From oral infection to autoimmunity : studies of antibodies and B cells on the path towards rheumatoid arthritis
Author: de Vries, Charlotte
Date: 2024-01-12
Location: Center for Molecular Medicine (CMM) Lecture hall, L8:00, Karolinska University Hospital, Solna
Time: 09.00
Department: Inst för medicin, Solna / Dept of Medicine, Solna
View/ Open:
Thesis (1.332Mb)
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation of the synovial joints, which can lead to irreversible joint destruction and disability if not treated properly. The majority of patients are seropositive, defined by presence of autoantibodies, i.e., rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA). My thesis work focuses on ACPA+ RA, which is known for its more severe disease course. ACPA can be detected in the blood years before clinical signs of RA and were for a long time suggested to contribute to pathology, an hypothesis which is currently under debate. Still, the presence of ACPA, and the successful use of B-cell depleting therapies in RA, points to an important role for autoantibodies and B cells in the development of RA.
Notably, most known risk factors for RA, in particular smoking and HLA-DRB1 shared epitope (SE) alleles, are specifically linked to onset of ACPA+ RA. My studies have investigated another potential risk factor for RA, namely the oral pathogen Porphyromonas gingivalis (Pg), one of the main drivers of periodontitis (PD). PD is a common disease that is driven by dysbiosis in the oral cavity triggering gingivitis and eventually leads to destruction of the jawbone and toothsupporting surrounding soft tissues. PD has a higher prevalence in RA than in the general population. Interestingly, Pg has the unique characteristic to express its own citrullinating enzyme and has therefore been suggested to contribute to the generation of RA autoantigens, break of tolerance and systemic ACPA production.
The overall aims of my thesis were: 1) to determine if presence of antibodies against the Pg virulence factor RgpB could serve as biomarker to identify patients with PD at increased risk for systemic autoimmunity and onset of RA; 2) to explore the gingiva as a site for ACPA production, and Pg as a driver of the ACPA response; and 3) to phenotypically characterise peripheral blood B cells in the risk-RA phase, to understand B-cell dysregulation prior to RA onset.
Investigating the anti-Rgp IgG response in two PD cohorts showed that this antibody response could only poorly discriminate PD from controls. However, elevated anti-Rgp IgG levels defined a subset of PD patients with active gingivitis and advanced marginal jawbone loss. We also showed a higher prevalence of ACPA+ individuals in PD versus controls, and higher anti-Rgp IgG levels in ACPA+ versus ACPA- individuals. Moreover, in a prospective study of ACPA+ individuals at increased risk for RA we found significantly higher anti-Rgp IgG levels compared to controls, but antibody levels did not differ between those who progressed to arthritis and those who remained arthritis free.
Generation of monoclonal antibodies derived from RA gingival tissue B cells demonstrated the presence of citrulline-reactive clones binding epitopes on both Pg and self-proteins, and this cross-reactivity was also shown for an RA peripheral blood-derived ACPA+ clone. Investigating the serum polyclonal response, 11% of patients with early RA were positive for antibodies targeting a citrullinated Pg peptide. When assessing peripheral blood B cells in ACPA+ Risk-RA individuals, we detected dysregulation of B-cell subsets already before clinical onset, specifically showing loss of CD27 on class-switched IgG+ memory B cells, a feature previously described in autoimmunity.
Collectively, these studies can link anti-Pg antibodies – as a proxy for Pg infection – to severe forms of PD and to the ACPA response, but not to arthritis onset. Thus, suggesting Pg-infection could be an early event in the natural history of RA, possibly triggering ACPA production in the gum mucosa by mechanisms of molecular mimicry. Moreover, the detection of B-cell changes already in the at-risk phase, supports the use of immune monitoring to capture individuals at risk of RA onset, that may benefit the most from pre-clinical intervention.
Notably, most known risk factors for RA, in particular smoking and HLA-DRB1 shared epitope (SE) alleles, are specifically linked to onset of ACPA+ RA. My studies have investigated another potential risk factor for RA, namely the oral pathogen Porphyromonas gingivalis (Pg), one of the main drivers of periodontitis (PD). PD is a common disease that is driven by dysbiosis in the oral cavity triggering gingivitis and eventually leads to destruction of the jawbone and toothsupporting surrounding soft tissues. PD has a higher prevalence in RA than in the general population. Interestingly, Pg has the unique characteristic to express its own citrullinating enzyme and has therefore been suggested to contribute to the generation of RA autoantigens, break of tolerance and systemic ACPA production.
The overall aims of my thesis were: 1) to determine if presence of antibodies against the Pg virulence factor RgpB could serve as biomarker to identify patients with PD at increased risk for systemic autoimmunity and onset of RA; 2) to explore the gingiva as a site for ACPA production, and Pg as a driver of the ACPA response; and 3) to phenotypically characterise peripheral blood B cells in the risk-RA phase, to understand B-cell dysregulation prior to RA onset.
Investigating the anti-Rgp IgG response in two PD cohorts showed that this antibody response could only poorly discriminate PD from controls. However, elevated anti-Rgp IgG levels defined a subset of PD patients with active gingivitis and advanced marginal jawbone loss. We also showed a higher prevalence of ACPA+ individuals in PD versus controls, and higher anti-Rgp IgG levels in ACPA+ versus ACPA- individuals. Moreover, in a prospective study of ACPA+ individuals at increased risk for RA we found significantly higher anti-Rgp IgG levels compared to controls, but antibody levels did not differ between those who progressed to arthritis and those who remained arthritis free.
Generation of monoclonal antibodies derived from RA gingival tissue B cells demonstrated the presence of citrulline-reactive clones binding epitopes on both Pg and self-proteins, and this cross-reactivity was also shown for an RA peripheral blood-derived ACPA+ clone. Investigating the serum polyclonal response, 11% of patients with early RA were positive for antibodies targeting a citrullinated Pg peptide. When assessing peripheral blood B cells in ACPA+ Risk-RA individuals, we detected dysregulation of B-cell subsets already before clinical onset, specifically showing loss of CD27 on class-switched IgG+ memory B cells, a feature previously described in autoimmunity.
Collectively, these studies can link anti-Pg antibodies – as a proxy for Pg infection – to severe forms of PD and to the ACPA response, but not to arthritis onset. Thus, suggesting Pg-infection could be an early event in the natural history of RA, possibly triggering ACPA production in the gum mucosa by mechanisms of molecular mimicry. Moreover, the detection of B-cell changes already in the at-risk phase, supports the use of immune monitoring to capture individuals at risk of RA onset, that may benefit the most from pre-clinical intervention.
List of papers:
I. Antibodies to Porphyromonas gingivalis Are Increased in Patients with Severe Periodontitis, and Associate with Presence of Specific Autoantibodies and Myocardial Infarction. de Vries C*, Ruacho G*, Kindstedt E, Potempa BA, Potempa J, Klinge B, Lundberg P, Svenungsson E, Lundberg K. J Clin Med. 2022 Feb 15;11(4):1008. *These authors contributed equally and share first authorship.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Antibodies to Porphyromonas gingivalis gingipains associate with gingival inflammation and advanced marginal jawbone loss – data from the PerioGene North case-control study. Kindstedt E, de Vries C, Wänman M, Potempa BA, Potempa J, Lindquist S, Esberg A, Lundberg K, Lundberg P. [Manuscript]
III. Porphyromonas gingivalis associates with presence of anti-citrullinated protein antibodies, but not with onset of arthritis – studies in an at-risk population. de Vries C, Cîrciumaru A, Potempa BA, Potempa J, Lundberg K#, Hensvold A#. #These authors contributed equally and share senior authorship. [Manuscript]
IV. 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 N, de Vries C, Kharlamova N, Sippl N, Jiang X, Brynedahl 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. Front Immunol. 2022 Apr 20;13:804822.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. B-cell changes in the at-risk phase leading up to ACPA-positive rheumatoid arthritis. de Vries C, Huang W, Sharma RK, Turcinov S, Argyriou A, Horuluoglu B, Wangriatisak K, Cîrciumaru A, Rönnblom L, Grönwall C, Malmström V#, Hensvold A#, Lundberg K#. #These authors contributed equally and share senior authorship. [Manuscript]
I. Antibodies to Porphyromonas gingivalis Are Increased in Patients with Severe Periodontitis, and Associate with Presence of Specific Autoantibodies and Myocardial Infarction. de Vries C*, Ruacho G*, Kindstedt E, Potempa BA, Potempa J, Klinge B, Lundberg P, Svenungsson E, Lundberg K. J Clin Med. 2022 Feb 15;11(4):1008. *These authors contributed equally and share first authorship.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Antibodies to Porphyromonas gingivalis gingipains associate with gingival inflammation and advanced marginal jawbone loss – data from the PerioGene North case-control study. Kindstedt E, de Vries C, Wänman M, Potempa BA, Potempa J, Lindquist S, Esberg A, Lundberg K, Lundberg P. [Manuscript]
III. Porphyromonas gingivalis associates with presence of anti-citrullinated protein antibodies, but not with onset of arthritis – studies in an at-risk population. de Vries C, Cîrciumaru A, Potempa BA, Potempa J, Lundberg K#, Hensvold A#. #These authors contributed equally and share senior authorship. [Manuscript]
IV. 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 N, de Vries C, Kharlamova N, Sippl N, Jiang X, Brynedahl 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. Front Immunol. 2022 Apr 20;13:804822.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. B-cell changes in the at-risk phase leading up to ACPA-positive rheumatoid arthritis. de Vries C, Huang W, Sharma RK, Turcinov S, Argyriou A, Horuluoglu B, Wangriatisak K, Cîrciumaru A, Rönnblom L, Grönwall C, Malmström V#, Hensvold A#, Lundberg K#. #These authors contributed equally and share senior authorship. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Lundberg, Karin
Co-supervisor: Malmström, Vivianne; Hensvold, Aase
Issue date: 2023-12-08
Rights:
Publication year: 2023
ISBN: 978-91-8017-214-1
Statistics
Total Visits
Views | |
---|---|
From ... | 1415 |
Total Visits Per Month
March 2024 | April 2024 | May 2024 | June 2024 | July 2024 | August 2024 | September 2024 | |
---|---|---|---|---|---|---|---|
From ... | 34 | 16 | 247 | 17 | 12 | 17 | 5 |
File Visits
Views | |
---|---|
Thesis_Charlotte_de_Vries.pdf | 320 |
Top country views
Views | |
---|---|
Sweden | 1163 |
United States | 66 |
Netherlands | 15 |
United Kingdom | 14 |
Ireland | 11 |
China | 10 |
Germany | 7 |
Japan | 7 |
Russia | 6 |
Egypt | 5 |
Top cities views
Views | |
---|---|
Karlstad | 1079 |
Solna | 18 |
Stockholm | 7 |
Muskegon | 6 |
Norrköping | 6 |
Dublin | 5 |
Esna | 5 |
Ashburn | 4 |
Leiden | 4 |
London | 4 |