Malissen, and collaborators report the discovery of human RLTPR deficiency, the first primary immunodeficiency of the human CD28 pathway in T cells.
Abstract: Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell–intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR , the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4+ T cells are reduced. Their CD4+ T cells do not respond to CD28 stimulation. Their CD4+ T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients’ B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.
89 citations
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TL;DR: A strong enrichment of P1104A homozygotes in a British sample of 620 patients with TB (1%), relative to 114,473 controls, suggests that homozygosity for the P 1104A TYK2 variant may underlie TB in ∼1% of European patients.
Abstract: The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 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, P = 2 × 10−3]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, 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 TYK2 P1104A may account for ∼1% of TB cases in Europeans.
85 citations
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01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
4,409 citations
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TL;DR: The COVID Human Genetic Effort established to test the general hypothesis that life-threatening COVID-19 in some or most patients may be caused by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or complete penetrance finds an enrichment in variants predicted to be loss-of-function (pLOF), with a minor allele frequency <0.001.
Abstract: 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.
1,659 citations
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Garvan Institute of Medical Research1, Kuwait University2, Boston Children's Hospital3, Icahn School of Medicine at Mount Sinai4, University of Antioquia5, National Institutes of Health6, Ludwig Maximilian University of Munich7, Tokyo Medical and Dental University8, Seattle Children's Research Institute9, Paris Diderot University10, University of Paris11, University of California, San Francisco12, Rockefeller University13, Children's Hospital of Philadelphia14
TL;DR: This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies.
Abstract: We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.
825 citations
01 Jan 2012
TL;DR: A meta-analysis of genome-wide association studies and independent data sets genotyped on the Immunochip identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals, and identified five independent signals within previously known loci.
Abstract: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense. © 2012 Nature America, Inc. All rights reserved.
464 citations
01 Nov 2017
TL;DR: ChromHMM combines multiple genome-wide epigenomic maps, and uses combinatorial and spatial mark patterns to infer a complete annotation for each cell type, and provides an automated enrichment analysis of the resulting annotations to facilitate the functional interpretations of each chromatin state.
Abstract: Noncoding DNA regions have central roles in human biology, evolution, and disease. ChromHMM helps to annotate the noncoding genome using epigenomic information across one or multiple cell types. It combines multiple genome-wide epigenomic maps, and uses combinatorial and spatial mark patterns to infer a complete annotation for each cell type. ChromHMM learns chromatin-state signatures using a multivariate hidden Markov model (HMM) that explicitly models the combinatorial presence or absence of each mark. ChromHMM uses these signatures to generate a genome-wide annotation for each cell type by calculating the most probable state for each genomic segment. ChromHMM provides an automated enrichment analysis of the resulting annotations to facilitate the functional interpretations of each chromatin state. ChromHMM is distinguished by its modeling emphasis on combinations of marks, its tight integration with downstream functional enrichment analyses, its speed, and its ease of use. Chromatin states are learned, annotations are produced, and enrichments are computed within 1 d.
364 citations