@article{81c5532e5cd146b78d0a5665cae4f3e4,
title = "Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis",
abstract = "Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We found that patients with RA and periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of ISG15+HLADRhi and CD48highS100A2pos monocytes, recently identified in inflamed RA synovia and blood of those with RA flares. The oral bacteria observed transiently in blood were broadly citrullinated in the mouth, and their in situ citrullinated epitopes were targeted by extensively somatically hypermutated ACPAs encoded by RA blood plasmablasts. Together, these results suggest that (i) periodontal disease results in repeated breaches of the oral mucosa that release citrullinated oral bacteria into circulation, which (ii) activate inflammatory monocyte subsets that are observed in inflamed RA synovia and blood of RA patients with flares and (iii) activate ACPA B cells, thereby promoting affinity maturation and epitope spreading to citrullinated human antigens.",
author = "Brewer, {R. Camille} and Lanz, {Tobias V.} and Hale, {Caryn R.} and Sepich-Poore, {Gregory D.} and Cameron Martino and Swafford, {Austin D.} and Carroll, {Thomas S.} and Sarah Kongpachith and Blum, {Lisa K.} and Elliott, {Serra E.} and Blachere, {Nathalie E.} and Salina Parveen and John Fak and Vicky Yao and Olga Troyanskaya and Frank, {Mayu O.} and Bloom, {Michelle S.} and Shaghayegh Jahanbani and Gomez, {Alejandro M.} and Radhika Iyer and Ramadoss, {Nitya S.} and Orr Sharpe and Sangeetha Chandrasekaran and Kelmenson, {Lindsay B.} and Qian Wang and Heidi Wong and Torres, {Holly L.} and Mark Wiesen and Graves, {Dana T.} and Deane, {Kevin D.} and Holers, {V. Michael} and Rob Knight and Darnell, {Robert B.} and Robinson, {William H.} and Orange, {Dana E.}",
note = "Funding Information: We thank the VA Palo Alto FACS facility and Stanford University Mass Spectrometry Core as well as the staff of the Rockefeller University Hospital for assistance. We also thank L. Shenhav, S. Culshaw, and M. Kurowska-Stolarska for the helpful discussions and edits. The research reported in this publication was supported by National Institutes of Health (NIH) R01 AR063676 (to W.H.R.), NIH R01 AR078268 (to W.H.R. and D.E.O.), NIH U19 AI110491 (to W.H.R.), NIH U01 AI101981 (to V.M.H. and W.H.R.), NIH T32 HG003284 (to V.Y.), NIH R01 GM071966 (to O.T.), NIH T32 AI007290-35 (to R.C.B.), NIH P30 AR079369 (to V.M.H. and K.D.D.), NIH UC2 AR082186 (to D.E.O), National Science Foundation (NSF) Graduate Research Fellowship (to R.C.B.), Robertson Foundation (to D.E.O.), Rockefeller University UL1 TR001866 (to D.E.O.), Bernard and Irene Schwartz Foundation (to D.E.O.), Iris and Junming Le Foundation (to D.E.O.), Rockefeller Clinical and Translational Science Award Program Pilot Award (to D.E.O.), Rheumatology Research Foundation (to L.B.K.), and National Cancer Institute (NCI) F30 CA243480 (to G.D.S.-P.). Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",
year = "2023",
month = feb,
day = "22",
doi = "10.1126/scitranslmed.abq8476",
language = "English (US)",
volume = "15",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "684",
}