Antibodies to a Citrullinated Porphyromonas gingivalis Epitope Are Increased in Early Rheumatoid Arthritis, and Can Be Produced by Gingival Tissue B Cells: Implications for a Bacterial Origin in RA Etiology

Natalia Sherina; Charlotte de Vries; Nastya Kharlamova; Natalie Sippl; Xia Jiang; Boel Brynedal; Elin Kindstedt; Monika Hansson; Linda Mathsson-Alm; Lena Israelsson; Ragnhild Stålesen; Saedis Saevarsdottir; Rikard Holmdahl; Aase Hensvold; Gunnar Johannsen; Kaja Eriksson; Federica Sallusto; Anca I. Catrina; Johan Rönnelid; Caroline Grönwall; Tülay Yucel-Lindberg; Lars Alfredsson; Lars Klareskog; Luca Piccoli; Vivianne Malmström; Khaled Amara; Karin Lundberg

doi:10.3389/fimmu.2022.804822

Antibodies to a Citrullinated Porphyromonas gingivalis Epitope Are Increased in Early Rheumatoid Arthritis, and Can Be Produced by Gingival Tissue B Cells: Implications for a Bacterial Origin in RA Etiology

Natalia Sherina, Charlotte de Vries, Nastya Kharlamova, Natalie Sippl, Xia Jiang, Boel Brynedal, Elin Kindstedt, Monika Hansson, Linda Mathsson-Alm, Lena Israelsson, Ragnhild Stålesen, Saedis Saevarsdottir, Rikard Holmdahl, Aase Hensvold, Gunnar Johannsen, Kaja Eriksson, Federica Sallusto, Anca I. Catrina, Johan Rönnelid, Caroline GrönwallTülay Yucel-Lindberg, Lars Alfredsson, Lars Klareskog, Luca Piccoli, Vivianne Malmström, Khaled Amara, Karin Lundberg^*

^*Corresponding author for this work

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

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Abstract

Based on the epidemiological link between periodontitis and rheumatoid arthritis (RA), and the unique feature of the periodontal bacterium Porphyromonas gingivalis to citrullinate proteins, it has been suggested that production of anti-citrullinated protein antibodies (ACPA), which are present in a majority of RA patients, may be triggered in the gum mucosa. To address this hypothesis, we investigated the antibody response to a citrullinated P. gingivalis peptide in relation to the autoimmune ACPA response in early RA, and examined citrulline-reactivity in monoclonal antibodies derived from human gingival B cells. Antibodies to a citrullinated peptide derived from P. gingivalis (denoted CPP3) and human citrullinated peptides were analyzed by multiplex array in 2,807 RA patients and 372 controls; associations with RA risk factors and clinical features were examined. B cells from inflamed gingival tissue were single-cell sorted, and immunoglobulin (Ig) genes were amplified, sequenced, cloned and expressed (n=63) as recombinant monoclonal antibodies, and assayed for citrulline-reactivities by enzyme-linked immunosorbent assay. Additionally, affinity-purified polyclonal anti-cyclic-citrullinated peptide (CCP2) IgG, and monoclonal antibodies derived from RA blood and synovial fluid B cells (n=175), were screened for CPP3-reactivity. Elevated anti-CPP3 antibody levels were detected in RA (11%), mainly CCP2+ RA, compared to controls (2%), p<0.0001, with a significant association to HLA-DRB1 shared epitope alleles, smoking and baseline pain, but with low correlation to autoimmune ACPA fine-specificities. Monoclonal antibodies derived from gingival B cells showed cross-reactivity between P. gingivalis CPP3 and human citrullinated peptides, and a CPP3+/CCP2+ clone, derived from an RA blood memory B cell, was identified. Our data support the possibility that immunity to P. gingivalis derived citrullinated antigens, triggered in the inflamed gum mucosa, may contribute to the presence of ACPA in RA patients, through mechanisms of molecular mimicry.

Original language	English
Article number	804822
Pages (from-to)	804822
Journal	Frontiers in Immunology
Volume	13
DOIs	https://doi.org/10.3389/fimmu.2022.804822
Publication status	Published - 20 Apr 2022

Bibliographical note

Funding Information:
This work was supported by grants from the Swedish Research Council (2017-01696), King Gustav V:s 80-year foundation (FAI-2016-0273), the Swedish Rheumatism foundation (R-931647), Professor Nanna Svartz’s foundation (2019-00292), and the EU/EFPIA Innovative Medicines Initiative Joint Undertaking RTCure (777357). FS and the Institute for Research in Biomedicine are supported by the Helmut Horten Foundation.

Funding Information:
We thank EIRA study participants, the EIRA study group, and patients donating tissue biopsies to the project, for their contributions. We would also like to thank Gloria Rostvall, Susana Hernandez Machado and Julia Norkko at Karolinska Institutet for managing the EIRA blood samples and biobank, as well as scientists involved in the generation of EIRA data: Dr Leonid Padyukov, Dr Patrick Stolt, and Dr Camilla Bengtsson. Also, Per Matsson, Mats Nystrand and Thomas Schlederer at Thermo Fisher Scientific for scientific support regarding the multiplex platform, and Michael Kramer, Institute for Research in Biomedicine, for work on BVCA1.

Publisher Copyright:
Copyright © 2022 Sherina, de Vries, Kharlamova, Sippl, Jiang, Brynedal, Kindstedt, Hansson, Mathsson-Alm, Israelsson, Stålesen, Saevarsdottir, Holmdahl, Hensvold, Johannsen, Eriksson, Sallusto, Catrina, Rönnelid, Grönwall, Yucel-Lindberg, Alfredsson, Klareskog, Piccoli, Malmström, Amara and Lundberg.

Other keywords

anti-citrullinated protein antibodies (ACPA)
B cells
monoclonal antibodies (mAbs)
periodontitis (PD)
Porphyromonas gingivalis (Pg)
rheumatoid arthritis (RA)

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Sherina, N., de Vries, C., Kharlamova, N., Sippl, N., Jiang, X., Brynedal, B., Kindstedt, E., Hansson, M., Mathsson-Alm, L., Israelsson, L., Stålesen, R., Saevarsdottir, S., Holmdahl, R., Hensvold, A., Johannsen, G., Eriksson, K., Sallusto, F., Catrina, A. I., Rönnelid, J., ... Lundberg, K. (2022). Antibodies to a Citrullinated Porphyromonas gingivalis Epitope Are Increased in Early Rheumatoid Arthritis, and Can Be Produced by Gingival Tissue B Cells: Implications for a Bacterial Origin in RA Etiology. Frontiers in Immunology, 13, 804822. [804822]. https://doi.org/10.3389/fimmu.2022.804822

@article{f6f05b8d0ee6455fb993cbc6b41c89ed,

title = "Antibodies to a Citrullinated Porphyromonas gingivalis Epitope Are Increased in Early Rheumatoid Arthritis, and Can Be Produced by Gingival Tissue B Cells: Implications for a Bacterial Origin in RA Etiology",

abstract = "Based on the epidemiological link between periodontitis and rheumatoid arthritis (RA), and the unique feature of the periodontal bacterium Porphyromonas gingivalis to citrullinate proteins, it has been suggested that production of anti-citrullinated protein antibodies (ACPA), which are present in a majority of RA patients, may be triggered in the gum mucosa. To address this hypothesis, we investigated the antibody response to a citrullinated P. gingivalis peptide in relation to the autoimmune ACPA response in early RA, and examined citrulline-reactivity in monoclonal antibodies derived from human gingival B cells. Antibodies to a citrullinated peptide derived from P. gingivalis (denoted CPP3) and human citrullinated peptides were analyzed by multiplex array in 2,807 RA patients and 372 controls; associations with RA risk factors and clinical features were examined. B cells from inflamed gingival tissue were single-cell sorted, and immunoglobulin (Ig) genes were amplified, sequenced, cloned and expressed (n=63) as recombinant monoclonal antibodies, and assayed for citrulline-reactivities by enzyme-linked immunosorbent assay. Additionally, affinity-purified polyclonal anti-cyclic-citrullinated peptide (CCP2) IgG, and monoclonal antibodies derived from RA blood and synovial fluid B cells (n=175), were screened for CPP3-reactivity. Elevated anti-CPP3 antibody levels were detected in RA (11%), mainly CCP2+ RA, compared to controls (2%), p<0.0001, with a significant association to HLA-DRB1 shared epitope alleles, smoking and baseline pain, but with low correlation to autoimmune ACPA fine-specificities. Monoclonal antibodies derived from gingival B cells showed cross-reactivity between P. gingivalis CPP3 and human citrullinated peptides, and a CPP3+/CCP2+ clone, derived from an RA blood memory B cell, was identified. Our data support the possibility that immunity to P. gingivalis derived citrullinated antigens, triggered in the inflamed gum mucosa, may contribute to the presence of ACPA in RA patients, through mechanisms of molecular mimicry.",

keywords = "anti-citrullinated protein antibodies (ACPA), B cells, monoclonal antibodies (mAbs), periodontitis (PD), Porphyromonas gingivalis (Pg), rheumatoid arthritis (RA)",

author = "Natalia Sherina and {de Vries}, Charlotte and Nastya Kharlamova and Natalie Sippl and Xia Jiang and Boel Brynedal and Elin Kindstedt and Monika Hansson and Linda Mathsson-Alm and Lena Israelsson and Ragnhild St{\aa}lesen and Saedis Saevarsdottir and Rikard Holmdahl and Aase Hensvold and Gunnar Johannsen and Kaja Eriksson and Federica Sallusto and Catrina, {Anca I.} and Johan R{\"o}nnelid and Caroline Gr{\"o}nwall and T{\"u}lay Yucel-Lindberg and Lars Alfredsson and Lars Klareskog and Luca Piccoli and Vivianne Malmstr{\"o}m and Khaled Amara and Karin Lundberg",

note = "Funding Information: This work was supported by grants from the Swedish Research Council (2017-01696), King Gustav V:s 80-year foundation (FAI-2016-0273), the Swedish Rheumatism foundation (R-931647), Professor Nanna Svartz{\textquoteright}s foundation (2019-00292), and the EU/EFPIA Innovative Medicines Initiative Joint Undertaking RTCure (777357). FS and the Institute for Research in Biomedicine are supported by the Helmut Horten Foundation. Funding Information: We thank EIRA study participants, the EIRA study group, and patients donating tissue biopsies to the project, for their contributions. We would also like to thank Gloria Rostvall, Susana Hernandez Machado and Julia Norkko at Karolinska Institutet for managing the EIRA blood samples and biobank, as well as scientists involved in the generation of EIRA data: Dr Leonid Padyukov, Dr Patrick Stolt, and Dr Camilla Bengtsson. Also, Per Matsson, Mats Nystrand and Thomas Schlederer at Thermo Fisher Scientific for scientific support regarding the multiplex platform, and Michael Kramer, Institute for Research in Biomedicine, for work on BVCA1. Publisher Copyright: Copyright {\textcopyright} 2022 Sherina, de Vries, Kharlamova, Sippl, Jiang, Brynedal, Kindstedt, Hansson, Mathsson-Alm, Israelsson, St{\aa}lesen, Saevarsdottir, Holmdahl, Hensvold, Johannsen, Eriksson, Sallusto, Catrina, R{\"o}nnelid, Gr{\"o}nwall, Yucel-Lindberg, Alfredsson, Klareskog, Piccoli, Malmstr{\"o}m, Amara and Lundberg.",

year = "2022",

month = apr,

day = "20",

doi = "10.3389/fimmu.2022.804822",

language = "English",

volume = "13",

pages = "804822",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Media S.A.",

}

Sherina, N, de Vries, C, Kharlamova, N, Sippl, N, Jiang, X, Brynedal, B, Kindstedt, E, Hansson, M, Mathsson-Alm, L, Israelsson, L, Stålesen, R, Saevarsdottir, S, Holmdahl, R, Hensvold, A, Johannsen, G, Eriksson, K, Sallusto, F, Catrina, AI, Rönnelid, J, Grönwall, C, Yucel-Lindberg, T, Alfredsson, L, Klareskog, L, Piccoli, L, Malmström, V, Amara, K & Lundberg, K 2022, 'Antibodies to a Citrullinated Porphyromonas gingivalis Epitope Are Increased in Early Rheumatoid Arthritis, and Can Be Produced by Gingival Tissue B Cells: Implications for a Bacterial Origin in RA Etiology', Frontiers in Immunology, vol. 13, 804822, pp. 804822. https://doi.org/10.3389/fimmu.2022.804822

Antibodies to a Citrullinated Porphyromonas gingivalis Epitope Are Increased in Early Rheumatoid Arthritis, and Can Be Produced by Gingival Tissue B Cells : Implications for a Bacterial Origin in RA Etiology. / Sherina, Natalia; de Vries, Charlotte; Kharlamova, Nastya et al.

In: Frontiers in Immunology, Vol. 13, 804822, 20.04.2022, p. 804822.

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

TY - JOUR

T1 - Antibodies to a Citrullinated Porphyromonas gingivalis Epitope Are Increased in Early Rheumatoid Arthritis, and Can Be Produced by Gingival Tissue B Cells

T2 - Implications for a Bacterial Origin in RA Etiology

AU - Sherina, Natalia

AU - de Vries, Charlotte

AU - Kharlamova, Nastya

AU - Sippl, Natalie

AU - Jiang, Xia

AU - Brynedal, Boel

AU - Kindstedt, Elin

AU - Hansson, Monika

AU - Mathsson-Alm, Linda

AU - Israelsson, Lena

AU - Stålesen, Ragnhild

AU - Saevarsdottir, Saedis

AU - Holmdahl, Rikard

AU - Hensvold, Aase

AU - Johannsen, Gunnar

AU - Eriksson, Kaja

AU - Sallusto, Federica

AU - Catrina, Anca I.

AU - Rönnelid, Johan

AU - Grönwall, Caroline

AU - Yucel-Lindberg, Tülay

AU - Alfredsson, Lars

AU - Klareskog, Lars

AU - Piccoli, Luca

AU - Malmström, Vivianne

AU - Amara, Khaled

AU - Lundberg, Karin

N1 - Funding Information: This work was supported by grants from the Swedish Research Council (2017-01696), King Gustav V:s 80-year foundation (FAI-2016-0273), the Swedish Rheumatism foundation (R-931647), Professor Nanna Svartz’s foundation (2019-00292), and the EU/EFPIA Innovative Medicines Initiative Joint Undertaking RTCure (777357). FS and the Institute for Research in Biomedicine are supported by the Helmut Horten Foundation. Funding Information: We thank EIRA study participants, the EIRA study group, and patients donating tissue biopsies to the project, for their contributions. We would also like to thank Gloria Rostvall, Susana Hernandez Machado and Julia Norkko at Karolinska Institutet for managing the EIRA blood samples and biobank, as well as scientists involved in the generation of EIRA data: Dr Leonid Padyukov, Dr Patrick Stolt, and Dr Camilla Bengtsson. Also, Per Matsson, Mats Nystrand and Thomas Schlederer at Thermo Fisher Scientific for scientific support regarding the multiplex platform, and Michael Kramer, Institute for Research in Biomedicine, for work on BVCA1. Publisher Copyright: Copyright © 2022 Sherina, de Vries, Kharlamova, Sippl, Jiang, Brynedal, Kindstedt, Hansson, Mathsson-Alm, Israelsson, Stålesen, Saevarsdottir, Holmdahl, Hensvold, Johannsen, Eriksson, Sallusto, Catrina, Rönnelid, Grönwall, Yucel-Lindberg, Alfredsson, Klareskog, Piccoli, Malmström, Amara and Lundberg.

PY - 2022/4/20

Y1 - 2022/4/20

N2 - Based on the epidemiological link between periodontitis and rheumatoid arthritis (RA), and the unique feature of the periodontal bacterium Porphyromonas gingivalis to citrullinate proteins, it has been suggested that production of anti-citrullinated protein antibodies (ACPA), which are present in a majority of RA patients, may be triggered in the gum mucosa. To address this hypothesis, we investigated the antibody response to a citrullinated P. gingivalis peptide in relation to the autoimmune ACPA response in early RA, and examined citrulline-reactivity in monoclonal antibodies derived from human gingival B cells. Antibodies to a citrullinated peptide derived from P. gingivalis (denoted CPP3) and human citrullinated peptides were analyzed by multiplex array in 2,807 RA patients and 372 controls; associations with RA risk factors and clinical features were examined. B cells from inflamed gingival tissue were single-cell sorted, and immunoglobulin (Ig) genes were amplified, sequenced, cloned and expressed (n=63) as recombinant monoclonal antibodies, and assayed for citrulline-reactivities by enzyme-linked immunosorbent assay. Additionally, affinity-purified polyclonal anti-cyclic-citrullinated peptide (CCP2) IgG, and monoclonal antibodies derived from RA blood and synovial fluid B cells (n=175), were screened for CPP3-reactivity. Elevated anti-CPP3 antibody levels were detected in RA (11%), mainly CCP2+ RA, compared to controls (2%), p<0.0001, with a significant association to HLA-DRB1 shared epitope alleles, smoking and baseline pain, but with low correlation to autoimmune ACPA fine-specificities. Monoclonal antibodies derived from gingival B cells showed cross-reactivity between P. gingivalis CPP3 and human citrullinated peptides, and a CPP3+/CCP2+ clone, derived from an RA blood memory B cell, was identified. Our data support the possibility that immunity to P. gingivalis derived citrullinated antigens, triggered in the inflamed gum mucosa, may contribute to the presence of ACPA in RA patients, through mechanisms of molecular mimicry.

AB - Based on the epidemiological link between periodontitis and rheumatoid arthritis (RA), and the unique feature of the periodontal bacterium Porphyromonas gingivalis to citrullinate proteins, it has been suggested that production of anti-citrullinated protein antibodies (ACPA), which are present in a majority of RA patients, may be triggered in the gum mucosa. To address this hypothesis, we investigated the antibody response to a citrullinated P. gingivalis peptide in relation to the autoimmune ACPA response in early RA, and examined citrulline-reactivity in monoclonal antibodies derived from human gingival B cells. Antibodies to a citrullinated peptide derived from P. gingivalis (denoted CPP3) and human citrullinated peptides were analyzed by multiplex array in 2,807 RA patients and 372 controls; associations with RA risk factors and clinical features were examined. B cells from inflamed gingival tissue were single-cell sorted, and immunoglobulin (Ig) genes were amplified, sequenced, cloned and expressed (n=63) as recombinant monoclonal antibodies, and assayed for citrulline-reactivities by enzyme-linked immunosorbent assay. Additionally, affinity-purified polyclonal anti-cyclic-citrullinated peptide (CCP2) IgG, and monoclonal antibodies derived from RA blood and synovial fluid B cells (n=175), were screened for CPP3-reactivity. Elevated anti-CPP3 antibody levels were detected in RA (11%), mainly CCP2+ RA, compared to controls (2%), p<0.0001, with a significant association to HLA-DRB1 shared epitope alleles, smoking and baseline pain, but with low correlation to autoimmune ACPA fine-specificities. Monoclonal antibodies derived from gingival B cells showed cross-reactivity between P. gingivalis CPP3 and human citrullinated peptides, and a CPP3+/CCP2+ clone, derived from an RA blood memory B cell, was identified. Our data support the possibility that immunity to P. gingivalis derived citrullinated antigens, triggered in the inflamed gum mucosa, may contribute to the presence of ACPA in RA patients, through mechanisms of molecular mimicry.

KW - anti-citrullinated protein antibodies (ACPA)

KW - B cells

KW - monoclonal antibodies (mAbs)

KW - periodontitis (PD)

KW - Porphyromonas gingivalis (Pg)

KW - rheumatoid arthritis (RA)

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U2 - 10.3389/fimmu.2022.804822

DO - 10.3389/fimmu.2022.804822

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VL - 13

SP - 804822

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 804822

ER -