Graphical Abstract
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.
Authors
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R. Camille Brewer https://orcid.org/0000-0002-0342-1826
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Roles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, and Writing – review & editing.
Tobias V. Lanz https://orcid.org/0000-0001-7106-8801
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68167, Germany.Roles: Investigation and Methodology.
Caryn R. Hale https://orcid.org/0000-0002-2860-0994
Rockefeller University, New York City, NY 10065, USA.Roles: Conceptualization, Formal analysis, Methodology, Software, Validation, Visualization, Writing – original draft, and Writing – review & editing.
Gregory D. Sepich-Poore https://orcid.org/0000-0002-3443-3715
Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.Roles: Formal analysis and Software.Present address: Micronoma, San Diego, CA 92121, USA.
Cameron Martino
Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093, USA.Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA.Roles: Formal analysis, Investigation, Software, Validation, Visualization, and Writing – review & editing.
Austin D. Swafford https://orcid.org/0000-0001-5655-8300
Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093, USA.Roles: Data curation, Methodology, Resources, Supervision, and Visualization.
Thomas S. Carroll
Bioinformatics Resource Center, Rockefeller University, 1230 York Ave., New York, NY 10065, USA.Roles: Formal analysis and Software.
Sarah Kongpachith https://orcid.org/0000-0002-8462-6881
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Role: Software.
Lisa K. Blum https://orcid.org/0000-0002-7921-8939
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Roles: Data curation, Methodology, and Resources.
Serra E. Elliott https://orcid.org/0000-0003-4808-7814
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Roles: Methodology and Software.
Nathalie E. Blachere https://orcid.org/0000-0002-5858-6097
Rockefeller University, New York City, NY 10065, USA.Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.Roles: Conceptualization, Methodology, and Resources.
Salina Parveen https://orcid.org/0000-0002-2698-0575
Rockefeller University, New York City, NY 10065, USA.Role: Resources.
John Fak https://orcid.org/0000-0002-7237-4699
Rockefeller University, New York City, NY 10065, USA.Roles: Conceptualization, Investigation, Methodology, and Validation.
Vicky Yao
Department of Computer Science, Rice University, Houston, TX 77005, USA.Department of Computer Science, Princeton University, Princeton, NJ 08544, USA.Roles: Conceptualization, Formal analysis, and Software.
Olga Troyanskaya https://orcid.org/0000-0002-5676-5737
Department of Computer Science, Princeton University, Princeton, NJ 08544, USA.Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.Flatiron Institute, Simons Foundation, New York, NY 10010, USA.Role: Methodology.
Mayu O. Frank https://orcid.org/0000-0002-5597-4828
Rockefeller University, New York City, NY 10065, USA.Role: Writing – review & editing.
Michelle S. Bloom
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Roles: Conceptualization, Project administration, Supervision, and Writing – original draft.
Shaghayegh Jahanbani https://orcid.org/0000-0001-7789-4856
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Role: Resources.
Alejandro M. Gomez https://orcid.org/0000-0003-4415-2615
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Roles: Conceptualization, Resources, and Writing – review & editing.
Radhika Iyer https://orcid.org/0000-0003-1287-3995
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Role: Resources.
Nitya S. Ramadoss
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Role: Resources.
Orr Sharpe
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Roles: Conceptualization, Data curation, Investigation, Project administration, Resources, and Supervision.
Sangeetha Chandrasekaran https://orcid.org/0000-0002-5144-6315
Division of Rheumatology, University of Colorado Denver, Aurora, CO 80045, USA.Roles: Conceptualization, Investigation, Methodology, Project administration, Resources, Validation, Visualization, and Writing – review & editing.
Lindsay B. Kelmenson https://orcid.org/0000-0002-7809-6722
Division of Rheumatology, University of Colorado Denver, Aurora, CO 80045, USA.Roles: Conceptualization, Funding acquisition, Investigation, and Writing – review & editing.
Qian Wang
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Role: Methodology.
Heidi Wong
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Roles: Conceptualization, Investigation, and Methodology.
Holly L. Torres https://orcid.org/0000-0002-8392-457X
VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Role: Investigation.
Mark Wiesen https://orcid.org/0000-0002-3124-9058
VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Roles: Investigation and Resources.
Dana T. Graves https://orcid.org/0000-0002-4664-8529
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.Role: Writing – review & editing.
Kevin D. Deane https://orcid.org/0000-0003-2211-4861
Division of Rheumatology, University of Colorado Denver, Aurora, CO 80045, USA.Roles: Conceptualization, Funding acquisition, Investigation, Methodology, Resources, Visualization, and Writing – review & editing.
V. Michael Holers
Division of Rheumatology, University of Colorado Denver, Aurora, CO 80045, USA.Roles: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Validation, Writing – original draft, and Writing – review & editing.
Rob Knight https://orcid.org/0000-0002-0975-9019
Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093, USA.Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92093, USA.Roles: Conceptualization and Supervision.
Robert B. Darnell https://orcid.org/0000-0002-5134-8088
Rockefeller University, New York City, NY 10065, USA.Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.Roles: Conceptualization, Funding acquisition, Supervision, and Writing – review & editing.
William H. Robinson*,‡ https://orcid.org/0000-0003-4385-704X w.robinson@stanford.edu
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.Roles: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, and Writing – review & editing.
Dana E. Orange*,‡ https://orcid.org/0000-0001-9859-7199 w.robinson@stanford.edu
Rockefeller University, New York City, NY 10065, USA.Hospital for Special Surgery, New York City, NY 10075, USA.Roles: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, and Writing – review & editing.