Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis-Reference-Cited by-同舟云学术

Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis

Published:2023-02-22 Issue:684 Volume:15 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Brewer R. Camille¹²^ORCID,Lanz Tobias V.¹²³^ORCID,Hale Caryn R.⁴^ORCID,Sepich-Poore Gregory D.⁵^ORCID,Martino Cameron⁶⁷⁸,Swafford Austin D.⁷^ORCID,Carroll Thomas S.⁹,Kongpachith Sarah¹²^ORCID,Blum Lisa K.¹²^ORCID,Elliott Serra E.¹²^ORCID,Blachere Nathalie E.⁴¹⁰^ORCID,Parveen Salina⁴^ORCID,Fak John⁴^ORCID,Yao Vicky¹¹¹²,Troyanskaya Olga¹²¹³¹⁴^ORCID,Frank Mayu O.⁴^ORCID,Bloom Michelle S.¹²,Jahanbani Shaghayegh¹²^ORCID,Gomez Alejandro M.¹²^ORCID,Iyer Radhika¹²^ORCID,Ramadoss Nitya S.¹²,Sharpe Orr¹²,Chandrasekaran Sangeetha¹⁵^ORCID,Kelmenson Lindsay B.¹⁵^ORCID,Wang Qian¹²,Wong Heidi¹²,Torres Holly L.²^ORCID,Wiesen Mark²^ORCID,Graves Dana T.¹⁶^ORCID,Deane Kevin D.¹⁵^ORCID,Holers V. Michael¹⁵,Knight Rob⁵⁶⁷¹⁷^ORCID,Darnell Robert B.⁴¹⁰^ORCID,Robinson William H.¹²^ORCID,Orange Dana E.⁴¹⁸^ORCID

Affiliation:

1. Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.

2. VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.

3. Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68167, Germany.

4. Rockefeller University, New York City, NY 10065, USA.

5. Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.

6. Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.

7. Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093, USA.

8. Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA.

9. Bioinformatics Resource Center, Rockefeller University, 1230 York Ave., New York, NY 10065, USA.

10. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

11. Department of Computer Science, Rice University, Houston, TX 77005, USA.

12. Department of Computer Science, Princeton University, Princeton, NJ 08544, USA.

13. Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.

14. Flatiron Institute, Simons Foundation, New York, NY 10010, USA.

15. Division of Rheumatology, University of Colorado Denver, Aurora, CO 80045, USA.

16. Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

17. Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92093, USA.

18. Hospital for Special Surgery, New York City, NY 10075, USA.

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 + HLADR hi and CD48 high S100A2 pos 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

Link

https://www.science.org/doi/pdf/10.1126/scitranslmed.abq8476

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