{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T12:03:53Z","timestamp":1792843433705,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T00:00:00Z","timestamp":1621468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p><jats:italic>Tropheryma whipplei<\/jats:italic>is the agent of Whipple\u2019s disease, a rare systemic disease characterized by macrophage infiltration of the intestinal mucosa. The disease first manifests as arthralgia and\/or arthropathy that usually precede the diagnosis by years, and which may push clinicians to prescribe Tumor necrosis factor inhibitors (TNFI) to treat unexplained arthralgia. However, such therapies have been associated with exacerbation of subclinical undiagnosed Whipple\u2019s disease. The objective of this study was to delineate the biological basis of disease exacerbation. We found that etanercept, adalimumab or certolizumab treatment of monocyte-derived macrophages from healthy subjects significantly increased bacterial replication<jats:italic>in vitro<\/jats:italic>without affecting uptake. Interestingly, this effect was associated with macrophage repolarization and increased rate of apoptosis. Further analysis revealed that in patients for whom Whipple\u2019s disease diagnosis was made while under TNFI therapy, apoptosis was increased in duodenal tissue specimens as compared with control Whipple\u2019s disease patients who never received TNFI prior diagnosis. In addition, IFN-\u03b3 expression was increased in duodenal biopsy specimen and circulating levels of IFN-\u03b3 were higher in patients for whom Whipple\u2019s disease diagnosis was made while under TNFI therapy. Taken together, our findings establish that TNFI aggravate\/exacerbate latent or subclinical undiagnosed Whipple\u2019s disease by promoting a strong inflammatory response and apoptosis and confirm that patients may be screened for<jats:italic>T. whipplei<\/jats:italic>prior to introduction of TNFI therapy.<\/jats:p>","DOI":"10.3389\/fimmu.2021.667357","type":"journal-article","created":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T07:11:58Z","timestamp":1621494718000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Tumor Necrosis Factor Inhibitors Exacerbate Whipple\u2019s Disease by Reprogramming Macrophage and Inducing Apoptosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Asma","family":"Boumaza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soraya","family":"Mezouar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Bardou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Raoult","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"M\u00e8ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit","family":"Desnues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s1473-3099(15)00537-x","article-title":"Tropheryma Whipplei Infection and Whipple\u2019s Disease","volume":"16","author":"Marth","year":"2016","journal-title":"Lancet Infect Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy668","article-title":"From Whipple Disease to Tropheryma Whipplei Infection","volume":"68","author":"Raoult","year":"2019","journal-title":"Clin Infect Dis an Off Publ Infect Dis Soc America"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e32340","DOI":"10.7554\/eLife.32340","article-title":"IRF4 Haploinsufficiency in a Family With Whipple\u2019s Disease","volume":"7","author":"Gu\u00e9rin","year":"2018","journal-title":"eLife"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/00002281-200101000-00012","article-title":"Whipple Disease and Arthritis","volume":"13","author":"Pu\u00e9chal","year":"2001","journal-title":"Curr Opin Rheumatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2005.40128.x","article-title":"Immunosuppressive Therapy in Whipple\u2019s Disease Patients is Associated With the Appearance of Gastrointestinal Manifestations","volume":"100","author":"Mahnel","year":"2005","journal-title":"Am J Gastroenterol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/apt.13140","article-title":"Systematic Review: Whipple\u2019s Disease (Tropheryma Whipplei Infection) and its Unmasking by Tumour Necrosis Factor Inhibitors","volume":"41","author":"Marth","year":"2015","journal-title":"Aliment Pharmacol Ther"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2017.22","article-title":"Beyond TNF: TNF Superfamily Cytokines as Targets for the Treatment of Rheumatic Diseases","volume":"13","author":"Croft","year":"2017","journal-title":"Nat Rev Rheumatol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"79","DOI":"10.2147\/dhps.S28801","article-title":"Clinical Use of anti-TNF Therapy and Increased Risk of Infections","volume":"5","author":"Ali","year":"2013","journal-title":"Drug Healthc Patient Saf"},{"key":"B9","doi-asserted-by":"publisher","first-page":"S10","DOI":"10.1016\/j.cmi.2017.12.025","article-title":"Escmid Study Group for Infections in Compromised Hosts (Esgich) Consensus Document on the Safety of Targeted and Biological Therapies: An Infectious Diseases Perspective (Soluble Immune Effector Molecules [I]: Anti-Tumor Necrosis Factor-\u03b1 Agents)","volume":"24","author":"Baddley","year":"2018","journal-title":"Clin Microbiol infect Off Publ Eur Soc Clin Microbiol Infect Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2006.05.027","article-title":"Hepatitis B Virus Reactivation After Cytotoxic Chemotherapy: The Disease and its Prevention","volume":"4","author":"Mindikoglu","year":"2006","journal-title":"Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc"},{"key":"B11","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.cyto.2016.08.014","article-title":"Molecular Mechanisms of Action of Anti-TNF-\u03b1 Agents - Comparison Among Therapeutic TNF-\u03b1 Antagonists","volume":"101","author":"Mitoma","year":"2018","journal-title":"Cytokine"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.07.034","article-title":"Tropheryma Whipplei Increases Expression of Human Leukocyte Antigen-G on Monocytes to Reduce Tumor Necrosis Factor and Promote Bacterial Replication","volume":"155","author":"Ben Azzouz","year":"2018","journal-title":"Gastroenterology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01947","article-title":"Tumor Necrosis Factor-Alpha Antagonist Interferes With the Formation of Granulomatous Multinucleated Giant Cells: New Insights Into Mycobacterium Tuberculosis Infection","volume":"10","author":"Mezouar","year":"2019","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9343(02)01174-9","article-title":"Immunohistological Detection of Tropheryma Whipplei (Whipple Bacillus) in Lymph Nodes","volume":"113","author":"Lepidi","year":"2002","journal-title":"Am J Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.7.4575","article-title":"Il-16 is Critical for Tropheryma Whipplei Replication in Whipple\u2019s Disease","volume":"175","author":"Desnues","year":"2005","journal-title":"J Immunol (Baltimore Md 1950)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v22.i42.9300","article-title":"Molecular Mechanism of Action of Anti-Tumor Necrosis Factor Antibodies in Inflammatory Bowel Diseases","volume":"22","author":"Billmeier","year":"2016","journal-title":"World J Gastroenterol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e1000722","DOI":"10.1371\/journal.ppat.1000722","article-title":"Type I Interferon Induction is Detrimental During Infection With the Whipple\u2019s Disease Bacterium, Tropheryma Whipplei","volume":"6","author":"Al Moussawi","year":"2010","journal-title":"PloS Pathog"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e34","DOI":"10.1038\/cddis.2010.11","article-title":"Tropheryma Whipplei, the Whipple\u2019s Disease Bacillus, Induces Macrophage Apoptosis Through the Extrinsic Pathway","volume":"1","author":"Gorvel","year":"2010","journal-title":"Cell Death Dis"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4330\/wjc.v6.i12.1278","article-title":"Complicated Whipple\u2019s Disease and Endocarditis Following Tumor Necrosis Factor Inhibitors","volume":"6","author":"Marth","year":"2014","journal-title":"World J Cardiol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e000216","DOI":"10.1136\/bmjgast-2018-000216","article-title":"Tnf\u03b1 Inhibitors Exacerbate Mycobacterium Paratuberculosis Infection in Tissue Culture: A Rationale for Poor Response of Patients With Crohn\u2019s Disease to Current Approved Therapy","volume":"5","author":"Qasem","year":"2018","journal-title":"BMJ Open gastroenterol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1128\/iai.69.6.3947-3953.2001","article-title":"Legionella Pneumophila Replication in Macrophages Inhibited by Selective Immunomodulatory Effects on Cytokine Formation by Epigallocatechin Gallate, a Major Form of Tea Catechins","volume":"69","author":"Matsunaga","year":"2001","journal-title":"Infect Immun"},{"key":"B22","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.160.3.1290","article-title":"Cytokine Activation Leads to Acidification and Increases Maturation of Mycobacterium Avium-Containing Phagosomes in Murine Macrophages","volume":"160","author":"Schaible","year":"1998","journal-title":"J Immunol (Baltimore Md 1950)"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.64.8.3236-3243.1996","article-title":"Roles for Tumor Necrosis Factor Alpha and Nitric Oxide in Resistance of Rat Alveolar Macrophages to Legionella Pneumophila","volume":"64","author":"Skerrett","year":"1996","journal-title":"Infect Immun"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.61.12.4980-4983.1993","article-title":"Involvement of Tumor Necrosis Factor Alpha in Intracellular Multiplication of Legionella Pneumophila in Human Monocytes","volume":"61","author":"Matsiota-Bernard","year":"1993","journal-title":"Infect Immun"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1086\/593174","article-title":"Tumor Necrosis Factor Blockers Influence Macrophage Responses to Mycobacterium Tuberculosis","volume":"198","author":"Harris","year":"2008","journal-title":"J Infect Dis"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.175.4.1111","article-title":"Killing of Virulent Mycobacterium Tuberculosis by Reactive Nitrogen Intermediates Produced by Activated Murine Macrophages","volume":"175","author":"Chan","year":"1992","journal-title":"J Exp Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.62.3.1089-1100.1994","article-title":"Nitric Oxide Produced During Murine Listeriosis is Protective","volume":"62","author":"Boockvar","year":"1994","journal-title":"Infect Immun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.63.9.3253-3258.1995","article-title":"In Vivo Regulation of Replicative Legionella Pneumophila Lung Infection by Endogenous Tumor Necrosis Factor Alpha and Nitric Oxide","volume":"63","author":"Brieland","year":"1995","journal-title":"Infect Immun"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.022","article-title":"TNF Dually Mediates Resistance and Susceptibility to Mycobacteria Via Mitochondrial Reactive Oxygen Species","volume":"153","author":"Roca","year":"2013","journal-title":"Cell"},{"key":"B30","article-title":"Effects of TNF Inhibitors on Human Monocytes","volume":"44","author":"Tono","year":"2014","journal-title":"Kitasato Med J"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/art.23447","article-title":"Mechanisms for Cytotoxic Effects of Anti-Tumor Necrosis Factor Agents on Transmembrane Tumor Necrosis Factor Alpha-Expressing Cells: Comparison Among Infliximab, Etanercept, and Adalimumab","volume":"58","author":"Mitoma","year":"2008","journal-title":"Arthritis Rheumatism"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1136\/gut.50.2.206","article-title":"Infliximab Treatment Induces Apoptosis of Lamina Propria T Lymphocytes in Crohn\u2019s Disease","volume":"50","author":"ten Hove","year":"2002","journal-title":"Gut"},{"key":"B33","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1002\/art.20764","article-title":"Evidence That Anti-Tumor Necrosis Factor Therapy With Both Etanercept and Infliximab Induces Apoptosis in Macrophages, But Not Lymphocytes, in Rheumatoid Arthritis Joints: Extended Report","volume":"52","author":"Catrina","year":"2005","journal-title":"Arthritis Rheumatism"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e494","DOI":"10.1371\/journal.pone.0000494","article-title":"Increased Levels of Circulating IL-16 and Apoptosis Markers are Related to the Activity of Whipple\u2019s Disease","volume":"2","author":"Benoit","year":"2007","journal-title":"PloS One"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2013.0123","article-title":"Etanercept Exacerbates Inflammation and Pathology in a Rabbit Model of Active Pulmonary Tuberculosis","volume":"34","author":"Tsenova","year":"2014","journal-title":"J Interferon Cytokine Res Off J Int Soc Interferon Cytokine Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.36583","article-title":"Dysregulated Peripheral and Mucosal Th1\/Th2 Response in Whipple\u2019s Disease","volume":"123","author":"Marth","year":"2002","journal-title":"Gastroenterology"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1086\/491745","article-title":"Whipple Disease: Intestinal Infiltrating Cells Exhibit a Transcriptional Pattern of M2\/alternatively Activated Macrophages","volume":"192","author":"Desnues","year":"2005","journal-title":"J Infect Dis"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.07.066","article-title":"Impaired Immune Functions of Monocytes and Macrophages in Whipple\u2019s Disease","volume":"138","author":"Moos","year":"2010","journal-title":"Gastroenterology"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/iai.02463-14","article-title":"Role of Dendritic Cells in the Pathogenesis of Whipple\u2019s Disease","volume":"83","author":"Schinnerling","year":"2015","journal-title":"Infect Immun"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.3.2015","article-title":"Reduced Peripheral and Mucosal Tropheryma Whipplei-Specific Th1 Response in Patients With Whipple\u2019s Disease","volume":"177","author":"Moos","year":"2006","journal-title":"J Immunol (Baltimore Md 1950)"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.10.008","article-title":"Anti-Tumor Necrosis Factor-\u03b1 Antibodies Induce Regulatory Macrophages in an Fc Region-Dependent Manner","volume":"140","author":"Vos","year":"2011","journal-title":"Gastroenterology"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2018.05.009","article-title":"Treatment With TNF-\u03b1 Inhibitor Rectifies M1 Macrophage Polarization From Blood CD14+ Monocytes in Patients With Psoriasis Independent of STAT1 and IRF-1 Activation","volume":"91","author":"Lin","year":"2018","journal-title":"J Dermatol Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00553","article-title":"Phagocytosis of Apoptotic Cells in Resolution of Inflammation","volume":"11","author":"Kourtzelis","year":"2020","journal-title":"Front Immunol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s40779-015-0039-0","article-title":"Programmed Cell Death and its Role in Inflammation","volume":"2","author":"Yang","year":"2015","journal-title":"Mil Med Res"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1136\/ard.60.2.133","article-title":"Increased Peripheral T Cell Reactivity to Microbial Antigens and Collagen Type II in Rheumatoid Arthritis After Treatment With Soluble TNFalpha Receptors","volume":"60","author":"Berg","year":"2001","journal-title":"Ann Rheumatic Dis"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1136\/ard.60.8.750","article-title":"Impaired Th1 Cytokine Production in Spondyloarthropathy is Restored by Anti-Tnfalpha","volume":"60","author":"Baeten","year":"2001","journal-title":"Ann Rheumatic Dis"},{"key":"B47","doi-asserted-by":"publisher","first-page":"26","DOI":"10.2340\/00015555-1650","article-title":"Infliximab Does Not Lead to Reduction in the Interferon-Gamma and Lymphoproliferative Responses of Patients With Moderate to Severe Psoriasis","volume":"94","author":"Ortigosa","year":"2014","journal-title":"Acta Dermato-Venereol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.23.13806","article-title":"Inhibition of Interferon Gamma Induced Interleukin 12 Production: A Potential Mechanism for the Anti-Inflammatory Activities of Tumor Necrosis Factor","volume":"95","author":"Hodge-Dufour","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1172\/jci18991","article-title":"TNF-Alpha is a Critical Negative Regulator of Type 1 Immune Activation During Intracellular Bacterial Infection","volume":"113","author":"Zganiacz","year":"2004","journal-title":"J Clin Invest"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1128\/iai.01011-07","article-title":"Tumor Necrosis Factor Blockade in Chronic Murine Tuberculosis Enhances Granulomatous Inflammation and Disorganizes Granulomas in the Lungs","volume":"76","author":"Chakravarty","year":"2008","journal-title":"Infect Immun"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00028510","article-title":"The Risk of Tuberculosis Related to Tumour Necrosis Factor Antagonist Therapies: A TBNET Consensus Statement","volume":"36","author":"Solovic","year":"2010","journal-title":"Eur Respir J"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.667357\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T23:18:39Z","timestamp":1699053519000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.667357\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,20]]},"references-count":51,"alternative-id":["10.3389\/fimmu.2021.667357"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.667357","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,20]]},"article-number":"667357"}}