{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:04:34Z","timestamp":1740146674703,"version":"3.37.3"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T00:00:00Z","timestamp":1609372800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011103","name":"Sixth Framework Programme","doi-asserted-by":"publisher","award":["LSHP-CT-2007-037659-TBIRIS"],"award-info":[{"award-number":["LSHP-CT-2007-037659-TBIRIS"]}],"id":[{"id":"10.13039\/100011103","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in HIV-TB co-infected patients receiving antiretroviral therapy (ART) has been linked to neutrophil activation. Anti-neutrophil cytoplasmic antibodies (ANCAs) are also associated with neutrophil activation. Since ANCAs are reportedly skewed in TB and HIV infections, we investigated plasma levels of 7 ANCAs in TB-IRIS patients.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We retrospectively compared 17 HIV-TB patients who developed TB-IRIS with controls of similar CD4 count, age and gender who did not (HIV<jats:sup>+<\/jats:sup>TB<jats:sup>+<\/jats:sup> n = 17), HIV-infected patients without TB (HIV<jats:sup>+<\/jats:sup>TB<jats:sup>-<\/jats:sup>, n = 17) and 10 HIV-negative (HIV<jats:sup>-<\/jats:sup>TB<jats:sup>-<\/jats:sup>) controls. Frozen plasma was collected before ART, at 3 and 9 months of ART, and examined by ELISA for levels of 7 ANCAs directed against; Proteinase 3 (PR3), Myeloperoxidase (MPO), Permeability-increasing protein (BPI), Elastase, Cathepsin, Lysozyme, and Lactoferrin.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Compared to HIV<jats:sup>+<\/jats:sup>TB<jats:sup>+<\/jats:sup> controls, pre-ART anti-elastase levels were lower in TB-IRIS patients (p = 0.026) and HIV<jats:sup>-<\/jats:sup>TB<jats:sup>-<\/jats:sup> controls (p = 0.044), whereas other ANCAs did not show significant differences between groups at any time point. A significant decrease over time could be observed in TB-IRIS patients during ART for anti -PR3 (p = 0.027), -lysozyme (p = 0.011), and -lactoferrin (p = 0.019). Conversely, HIV<jats:sup>+<\/jats:sup>TB<jats:sup>+<\/jats:sup> controls showed a significant decrease over time for anti -MPO (p = 0.002), -lyzosyme (p = 0.002) and -elastase (p &lt; 0.001).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>The lack of elevated anti-elastase levels in TB-IRIS patients as opposed to HIV<jats:sup>+<\/jats:sup>TB<jats:sup>+<\/jats:sup> controls correspond to previous findings of lowered immune capacity in patients that will develop TB-IRIS. This may suggest a specific role for anti-elastase, elastase or even matrix-metalloproteinases in TB-IRIS. The precise dynamics of neutrophil activation in HIV-TB merits further investigation and could provide more insight in the early mechanisms leading up to TB-IRIS.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0244800","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T20:45:54Z","timestamp":1609447554000},"page":"e0244800","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lack of elevated pre-ART elastase-ANCA levels in patients developing TB-IRIS"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4959-4677","authenticated-orcid":true,"given":"Odin","family":"Goovaerts","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marguerite","family":"Massinga-Loemb\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascale","family":"Ondoa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann","family":"Ceulemans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Worodria","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harriet","family":"Mayanja-Kizza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Colebunders","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc","family":"Kestens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the TB-IRIS Study Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2020,12,31]]},"reference":[{"key":"pone.0244800.ref001","first-page":"516","article-title":"Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings","author":"G Meintjes","journal-title":"Lancet Infect.Dis"},{"key":"pone.0244800.ref002","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S1473-3099(10)70026-8","article-title":"Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis","volume":"10","author":"M M\u00fcller","year":"2010","journal-title":"Lancet Infect Dis"},{"key":"pone.0244800.ref003","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/nrmicro2712","article-title":"Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none","volume":"10","author":"DL Barber","year":"2012","journal-title":"Nat Rev Microbiol"},{"key":"pone.0244800.ref004","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1742-6405-4-9","article-title":"Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options.","volume":"4","author":"DM Murdoch","year":"2007","journal-title":"AIDS Res Ther"},{"key":"pone.0244800.ref005","first-page":"1282","article-title":"Frequency, severity and duration of immune reconstitution events in HIV-related tuberculosis SUMMARY.","volume":"11","author":"W Burman","year":"2007"},{"key":"pone.0244800.ref006","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1586\/ers.09.8","article-title":"Coping with TB immune reconstitution inflammatory syndrome.","volume":"3","author":"W Worodria","year":"2009","journal-title":"Expert Rev Respir Med"},{"key":"pone.0244800.ref007","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1097\/QAI.0b013e31823801de","article-title":"Urinary lipoarabinomannan as predictor for the tuberculosis immune reconstitution inflammatory syndrome","volume":"58","author":"A Conesa-Botella","year":"2011","journal-title":"J Acquir Immune Defic Syndr"},{"key":"pone.0244800.ref008","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1097\/QAI.0b013e3182255dc2","article-title":"Incidence and predictors of mortality and the effect of tuberculosis immune reconstitution inflammatory syndrome in a cohort of TB\/HIV patients commencing antiretroviral therapy","volume":"58","author":"W Worodria","year":"2011","journal-title":"J Acquir Immune Defic Syndr"},{"key":"pone.0244800.ref009","first-page":"279","article-title":"Risk factors and frequency of tuberculosis-associated immune reconstitution inflammatory syndrome among HIV\/Tuberculosis co-infected patients in Southern India.","author":"R Vignesh","journal-title":"Indian J.Med.Microbiol"},{"key":"pone.0244800.ref010","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1586\/eri.11.21","article-title":"Pathogenesis and prevention of immune reconstitution disease during antiretroviral therapy.","volume":"9","author":"SD Lawn","year":"2011","journal-title":"Expert Rev Anti Infect Ther"},{"key":"pone.0244800.ref011","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1093\/infdis\/jis604","article-title":"Elevated interleukin 8 and T-helper 1 and T-helper 17 cytokine levels prior to antiretroviral therapy in participants who developed immune reconstitution inflammatory syndrome during ACTG A5164","volume":"206","author":"PM Grant","year":"2012","journal-title":"J Infect Dis"},{"key":"pone.0244800.ref012","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0215991","article-title":"Increased KLRG1 and PD-1 expression on CD8 T lymphocytes in TB-IRIS.","volume":"14","author":"O Goovaerts","year":"2019","journal-title":"PLoS One."},{"key":"pone.0244800.ref013","first-page":"882","article-title":"Immune reconstitution syndrome in tuberculosis and HIV-co-infected patients: Th1 explosion or cytokine storm?","author":"M Ruhwald","journal-title":"AIDS"},{"key":"pone.0244800.ref014","doi-asserted-by":"crossref","first-page":"e81856","DOI":"10.1371\/journal.pone.0081856","article-title":"LPS-binding protein and IL-6 mark paradoxical tuberculosis immune reconstitution inflammatory syndrome in HIV patients.","author":"O Goovaerts","year":"2013","journal-title":"PLoS.One"},{"key":"pone.0244800.ref015","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1164\/rccm.201201-0094OC","article-title":"Corticosteroid-modulated immune activation in the tuberculosis immune reconstitution inflammatory syndrome","volume":"186","author":"G Meintjes","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"pone.0244800.ref016","first-page":"429","article-title":"Immunological profiling of tuberculosis-associated immune reconstitution inflammatory syndrome and non-immune reconstitution inflammatory syndrome death in HIV-infected adults with pulmonary tuberculosis starting antiretroviral therapy: a prospective obse.","author":"S Ravimohan","journal-title":"Lancet Infect.Dis"},{"key":"pone.0244800.ref017","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1046\/j.1464-2662.2001.00096.x","article-title":"Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART","volume":"3","author":"SF Stone","year":"2002","journal-title":"HIV Med"},{"key":"pone.0244800.ref018","first-page":"1248","article-title":"Hypercytokinaemia accompanies HIV-tuberculosis immune reconstitution inflammatory syndrome.","volume":"37","author":"R Tadokera","year":"2011"},{"key":"pone.0244800.ref019","doi-asserted-by":"crossref","first-page":"101863","DOI":"10.1016\/j.tube.2019.101863","article-title":"TB-IRIS pathogenesis and new strategies for intervention: Insights from related inflammatory disorders","volume":"118","author":"PM Cevaal","year":"2019","journal-title":"Tuberculosis."},{"key":"pone.0244800.ref020","first-page":"279","article-title":"Immune dysfunction and immune restoration disease in HIV patients given highly active antiretroviral therapy.","author":"P Price","journal-title":"J.Clin.Virol"},{"key":"pone.0244800.ref021","article-title":"HIV-Tuberculosis-Associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling","volume":"6","author":"RPJ Lai","year":"2015","journal-title":"Nat Commun"},{"key":"pone.0244800.ref022","first-page":"252","article-title":"Cryptococcus-Related Immune Reconstitution Inflammatory Syndrome(IRIS): Pathogenesis and Its Clinical Implications.","author":"DL Wiesner","journal-title":"Curr.Fungal.Infect.Rep"},{"key":"pone.0244800.ref023","doi-asserted-by":"crossref","first-page":"e1004433","DOI":"10.1371\/journal.ppat.1004433","article-title":"Mycobacterial antigen driven activation of CD14++CD16- monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome.","volume":"10","author":"BB Andrade","year":"2014","journal-title":"PLoS Pathog"},{"key":"pone.0244800.ref024","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1097\/QAD.0b013e328348fb18","article-title":"TLR2-induced cytokine responses may characterize HIV-infected patients experiencing mycobacterial immune restoration disease","volume":"25","author":"DB a Tan","year":"2011","journal-title":"AIDS"},{"key":"pone.0244800.ref025","first-page":"100","article-title":"Matrix Metalloproteinases in Tuberculosis-Immune Reconstitution Inflammatory Syndrome and Impaired Lung Function Among Advanced HIV\/TB Co-infected Patients Initiating Antiretroviral Therapy.","author":"S Ravimohan","journal-title":"EBioMedicine"},{"key":"pone.0244800.ref026","first-page":"127","article-title":"Matrix metalloproteinases and tissue damage in HIV-tuberculosis immune reconstitution inflammatory syndrome","author":"R Tadokera","journal-title":"Eur.J.Immunol"},{"key":"pone.0244800.ref027","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1097\/QAI.0000000000001582","article-title":"Neutrophil Activation and Enhanced Release of Granule Products in HIV-TB Immune Reconstitution Inflammatory Syndrome.","volume":"77","author":"JK Nakiwala","year":"2018","journal-title":"J Acquir Immune Defic Syndr."},{"key":"pone.0244800.ref028","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1007\/s10067-019-04693-0","article-title":"Antineutrophil cytoplasmic antibodies and their relationship with disease activity and presence of staphylococcal superantigens in nasal swabs in patients having granulomatosis with polyangiitis: results of a study involving 115 patients from a single cen.","volume":"38","author":"J Fijolek","year":"2019","journal-title":"Clin Rheumatol. Clinical Rheumatology"},{"key":"pone.0244800.ref029","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.autrev.2011.04.004","article-title":"Dysregulated neutrophil-endothelial interaction in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides: Implications for pathogenesis and disease intervention.","volume":"10","author":"N Hu","year":"2011","journal-title":"Autoimmun Rev."},{"key":"pone.0244800.ref030","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1084\/jem.171.1.357","article-title":"Anti-neutrophil cytoplasm antibodies in Wegener\u2019s granulomatosis recognize an elastinolytic enzyme","volume":"171","author":"J Ludemann","year":"1990","journal-title":"J Exp Med"},{"key":"pone.0244800.ref031","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1136\/gut.33.5.657","article-title":"Clinical significance of antibodies against neutrophils in patients with inflammatory bowel disease and primary sclerosing cholangitis","volume":"33","author":"F Seibold","year":"1992","journal-title":"Gut"},{"key":"pone.0244800.ref032","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/j.1365-2249.1993.tb06215.x","article-title":"The clinical relevance of ANCA in vasculitis","volume":"93","author":"WL Gross","year":"1993","journal-title":"Clin Exp Immunol Suppl"},{"key":"pone.0244800.ref033","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1136\/gut.34.1.56","article-title":"Anti-lactoferrin antibodies and other types of ANCA in ulcerative colitis, primary sclerosing cholangitis, and Crohn\u2019s disease","volume":"34","author":"E Peen","year":"1993","journal-title":"Gut"},{"key":"pone.0244800.ref034","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.it.2018.04.003","article-title":"Divergent Roles of Antiself Antibodies during Infection","volume":"39","author":"J Rivera-Correa","year":"2018","journal-title":"Trends Immunol"},{"key":"pone.0244800.ref035","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/ofid\/ofz114","article-title":"Prevalence of Auto-antibodies in Pulmonary Tuberculosis.","volume":"6","author":"MP Cheng","year":"2019","journal-title":"Open Forum Infect Dis"},{"key":"pone.0244800.ref036","first-page":"270","article-title":"ANCA seropositivity in HIV: A serological pitfall.","volume":"63","author":"TLTA Jansen","year":"2005","journal-title":"Neth J Med."},{"key":"pone.0244800.ref037","doi-asserted-by":"crossref","DOI":"10.3851\/IMP2108","article-title":"Clinical spectrum, risk factors and outcome of immune reconstitution inflammatory syndrome in patients with tuberculosis-HIV coinfection.","author":"W Worodria","year":"2012","journal-title":"Antivir Ther"},{"key":"pone.0244800.ref038","doi-asserted-by":"crossref","first-page":"758350","DOI":"10.1155\/2011\/758350","article-title":"Antiretroviral treatment-associated tuberculosis in a prospective cohort of HIV-infected patients starting ART","volume":"2011","author":"W Worodria","year":"2011","journal-title":"Clin Dev Immunol"},{"key":"pone.0244800.ref039"},{"key":"pone.0244800.ref040","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3390\/jof3020028","article-title":"Monocyte Phenotype and IFN-\u03b3-Inducible Cytokine Responses Are Associated with Cryptococcal Immune Reconstitution Inflammatory Syndrome.","volume":"3","author":"D Meya","year":"2017","journal-title":"J Fungi"},{"key":"pone.0244800.ref041","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1183\/09031936.00212114","article-title":"Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis","volume":"46","author":"LW Garratt","year":"2015","journal-title":"Eur Respir J"},{"key":"pone.0244800.ref042","first-page":"258","article-title":"Neutrophil anti-neutrophil cytoplasmic autoantibody proteins: Bactericidal increasing protein, lactoferrin, cathepsin, and elastase as serological markers of inflammatory bowel and other diseases.","author":"KS Kyriakidi","year":"2016","journal-title":"Annals of Gastroenterology."},{"key":"pone.0244800.ref043","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0133924","article-title":"Lower pre-treatment T cell activation in early-and late-onset tuberculosis-associated immune reconstitution inflammatory syndrome","volume":"10","author":"O Goovaerts","year":"2015","journal-title":"PLoS One"},{"key":"pone.0244800.ref044","doi-asserted-by":"crossref","first-page":"e113101","DOI":"10.1371\/journal.pone.0113101","article-title":"Antigen-Specific Interferon-Gamma Responses and Innate Cytokine Balance in TB-IRIS.","author":"O Goovaerts","year":"2014","journal-title":"PLoS.One"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0244800","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T20:46:11Z","timestamp":1609447571000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0244800"}},"subtitle":[],"editor":[{"given":"Leo","family":"Carlin","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2020,12,31]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0244800","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2020,12,31]]}}}