{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:23:54Z","timestamp":1790738634248,"version":"4.1.0"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T00:00:00Z","timestamp":1472688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The chronic course of lepromatous leprosy may be interrupted by acute inflammatory episodes known as erythema nodosum leprosum (ENL). Despite its being a major cause of peripheral nerve damage in leprosy patients, the immunopathogenesis of ENL remains ill-defined. Recognized by distinct families of germline-encoded pattern recognition receptors, endogenous and pathogen-derived nucleic acids are highly immunostimulatory molecules that play a major role in the host defense against infections, autoimmunity, and autoinflammation. The aim of this work was to investigate whether DNA sensing via TLR-9 constitutes a major inflammatory pathway during ENL. Flow cytometry and immunohistochemistry analysis showed significantly higher TLR-9 expression in ENL when compared with nonreactional lepromatous patients, both locally in the skin lesions and in circulating mononuclear cells. The levels of endogenous and pathogen-derived TLR-9 ligands in the circulation of ENL patients were also higher. Furthermore, PBMCs isolated from the ENL patients secreted higher levels of TNF, IL-6, and IL-1\u03b2 in response to a TLR-9 agonist than those of the nonreactional patients and healthy individuals. Finally, E6446, a TLR-9 synthetic antagonist, was able to significantly inhibit the secretion of proinflammatory cytokines by ENL PBMCs in response to Mycobacterium leprae lysate. Our data strongly indicate that DNA sensing via TLR-9 constitutes a major innate immunity pathway involved in the pathogenesis and evolution of ENL. Thus, the use of TLR-9 antagonists emerges as a potential alternative to more effectively treat ENL aiming to prevent the development of nerve injuries and deformities in leprosy.<\/jats:p>","DOI":"10.4049\/jimmunol.1600042","type":"journal-article","created":{"date-parts":[[2016,7,30]],"date-time":"2016-07-30T01:39:46Z","timestamp":1469842786000},"page":"1905-1913","source":"Crossref","is-referenced-by-count":33,"title":["DNA Sensing via TLR-9 Constitutes a Major Innate Immunity Pathway Activated during Erythema Nodosum Leprosum"],"prefix":"10.1093","volume":"197","author":[{"given":"Andr\u00e9 A","family":"Dias","sequence":"first","affiliation":[{"name":"Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila O","family":"Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Pedro S","family":"Santos","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3103-9613","authenticated-orcid":false,"given":"Leonardo R","family":"Batista-Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chyntia Carolina D","family":"Acosta","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda N B","family":"Fontes","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology Applied to Mycobacteria, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta O","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fl\u00e1vio A","family":"Lara","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice M","family":"Machado","sequence":"additional","affiliation":[{"name":"Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Augusto C","family":"Nery","sequence":"additional","affiliation":[{"name":"Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Euzenir N","family":"Sarno","sequence":"additional","affiliation":[{"name":"Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldo M B","family":"Pereira","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina V","family":"Pessolani","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ , Rio de Janeiro 20045-900,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,9,1]]},"reference":[{"key":"2025030617480424800_r1","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/ni.1863","article-title":"The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors","volume":"11","author":"Kawai","year":"2010","journal-title":"Nat. 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