{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:56:31Z","timestamp":1791593791992,"version":"4.3.4"},"reference-count":82,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2018,3,14]],"date-time":"2018-03-14T00:00:00Z","timestamp":1520985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,3,14]],"date-time":"2018-03-14T00:00:00Z","timestamp":1520985600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,3,14]],"date-time":"2018-03-14T00:00:00Z","timestamp":1520985600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R01AI089970-02"],"award-info":[{"award-number":["5R01AI089970-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1042925"],"award-info":[{"award-number":["1042925"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["281297"],"award-info":[{"award-number":["281297"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004963","name":"Seventh Framework Programme","doi-asserted-by":"publisher","award":["FP\/2007-2013"],"award-info":[{"award-number":["FP\/2007-2013"]}],"id":[{"id":"10.13039\/501100004963","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-IFNPHOX (ANR-13-ISV3-001-01)"],"award-info":[{"award-number":["ANR-IFNPHOX (ANR-13-ISV3-001-01)"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-10-LABX-62-IBEID"],"award-info":[{"award-number":["ANR-10-LABX-62-IBEID"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-GENMSMD (ANR-16-CE17-0005-01)"],"award-info":[{"award-number":["ANR-GENMSMD (ANR-16-CE17-0005-01)"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-14-CE14-0008-02"],"award-info":[{"award-number":["ANR-14-CE14-0008-02"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-14-CE14-0007-02"],"award-info":[{"award-number":["ANR-14-CE14-0007-02"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1113904"],"award-info":[{"award-number":["1113904"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["NKIR-ANR-13-PDOC-0025-01"],"award-info":[{"award-number":["NKIR-ANR-13-PDOC-0025-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Most humans are exposed to Tropheryma whipplei (Tw). Whipple\u2019s disease (WD) strikes only a small minority of individuals infected with Tw (&lt;0.01%), whereas asymptomatic chronic carriage is more common (&lt;25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.<\/jats:p>","DOI":"10.7554\/elife.32340","type":"journal-article","created":{"date-parts":[[2018,3,13]],"date-time":"2018-03-13T09:00:19Z","timestamp":1520931619000},"source":"Crossref","is-referenced-by-count":70,"title":["IRF4 haploinsufficiency in a family with Whipple\u2019s disease"],"prefix":"10.7554","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6810-1607","authenticated-orcid":true,"given":"Antoine","family":"Gu\u00e9rin","sequence":"first","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0146-9428","authenticated-orcid":true,"given":"Gaspard","family":"Kerner","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico","family":"Marr","sequence":"additional","affiliation":[{"name":"Sidra Medicine, Doha, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet G","family":"Markle","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Fenollar","sequence":"additional","affiliation":[{"name":"Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille, URMITE, UM63, CNRS 7278, IRD 198, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Wong","sequence":"additional","affiliation":[{"name":"Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia"},{"name":"St Vincent\u2019s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabri","family":"Boughorbel","sequence":"additional","affiliation":[{"name":"Sidra Medicine, Doha, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle T","family":"Avery","sequence":"additional","affiliation":[{"name":"Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia"},{"name":"St Vincent\u2019s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy S","family":"Ma","sequence":"additional","affiliation":[{"name":"Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia"},{"name":"St Vincent\u2019s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salim","family":"Bougarn","sequence":"additional","affiliation":[{"name":"Sidra Medicine, Doha, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Bouaziz","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivien","family":"B\u00e9ziat","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8733-7623","authenticated-orcid":true,"given":"Erika","family":"Della Mina","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Oleaga-Quintas","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomi","family":"Lazarov","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States"},{"name":"Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Worley","sequence":"additional","affiliation":[{"name":"Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia"},{"name":"St Vincent\u2019s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia"},{"name":"St Vincent\u2019s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Patin","sequence":"additional","affiliation":[{"name":"Human Evolutionary Genetics Unit, Department of Genomes and Genetics, Institut Pasteur, Paris, France"},{"name":"CNRS UMR2000, Paris, France"},{"name":"Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Deswarte","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"Martinez-Barricarte","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soraya","family":"Boucherit","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Ayral","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Cochin Hospital, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Edouard","sequence":"additional","affiliation":[{"name":"Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille, URMITE, UM63, CNRS 7278, IRD 198, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Boisson-Dupuis","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"},{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vimel","family":"Rattina","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Bigio","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Vogt","sequence":"additional","affiliation":[{"name":"Imagine Institute, Paris Descartes University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Geissmann","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States"},{"name":"Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, United States"},{"name":"Weill Cornell Graduate School of Medical Sciences, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lluis","family":"Quintana-Murci","sequence":"additional","affiliation":[{"name":"Human Evolutionary Genetics Unit, Department of Genomes and Genetics, Institut Pasteur, Paris, France"},{"name":"CNRS UMR2000, Paris, France"},{"name":"Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Chaussabel","sequence":"additional","affiliation":[{"name":"Sidra Medicine, Doha, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart G","family":"Tangye","sequence":"additional","affiliation":[{"name":"Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia"},{"name":"St Vincent\u2019s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Raoult","sequence":"additional","affiliation":[{"name":"Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille, URMITE, UM63, CNRS 7278, IRD 198, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Abel","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"},{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3439-2482","authenticated-orcid":true,"given":"Jacinta","family":"Bustamante","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"},{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States"},{"name":"Center for the Study of Primary Immunodeficiencies, Assistance Publique-H\u00f4pitaux de Paris, Necker Hospital for Sick Children, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7782-4169","authenticated-orcid":true,"given":"Jean-Laurent","family":"Casanova","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases,\u00a0Necker Branch, INSERM U1163, Paris, France"},{"name":"Imagine Institute, Paris Descartes University, Paris, France"},{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States"},{"name":"Pediatric Hematology and Immunology Unit, Assistance Publique-H\u00f4pitaux de Paris, Necker Hospital for Sick Children, Paris, France"},{"name":"Howard Hughes Medical Institute, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2018,3,14]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/ng786","article-title":"Merlin--rapid analysis of dense genetic maps using sparse gene flow trees","volume":"30","author":"Abecasis","year":"2002","journal-title":"Nature Genetics"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1038\/ni.3753","article-title":"BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency","volume":"18","author":"Afzali","year":"2017","journal-title":"Nature Immunology"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1038\/ni.3028","article-title":"A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4","volume":"15","author":"Alsina","year":"2014","journal-title":"Nature Immunology"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/s15010-002-3083-0","article-title":"Prevalence of Tropheryma whipplei DNA in patients with various gastrointestinal diseases and in healthy controls","volume":"31","author":"Amsler","year":"2003","journal-title":"Infection"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1084\/jem.20142274","article-title":"Functional IRF3 deficiency in a patient with herpes simplex encephalitis","volume":"212","author":"Andersen","year":"2015","journal-title":"The Journal of Experimental Medicine"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1086\/588706","article-title":"Acquired resistance to trimethoprim-sulfamethoxazole during Whipple disease and expression of the causative target gene","volume":"198","author":"Bakkali","year":"2008","journal-title":"The Journal of Infectious Diseases"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/nrg2698","article-title":"From evolutionary genetics to human immunology: how selection shapes host defence genes","volume":"11","author":"Barreiro","year":"2010","journal-title":"Nature Reviews Genetics"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"6713","DOI":"10.1073\/pnas.1606460113","article-title":"Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage","volume":"113","author":"Belkadi","year":"2016","journal-title":"PNAS"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"1684","DOI":"10.1126\/science.1224026","article-title":"Mycobacterial disease and impaired IFN-\u03b3 immunity in humans with inherited ISG15 deficiency","volume":"337","author":"Bogunovic","year":"2012","journal-title":"Science"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1093\/emboj\/18.4.977","article-title":"Assembly requirements of PU.1-Pip (IRF-4) activator complexes: inhibiting function in vivo using fused dimers","volume":"18","author":"Brass","year":"1999","journal-title":"The EMBO Journal"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3389\/fmed.2017.00087","article-title":"Fluorescence In Situ Hybridization for Diagnosis of Whipple's Disease in Formalin-Fixed Paraffin-Embedded Tissue","volume":"4","author":"Braubach","year":"2017","journal-title":"Frontiers in Medicine"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1084\/jem.20170057","article-title":"Transcriptional and functional profiling defines human small intestinal macrophage subsets","volume":"215","author":"Bujko","year":"2018","journal-title":"The Journal of Experimental Medicine"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"2307","DOI":"10.1084\/jem.20101597","article-title":"Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma","volume":"207","author":"Byun","year":"2010","journal-title":"The Journal of Experimental Medicine"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"E7118","DOI":"10.1073\/pnas.1521644112","article-title":"Human genetic basis of interindividual variability in the course of infection","volume":"112","author":"Casanova","year":"2015","journal-title":"PNAS"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"E7128","DOI":"10.1073\/pnas.1521651112","article-title":"Severe infectious diseases of childhood as monogenic inborn errors of immunity","volume":"112","author":"Casanova","year":"2015","journal-title":"PNAS"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1126\/science.aaa1578","article-title":"Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency","volume":"348","author":"Ciancanelli","year":"2015","journal-title":"Science"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1016\/j.micinf.2010.08.001","article-title":"New insights into Whipple's disease and Tropheryma whipplei infections","volume":"12","author":"Desnues","year":"2010","journal-title":"Microbes and Infection"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1007\/BF01391638","article-title":"Is there an immune deficit in Whipple's disease?","volume":"26","author":"Dobbins","year":"1981","journal-title":"Digestive Diseases and Sciences"},{"key":"bib19","volume-title":"Thomas Books","author":"Dobbins","year":"1987"},{"key":"bib20","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/00005792-199705000-00003","article-title":"Whipple disease. Clinical review of 52 cases. The SNFMI Research Group on Whipple Disease. Soci\u00e9t\u00e9 Nationale Fran\u00e7aise de M\u00e9decine Interne","volume":"76","author":"Durand","year":"1997","journal-title":"Medicine"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"3917","DOI":"10.1128\/JCM.01517-12","article-title":"The rise of Tropheryma whipplei: a 12-year retrospective study of PCR diagnoses in our reference center","volume":"50","author":"Edouard","year":"2012","journal-title":"Journal of Clinical Microbiology"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"2214","DOI":"10.1016\/S0140-6736(99)01776-6","article-title":"PCR-positive tests for Tropheryma whippelii in patients without Whipple's disease","volume":"353","author":"Ehrbar","year":"1999","journal-title":"The Lancet"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"e1002806","DOI":"10.1371\/journal.pcbi.1002806","article-title":"SnIPRE: selection inference using a Poisson random effects model","volume":"8","author":"Eilertson","year":"2012","journal-title":"PLoS Computational Biology"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1016\/S1097-2765(02)00703-7","article-title":"Crystal structure of PU.1\/IRF-4\/DNA ternary complex","volume":"10","author":"Escalante","year":"2002","journal-title":"Molecular Cell"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1086\/604717","article-title":"A paradoxical Tropheryma whipplei western blot differentiates patients with whipple disease from asymptomatic carriers","volume":"49","author":"Fenollar","year":"2009","journal-title":"Clinical Infectious Diseases"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.jinf.2014.05.008","article-title":"Tropheryma whipplei and Whipple's disease","volume":"69","author":"Fenollar","year":"2014","journal-title":"Journal of Infection"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1086\/590559","article-title":"Value of Tropheryma whipplei quantitative polymerase chain reaction assay for the diagnosis of Whipple disease: usefulness of saliva and stool specimens for first-line screening","volume":"47","author":"Fenollar","year":"2008","journal-title":"Clinical Infectious Diseases"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1086\/322666","article-title":"Whipple's endocarditis: review of the literature and comparisons with Q fever, Bartonella infection, and blood culture-positive endocarditis","volume":"33","author":"Fenollar","year":"2001","journal-title":"Clinical Infectious Diseases"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1056\/NEJMra062477","article-title":"Whipple's disease","volume":"356","author":"Fenollar","year":"2007","journal-title":"New England Journal of Medicine"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1086\/528693","article-title":"Prevalence of asymptomatic Tropheryma whipplei carriage among humans and nonhuman primates","volume":"197","author":"Fenollar","year":"2008","journal-title":"The Journal of Infectious Diseases"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1016\/S0025-6196(12)64884-8","article-title":"Whipple's disease: clinical, biochemical, and histopathologic features and assessment of treatment in 29 patients","volume":"63","author":"Fleming","year":"1988","journal-title":"Mayo Clinic Proceedings"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1093\/bioinformatics\/btg405","article-title":"affy--analysis of Affymetrix GeneChip data at the probe level","volume":"20","author":"Gautier","year":"2004","journal-title":"Bioinformatics"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"112","DOI":"10.7326\/0003-4819-131-2-199907200-00007","article-title":"Whipple endocarditis without overt gastrointestinal disease: report of four cases","volume":"131","author":"Gubler","year":"1999","journal-title":"Annals of Internal Medicine"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1101\/sqb.2013.78.020321","article-title":"The IRF family transcription factors at the interface of innate and adaptive immune responses","volume":"78","author":"Ikushima","year":"2013","journal-title":"Cold Spring Harbor Symposia on Quantitative Biology"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1093\/biostatistics\/4.2.249","article-title":"Exploration, normalization, and summaries of high density oligonucleotide array probe level data","volume":"4","author":"Irizarry","year":"2003","journal-title":"Biostatistics"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/j.cell.2017.01.039","article-title":"Human adaptive immunity rescues an inborn error of innate immunityImmunity","volume":"168","author":"Israel","year":"2017","journal-title":"Cell"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nmeth.3739","article-title":"The mutation significance cutoff: gene-level thresholds for variant predictions","volume":"13","author":"Itan","year":"2016","journal-title":"Nature Methods"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"13615","DOI":"10.1073\/pnas.1518646112","article-title":"The human gene damage index as a gene-level approach to prioritizing exome variants","volume":"112","author":"Itan","year":"2015","journal-title":"PNAS"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nature Genetics"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1038\/ni1357","article-title":"Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination","volume":"7","author":"Klein","year":"2006","journal-title":"Nature Immunology"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.1093\/jac\/dkq263","article-title":"Failure and relapse after treatment with trimethoprim\/sulfamethoxazole in classic Whipple's disease","volume":"65","author":"Lagier","year":"2010","journal-title":"Journal of Antimicrobial Chemotherapy"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1093\/jac\/dkr032","article-title":"Evidence of lifetime susceptibility to Tropheryma whipplei in patients with Whipple's disease","volume":"66","author":"Lagier","year":"2011","journal-title":"Journal of Antimicrobial Chemotherapy"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1084\/jem.20161759","article-title":"Recurrent rhinovirus infections in a child with inherited MDA5 deficiency","volume":"214","author":"Lamborn","year":"2017","journal-title":"The Journal of Experimental Medicine"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"7278","DOI":"10.1073\/pnas.97.13.7278","article-title":"Interferon regulatory factor subcellular localization is determined by a bipartite nuclear localization signal in the DNA-binding domain and interaction with cytoplasmic retention factors","volume":"97","author":"Lau","year":"2000","journal-title":"PNAS"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1099\/mic.0.2007\/011668-0","article-title":"Genotyping reveals a wide heterogeneity of Tropheryma whipplei","volume":"154","author":"Li","year":"2008","journal-title":"Microbiology"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1038\/nature11530","article-title":"BATF-JUN is critical for IRF4-mediated transcription in T cells","volume":"490","author":"Li","year":"2012","journal-title":"Nature"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"11808","DOI":"10.1073\/pnas.182425099","article-title":"Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4","volume":"99","author":"Lohoff","year":"2002","journal-title":"PNAS"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"3997","DOI":"10.1182\/blood-2011-11-392985","article-title":"Functional STAT3 deficiency compromises the generation of human T follicular helper cells","volume":"119","author":"Ma","year":"2012","journal-title":"Blood"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1084\/jem.20151467","article-title":"Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets","volume":"213","author":"Ma","year":"2016","journal-title":"The Journal of Experimental Medicine"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1111\/j.1572-0241.2005.40128.x","article-title":"Immunosuppressive therapy in Whipple's disease patients is associated with the appearance of gastrointestinal manifestations","volume":"100","author":"Mahnel","year":"2005","journal-title":"The American Journal of Gastroenterology"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"2466","DOI":"10.1128\/JCM.40.7.2466-2471.2002","article-title":"Detection of Tropheryma whipplei DNA in feces by PCR using a target capture method","volume":"40","author":"Maibach","year":"2002","journal-title":"Journal of Clinical Microbiology"},{"key":"bib55","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1097\/00005792-197005000-00001","article-title":"Whipple's disease: a review of 19 patients from one hospital and a review of the literature since 1950","volume":"49","author":"Maizel","year":"1970","journal-title":"Medicine"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"e13","DOI":"10.1016\/S1473-3099(15)00537-X","article-title":"Tropheryma whipplei infection and Whipple's disease","volume":"16","author":"Marth","year":"2016","journal-title":"The Lancet Infectious Diseases"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"2131","DOI":"10.1007\/s11606-008-0776-9","article-title":"Whipple's disease: neurological relapse presenting as headache for two years","volume":"23","author":"Marumganti","year":"2008","journal-title":"Journal of General Internal Medicine"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Research"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1126\/science.275.5299.540","article-title":"Requirement for the transcription factor LSIRF\/IRF4 for mature B and T lymphocyte function","volume":"275","author":"Mittr\u00fccker","year":"1997","journal-title":"Science"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"3543","DOI":"10.1172\/JCI92280","article-title":"Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections","volume":"127","author":"Ogunjimi","year":"2017","journal-title":"Journal of Clinical Investigation"},{"key":"bib61","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1007\/s10875-017-0464-9","article-title":"International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity","volume":"38","author":"Picard","year":"2018","journal-title":"Journal of Clinical Immunology"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1007\/BF02934754","article-title":"Whipple's disease in a father-son pair","volume":"1","author":"Ponz de Leon","year":"2006","journal-title":"Internal and Emergency Medicine"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"The American Journal of Human Genetics"},{"key":"bib64","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.jbspin.2016.07.001","article-title":"Whipple's arthritis","volume":"83","author":"Pu\u00e9chal","year":"2016","journal-title":"Joint Bone Spine"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.immuni.2010.08.014","article-title":"Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis","volume":"33","author":"P\u00e9rez de Diego","year":"2010","journal-title":"Immunity"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/nri3421","article-title":"Population genetic tools for dissecting innate immunity in humans","volume":"13","author":"Quintana-Murci","year":"2013","journal-title":"Nature Reviews Immunology"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1056\/NEJM200003023420903","article-title":"Cultivation of the bacillus of Whipple's disease","volume":"342","author":"Raoult","year":"2000","journal-title":"New England Journal of Medicine"},{"key":"bib68","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1056\/NEJM199207303270501","article-title":"Identification of the uncultured bacillus of Whipple's disease","volume":"327","author":"Relman","year":"1992","journal-title":"New England Journal of Medicine"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1126\/science.1260791","article-title":"Immunology. Autoimmunity by haploinsufficiency","volume":"345","author":"Rieux-Laucat","year":"2014","journal-title":"Science"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/1471-2180-7-48","article-title":"False positive PCR detection of Tropheryma whipplei in the saliva of healthy people","volume":"7","author":"Rolain","year":"2007","journal-title":"BMC Microbiology"},{"key":"bib71","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/S1473-3099(08)70042-2","article-title":"Whipple's disease: new aspects of pathogenesis and treatment","volume":"8","author":"Schneider","year":"2008","journal-title":"The Lancet Infectious Diseases"},{"key":"bib72","doi-asserted-by":"publisher","first-page":"2954","DOI":"10.1158\/1078-0432.CCR-08-1845","article-title":"IRF4: Immunity. Malignancy! Therapy?","volume":"15","author":"Shaffer","year":"2009","journal-title":"Clinical Cancer Research"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1016\/S0140-6736(99)03065-2","article-title":"Tropheryma whippelii DNA in saliva of healthy people","volume":"354","author":"Street","year":"1999","journal-title":"The Lancet"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"8981","DOI":"10.1073\/pnas.0402139101","article-title":"Critical roles of interferon regulatory factor 4 in CD11bhighCD8alpha- dendritic cell development","volume":"101","author":"Suzuki","year":"2004","journal-title":"PNAS"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"2573","DOI":"10.4049\/jimmunol.174.5.2573","article-title":"IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity","volume":"174","author":"Tamura","year":"2005","journal-title":"The Journal of Immunology"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/intimm\/dxg001","article-title":"Development of Th1 and not Th2 immune responses in mice lacking IFN-regulatory factor-4","volume":"15","author":"Tominaga","year":"2003","journal-title":"International Immunology"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"2752","DOI":"10.1056\/NEJMoa063265","article-title":"Human Trypanosoma evansi infection linked to a lack of apolipoprotein L-I","volume":"355","author":"Vanhollebeke","year":"2006","journal-title":"New England Journal of Medicine"},{"key":"bib78","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Research"},{"key":"bib79","first-page":"382","article-title":"A hitherto undescribed disease characterized anatomically by deposits of fat and fattyacids in the intestinal and mesentericlymphatic tissues","volume":"18","author":"Whipple","year":"1907","journal-title":"Bulletin of the Johns Hopkins Hospital"},{"key":"bib80","first-page":"80","article-title":"Combined electron and light microscopy in Whipple's disease. Demonstration of \"bacillary bodies\" in the intestine","volume":"109","author":"Yardley","year":"1961","journal-title":"Bulletin of the Johns Hopkins Hospital"},{"key":"bib81","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1038\/ni.3275","article-title":"Genomics is rapidly advancing precision medicine for immunological disorders","volume":"16","author":"Zhang","year":"2015","journal-title":"Nature Immunology"},{"key":"bib82","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1016\/j.cell.2018.02.019","article-title":"Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection","volume":"172","author":"Zhang","year":"2018","journal-title":"Cell"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/32340\/elife-32340-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/32340\/elife-32340-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/32340","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T20:49:44Z","timestamp":1697057384000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/32340"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,14]]},"references-count":82,"alternative-id":["10.7554\/eLife.32340"],"URL":"https:\/\/doi.org\/10.7554\/elife.32340","archive":["CLOCKSS"],"relation":{"is-supplemented-by":[{"id-type":"uri","id":"https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE102862","asserted-by":"subject"}],"has-preprint":[{"id-type":"doi","id":"10.1101\/197145","asserted-by":"object"}],"has-review":[{"id-type":"doi","id":"10.3410\/f.732842685.793572025","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.32340.035","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.32340.036","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,14]]},"article-number":"e32340"}}