On the origin of ACPA : exploring the role of P. gingivalis in the development of rheumatoid arthritis
Rheumatoid Arthritis (RA) is a systemic autoimmune disease characterized by chronic synovial inflammation, joint destruction, and the presence of anti-citrullinated protein autoantibodies (ACPA) in a majority of patients. Accumulating evidence suggests that ACPA play an important role in RA pathogenesis. ACPA are often detected years before the onset of clinical symptoms, with increasing levels and epitope-spreading preceding the diagnosis of RA. The presence of ACPA is associated with a more severe disease course and recent studies imply that ACPA may directly contribute to inflammation, mediate pain, osteoclast differentiation, and fibroblast migration, and ACPA have been shown to worsen experimental arthritis. Despite progress in revealing ACPA-mediated pathology, the origin of the ACPA response remains largely unknown. The best-known genetic risk factor for RA, HLA-DRB1 shared epitope (SE) alleles, and the most studied environmental risk factor, cigarette smoking, have been linked to ACPA-positive RA. In addition, chronic periodontitis (PD), an inflammatory disease of the tooth supporting tissue, has been epidemiologically linked to RA. Shared genetic and environmental risk factors, together with a unique ability of the periodontal pathogen Porphyromonas gingivalis to express an enzyme that can citrullinate proteins, led to the hypothesis that the initial brake of immune tolerance to citrullinated proteins may be triggered in the gum mucosa during chronic PD. Based on this hypothesis, the aim of my thesis was to investigate the role of P.gingivalis in the etiology of ACPA-positive RA.
We have examined the anti-P.gingivalis antibody response in a PD/non-PD cohort and in population-based RA/pre-RA case-control cohorts, and found that anti-P.gingivalis antibody levels are not only significantly elevated in PD patients compared to periodontally-healthy individuals, but in RA patients (in particular ACPA-positive RA) compared to non-RA controls. We identified an association between anti-P.gingivalis antibodies and RA, that was even stronger than the well-known association between smoking and RA, and we could show elevated anti-P.gingivalis antibody levels more than 10 years before clinical onset of RA. Moreover, we have shown that not only RA patients, but a substantial proportion of the general population (likely individuals with PD), have a citrulline-specific antibody response against P.gingivalis. Furthermore, analysis of gingiva-derived monoclonal antibodies from patients with PD revealed the presence of citrulline-reactive B cells in inflamed gingival tissue, and B cells with cross-reactivity between a citrullinated P.gingivalis peptide and citrullinated human antigens were found in the gingival tissue, as well as in peripheral blood and bronchoalveolar lavage of ACPA-positive RA patients. One of the most intriguing findings was that two of these clones were positive in the gold standard clinical CCP2 test, and when one of the clones was converted back to the predicted germline sequence, autoreactivity was lost, while some reactivity against P.gingivalis remained. These data suggest that the initial antibody response was directed against P.gingivalis, and that autoimmunity developed as a result of somatic mutations during affinity maturation of the B cell response.
In summary, this thesis supports the hypothesis that in a subset of RA patients, loss of tolerance to citrullinated self-proteins may be triggered in the gum mucosa during chronic PD caused by P.gingivalis. However, in order to establish a causative role for P.gingivalis in the development of ACPA-positive RA, further research is warranted.
List of scientific papers
I. Antibodies to Porphyromonas gingivalis indicate interaction between oral infection, smoking, and risk genes in rheumatoid arthritis etiology. Kharlamova N, Jiang X, Sherina N, Potempa B, Israelsson L, Quirke AM, Eriksson K, Yucel-Lindberg T, Venables PJ, Potempa J, Alfredsson L, Lundberg K. Arthritis Rheumatol. 2016 Mar; 68(3): 604-13.
https://doi.org/10.1002/art.39491
II. Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis. Johansson L*, Sherina N*, Kharlamova N, Potempa B, Larsson B, Israelsson L, Potempa J, Rantapää-Dahlqvist S, Lundberg K. Arthritis Res Ther. 2016 Sep 7;18:20. *These authors contributed equally to work and share first authorship.
https://doi.org/10.1186/s13075-016-1100-4
III. The antibody response to a citrullinated Porphyromonas gingivalis PAD peptide could give clues to the aetiology of ACPA-positive rheumatoid arthritis. Sherina N*, Kharlamova N*, de Vries C, Brynedal B, Jiang X, Hansson M, Mathsson-Alm L, Eriksson K, Saevarsdottir S, lsraelsson L, Yucel-Lindberg T, Rönnelid J, Alfredsson L, Lundberg K. *These authors contributed equally to work and share first authorship. [Manuscript]
IV. Citrulline-reactive B cells are present in inflamed gingival tissue and display cross-reactivity between P. gingivalis and human antigens. Sherina N, Sippl N, Liljefors L, Joshua V, Thyagarajan R, Israelsson L, Stålesen R, Wähämaa H, Kharlamova N, Hensvold AH, Eriksson K, Yucel-Lindberg T, Catrina AI, Lanzavecchia A, Piccoli L, Grönwall C, Malmström V, Amara K, Lundberg K. [Manuscript]
History
Defence date
2019-12-13Department
- Department of Medicine, Solna
Publisher/Institution
Karolinska InstitutetMain supervisor
Lundberg, KarinCo-supervisors
Amara, Khaled; Harris, RobertPublication year
2019Thesis type
- Doctoral thesis
ISBN
978-91-7831-577-2Number of supporting papers
4Language
- eng