{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:10:20Z","timestamp":1792465820615,"version":"4.5.0"},"reference-count":61,"publisher":"American Society for Clinical Investigation","issue":"21","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":83,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["1R37AI118841"],"award-info":[{"award-number":["1R37AI118841"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,3]]},"abstract":"<jats:p>\n                    Toll like receptor (TLR) 7 and 9, endosomal sensors for RNA and DNA, are key mediators of autoreactivity. Although generally considered homologous, they paradoxically have opposing effects on lupus: TLR7 exacerbates the disease while TLR9 protects from it  How they mediate opposing effects in autoimmunity remains undetermined. We hypothesized that differences in signaling qualities of the Toll-Interleukin 1 Receptor (TIR) domains of TLR7 and TLR9 could be responsible for their opposing effects. To test this, we introduced the TIR domain of TLR9 into the endogenous\n                    <jats:italic>Tlr7<\/jats:italic>\n                    locus and the TLR7 TIR domain into the endogenous\n                    <jats:italic>Tlr9<\/jats:italic>\n                    locus of mice, creating chimeric molecules termed TLR779 and TLR997. Lupus-prone MRL\/lpr mice carrying\n                    <jats:italic>\n                      Tlr\n                      <jats:sup>779<\/jats:sup>\n                    <\/jats:italic>\n                    had greatly ameliorated disease, while MRL\/lpr mice carrying\n                    <jats:italic>\n                      Tlr\n                      <jats:sup>997<\/jats:sup>\n                    <\/jats:italic>\n                    had markedly exacerbated disease compared with respective\n                    <jats:italic>\n                      Tlr\n                      <jats:sup>WT<\/jats:sup>\n                    <\/jats:italic>\n                    mice. These experiments establish that TLR7 and TLR9 TIR domains have divergent properties and control disease quality, thus explaining the longstanding \u201cTLR paradox\u201d.\n                  <\/jats:p>","DOI":"10.1172\/jci189566","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T16:00:30Z","timestamp":1755014430000},"source":"Crossref","is-referenced-by-count":9,"title":["Divergent TIR signaling domains in TLR7 and TLR9 control opposing effects on systemic autoimmunity"],"prefix":"10.1172","volume":"135","author":[{"given":"Claire","family":"Leibler","sequence":"first","affiliation":[{"name":"Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."},{"name":"Univ. 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