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

R. Camille Brewer; Tobias V. Lanz; Caryn R. Hale; Gregory D. Sepich-Poore; Cameron Martino; Austin D. Swafford; Thomas S. Carroll; Sarah Kongpachith; Lisa K. Blum; Serra E. Elliott; Nathalie E. Blachere; Salina Parveen; John Fak; Vicky Yao; Olga Troyanskaya; Mayu O. Frank; Michelle S. Bloom; Shaghayegh Jahanbani; Alejandro M. Gomez; Radhika Iyer; Nitya S. Ramadoss; Orr Sharpe; Sangeetha Chandrasekaran; Lindsay B. Kelmenson; Qian Wang; Heidi Wong; Holly L. Torres; Mark Wiesen; Dana T. Graves; Kevin D. Deane; V. Michael Holers; Rob Knight; Robert B. Darnell; William H. Robinson; Dana E. Orange

doi:10.1126/scitranslmed.abq8476

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

R. Camille Brewer, Tobias V. Lanz, Caryn R. Hale, Gregory D. Sepich-Poore, Cameron Martino, Austin D. Swafford, Thomas S. Carroll, Sarah Kongpachith, Lisa K. Blum, Serra E. Elliott, Nathalie E. Blachere, Salina Parveen, John Fak, Vicky Yao, Olga Troyanskaya, Mayu O. Frank, Michelle S. Bloom, Shaghayegh Jahanbani, Alejandro M. Gomez, Radhika IyerNitya S. Ramadoss, Orr Sharpe, Sangeetha Chandrasekaran, Lindsay B. Kelmenson, Qian Wang, Heidi Wong, Holly L. Torres, Mark Wiesen, Dana T. Graves, Kevin D. Deane, V. Michael Holers, Rob Knight, Robert B. Darnell, William H. Robinson, Dana E. Orange

Princeton University

Research output: Contribution to journal › Article › peer-review

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^highS100A2^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.

Original language	English (US)
Article number	eabq8476
Journal	Science translational medicine
Volume	15
Issue number	684
DOIs	https://doi.org/10.1126/scitranslmed.abq8476
State	Published - Feb 22 2023

All Science Journal Classification (ASJC) codes

General Medicine

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10.1126/scitranslmed.abq8476

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Brewer, R. C., Lanz, T. V., Hale, C. R., Sepich-Poore, G. D., Martino, C., Swafford, A. D., Carroll, T. S., Kongpachith, S., Blum, L. K., Elliott, S. E., Blachere, N. E., Parveen, S., Fak, J., Yao, V., Troyanskaya, O., Frank, M. O., Bloom, M. S., Jahanbani, S., Gomez, A. M., ... Orange, D. E. (2023). Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis. Science translational medicine, 15(684), Article eabq8476. https://doi.org/10.1126/scitranslmed.abq8476

@article{19bc39d260324cdcbdbd56d0e2503438,

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 = "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",

}

Brewer, RC, Lanz, TV, Hale, CR, Sepich-Poore, GD, Martino, C, Swafford, AD, Carroll, TS, Kongpachith, S, Blum, LK, Elliott, SE, Blachere, NE, Parveen, S, Fak, J, Yao, V, Troyanskaya, O, Frank, MO, Bloom, MS, Jahanbani, S, Gomez, AM, Iyer, R, Ramadoss, NS, Sharpe, O, Chandrasekaran, S, Kelmenson, LB, Wang, Q, Wong, H, Torres, HL, Wiesen, M, Graves, DT, Deane, KD, Holers, VM, Knight, R, Darnell, RB, Robinson, WH & Orange, DE 2023, 'Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis', Science translational medicine, vol. 15, no. 684, eabq8476. https://doi.org/10.1126/scitranslmed.abq8476

TY - JOUR

T1 - Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis

AU - Brewer, R. Camille

AU - Lanz, Tobias V.

AU - Hale, Caryn R.

AU - Sepich-Poore, Gregory D.

AU - Martino, Cameron

AU - Swafford, Austin D.

AU - Carroll, Thomas S.

AU - Kongpachith, Sarah

AU - Blum, Lisa K.

AU - Elliott, Serra E.

AU - Blachere, Nathalie E.

AU - Parveen, Salina

AU - Fak, John

AU - Yao, Vicky

AU - Troyanskaya, Olga

AU - Frank, Mayu O.

AU - Bloom, Michelle S.

AU - Jahanbani, Shaghayegh

AU - Gomez, Alejandro M.

AU - Iyer, Radhika

AU - Ramadoss, Nitya S.

AU - Sharpe, Orr

AU - Chandrasekaran, Sangeetha

AU - Kelmenson, Lindsay B.

AU - Wang, Qian

AU - Wong, Heidi

AU - Torres, Holly L.

AU - Wiesen, Mark

AU - Graves, Dana T.

AU - Deane, Kevin D.

AU - Holers, V. Michael

AU - Knight, Rob

AU - Darnell, Robert B.

AU - Robinson, William H.

AU - Orange, Dana E.

PY - 2023/2/22

Y1 - 2023/2/22

N2 - 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.

AB - 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.

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U2 - 10.1126/scitranslmed.abq8476

DO - 10.1126/scitranslmed.abq8476

M3 - Article

C2 - 36812347

SN - 1946-6234

VL - 15

JO - Science translational medicine

JF - Science translational medicine

IS - 684

M1 - eabq8476

ER -

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

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