Team Karin Lundberg

Research focus

Microbes as triggers of autoimmunity in rheumatoid arthritis

Introduction

Our research investigates whether specific oral pathogens are causatively linked to the development of rheumatoid arthritis (RA).

Rheumatoid arthritis is a common (0.5-1%) chronic autoimmune disease, that can have severe manifestations. Patients suffer joint inflammation, pain, disability, comorbidities and increased mortality. The cause of RA is still largely unknown and there is no cure.

Antibodies targeting proteins modified by citrullination (i.e. ACPA) are present in a majority of patients, associate with classical risk factors such as smoking and specific HLA-DRB1 alleles, and predict a more destructive disease. Since ACPA can be detected years before symptom onset of RA it has been suggested that break of immune tolerance to citrullinated proteins occurs at extra-articular sites. However, the initial trigger(s) of ACPA are still unknown, and we are only beginning to understand how ACPA may contribute to joint inflammation and destruction. In order to develop novel treatments and preventive strategies, we need a better understanding of the etiopathology underpinning the ACPA response in RA.

In epidemiological studies, RA has been linked to chronic periodontitis (PD) - inflammation in the gingival tissue that can cause tooth loss as a result of degraded jawbone. Gingival inflammation results in local protein citrullination, and in addition, the periodontal bacteria Porphyromonas gingivalis (Pg) - a keystone pathogen in the development of PD - is the only known prokaryote to express a citrullinating enzyme, denoted Pg PAD, capable of auto-citrullination as well as citrullination of human proteins. Hence, citrullinated proteins are present in the bacteria-rich inflamed gingival tissue, and we hypothesise that this milieu may facilitate break of immune tolerance and production of ACPA. In support of an etiological role for Pg, we have previously shown elevated anti-Pg antibody responses in ACPA+ RA patients compared to population controls, even years before RA symptom onset. Moreover, we have shown that ACPA purified from RA patients cross-react with Pg epitopes.

Major research focus

With this background, our research aims to determine whether there is a causative link between specific oral pathogens and the development of ACPA+ RA, using epidemiology (e.g. cohort studies) as well as molecular (e.g. generation and characterization of patient-derived monoclonal antibodies from the gingival tissue) and functional studies (e.g. in vitro cell assays and in vivo models to evaluate the pathogenic potential of patient-derived antibodies).

Collaborations

Prof. Hyun-Dong Chang, Deutsches Rheuma-Forschungszentrum Berlin
Prof. Federica Sallusto, Institute for Research in Biomedicine, Bellinzona
Prof. Jan Potempa, University of Louisville
Prof. Pernilla Lundberg, Umeå University

Team members

Charlotte de Vries, PhD student
Elin Kindstedt, Posdoc

Key publications

Presence of autoantibodies in "seronegative" rheumatoid arthritis associates with classical risk factors and high disease activity.
Reed E, Hedström AK, Hansson M, Mathsson-Alm L, Brynedal B, Saevarsdottir S, Cornillet M, Jakobsson PJ, Holmdahl R, Skriner K, Serre G, Alfredsson L, Rönnelid J, Lundberg K
Arthritis Res Ther 2020 07;22(1):170

A cross-sectional investigation into the association between Porphyromonas gingivalis and autoantibodies to citrullinated proteins in a German population.
Oluwagbemigun K, Yucel-Lindberg T, Dietrich T, Tour G, Sherina N, Hansson M, Bergmann M, Lundberg K, Boeing H
Ther Adv Musculoskelet Dis 2019 ;11():1759720X19883152

Periodontal Health and Oral Microbiota in Patients with Rheumatoid Arthritis.
Eriksson K, Fei G, Lundmark A, Benchimol D, Lee L, Hu YOO, Kats A, Saevarsdottir S, Catrina AI, Klinge B, Andersson AF, Klareskog L, Lundberg K, Jansson L, Yucel-Lindberg T
J Clin Med 2019 May;8(5):

Generation and Characterization of Anti-Citrullinated Protein Antibody-Producing B Cell Clones From Rheumatoid Arthritis Patients.
Germar K, Fehres CM, Scherer HU, van Uden N, Pollastro S, Yeremenko N, Hansson M, Kerkman PF, van der Voort EIH, Reed E, Maassen H, Kwakkenbos MJ, Bakker AQ, Klareskog L, Malmström V, de Vries N, Toes REM, Lundberg K, Spits H, Baeten DL
Arthritis Rheumatol 2019 03;71(3):340-350

Anticitrullinated protein/peptide antibody multiplexing defines an extended group of ACPA-positive rheumatoid arthritis patients with distinct genetic and environmental determinants.
Rönnelid J, Hansson M, Mathsson-Alm L, Cornillet M, Reed E, Jakobsson PJ, Alfredsson L, Holmdahl R, Skriner K, Serre G, Lundberg K, Klareskog L
Ann Rheum Dis 2018 02;77(2):203-211

Seropositivity combined with smoking is associated with increased prevalence of periodontitis in patients with rheumatoid arthritis.
Eriksson K, Nise L, Alfredsson L, Catrina AI, Askling J, Lundberg K, Klareskog L, Yucel-Lindberg T
Ann Rheum Dis 2018 08;77(8):1236-1238

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 09;18():201

Prevalence of Periodontitis in Patients with Established Rheumatoid Arthritis: A Swedish Population Based Case-Control Study.
Eriksson K, Nise L, Kats A, Luttropp E, Catrina AI, Askling J, Jansson L, Alfredsson L, Klareskog L, Lundberg K, Yucel-Lindberg T
PLoS One 2016 ;11(5):e0155956

Antibodies to carbamylated α-enolase epitopes in rheumatoid arthritis also bind citrullinated epitopes and are largely indistinct from anti-citrullinated protein antibodies.
Reed E, Jiang X, Kharlamova N, Ytterberg AJ, Catrina AI, Israelsson L, Mathsson-Alm L, Hansson M, Alfredsson L, Rönnelid J, Lundberg K
Arthritis Res Ther 2016 05;18(1):96

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

Changes in the anticitrullinated peptide antibody response in relation to therapeutic outcome in early rheumatoid arthritis: results from the SWEFOT trial.
Kastbom A, Forslind K, Ernestam S, Geborek P, Karlsson JA, Petersson IF, Saevarsdottir S, Klareskog L, van Vollenhoven RF, Lundberg K
Ann Rheum Dis 2016 Feb;75(2):356-61

Identification of an immunodominant peptide from citrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis.
Schwenzer A, Jiang X, Mikuls TR, Payne JB, Sayles HR, Quirke AM, Kessler BM, Fischer R, Venables PJ, Lundberg K, Midwood KS
Ann Rheum Dis 2016 10;75(10):1876-83

Protective effect of HLA-DRB1*13 alleles during specific phases in the development of ACPA-positive RA.
van Heemst J, Hensvold AH, Jiang X, van Steenbergen H, Klareskog L, Huizinga TW, van der Helm-van Mil A, Catrina AI, Toes RE, Lundberg K, van der Woude D
Ann Rheum Dis 2016 Oct;75(10):1891-8

Affinity purified anti-citrullinated protein/peptide antibodies target antigens expressed in the rheumatoid joint.
Ossipova E, Cerqueira CF, Reed E, Kharlamova N, Israelsson L, Holmdahl R, Nandakumar KS, Engström M, Harre U, Schett G, Catrina AI, Malmström V, Sommarin Y, Klareskog L, Jakobsson PJ, Lundberg K
Arthritis Res Ther 2014 Aug;16(4):R167