Karin Lundberg Team
About
Rheumatoid arthritis (RA) is a common (0.5-1% worldwide) chronic inflammatory autoimmune disease, where patients suffer joint pain and -destruction, disability, comorbidities and increased mortality, with an additional high socioeconomic cost. Early detection and early treatment are key for clinical outcome.
The etiology of RA and underlying disease mechanisms are to a large extent unknown, but antibodies to post-translationally modified self-proteins, in particular citrullinated proteins (ACPA), are thought to play a key role. These autoantibodies can be detected years prior clinical onset and are linked to specific HLA genes, smoking and periodontitis. However, the antigens triggering autoimmunity and the mechanisms involved in the transition from autoimmunity to clinical manifest RA remain to be clarified.
The mucosal origins hypothesis of RA – where microbes active at mucosal tissues have been suggested to drive the autoimmune response – is becoming increasingly popular. In support of this hypothesis, our studies show an epidemiological association between the periodontal pathogen Porphyromonas gingivalis and ACPA+ RA, and presence of citrulline-reactive B cells with bacterial cross-reactivity in RA gingival tissue and blood.
Research
The overall aim of our research is to clarify disease pathways underpinning RA and RA-related autoimmunity, and to identify predictive biomarkers as a basis for pre-clinical intervention and personalised targeted therapies, with the gum-joint axis in focus.
Current research projects include:
Biomarkers for prediction
With an ambition to prevent or slow down the disease process by early intervention, we want to identify at-risk individuals in the general population before they develop RA. We would also like to be able to predict response to RA-treatment on an individual basis, as some patients are refractory to (sometimes expensive and potentially harmful) biological therapies. By extensive antibody serology in unique cohorts, this project explores antibodies to Porphyromonas gingivalis and autoantibody profiles as potential predictive biomarkers.
Molecular mimicry as a driver of autoimmunity
Molecular mimicry between epitopes on microbes and self-proteins as a mechanism for driving autoimmunity is an attractive hypothesis that has been discussed for long, and a number of recent studies can now show microbial cross-reactivity in RA on the monoclonal level. With access to a large number of RA patient-derived monoclonal antibodies from different tissues, this project further examines microbial cross-reactivity by e.g. microbiota flow cytometry/shotgun sequencing/bioinformatics.
Deep phenotyping & monitoring of autoreactive B cells in at-risk individuals
Presence of ACPA predicts a more destructive form of RA, yet ACPA are present years before symptom onset. With the successful use of B-cell depleting therapies, the role of B cells in RA pathogenesis has been highlighted. This project investigates if changes in autoreactive B cell phenotypes – during the transition from autoimmunity to clinical manifest RA – can clarify disease mechanisms. The project use peptide-tetramers and an extensive B cell panel for deep phenotyping of circulating B cells in ACPA+ at-risk individuals over time by spectral-flow cytometry.
® Our research team at CMM work in close contact with the rheumatology clinics at Karolinska University Hospital and Centre for Rheumatology, and we collaborate with international experts in molecular periodontology and the microbiome research field, providing unique patient material and state-of-the-art technologies, with an aim to clarify molecular mechanisms linking PD/periodontal pathogens to RA and RA-related autoimmunity, as a basis for new targeted therapies and pre-clinical interventions.
Team Leader
Karin defended her PhD thesis on Arthritogenic and Immunogenic Properties of Modified Autoantigens in 2005 at Karolinska Institutet, Department of Medicine Solna, with Professor Helena Erlandsson Harris as main supervisor. During 2005-2010 she did a postdoc fellowship in Professor Patrick Venables lab at the Kennedy Institute of Rheumatology, Imperial College London, where she identified citrullinated a-enolase peptide 1 (CEP-1) as a major target of the autoimmune ACPA response in RA, and demonstrated cross-reactivity between CEP-1 and the bacterial counterpart expressed by the periodontal pathogen P. gingivalis. These findings formed the basis for Karin’s current research line, with focus on the mucosal origins hypothesis and oral microbes as drivers of autoimmunity in RA.
With a patent on the CEP-1 peptide, and large research grants from Vinnova, EU and the Swedish Research Council, Karin set up her own research team at CMM in 2010. She is currently principle supervisor for one PhD student, previously three PhD students, three postdocs and several master students.
In addition to research at CMM, Karin has recently worked part time as scientific adviser and writer at ELSA Science, a digital platform for people with rheumatic diseases.
Team members
Alumni
PhD students:
Natalia Sherina, 2014-2019
Nastya Kharlamova, 2012-2018
Evan Reed, 2013-2017
Post doc fellows:
Elin Kindstedt, 2020-2022
Erwan Le Maitre, 2019
Alf Kastbom, 2012
Master students:
Sabrina Kunz, 2022
Cecilia Bergman, 2021
Ailbhe Comyn, 2011
Collaborations
Current External Collaborators:
Professor Jan Potempa, University of Louisville, USA, and Jagiellonian University, Krakow, Poland
Professor Pernilla Lundberg, Umeå University
Professor Guy Gorochov, Inserm, Paris, France
Selected publications
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. doi: 10.3389/fimmu.2022.804822.
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. doi: 10.3390/jcm11041008.
A comprehensive evaluation of the relationship between different IgG and IgA anti-modified protein autoantibodies in rheumatoid arthritis. Caroline Grönwall, Lisa Liljefors, Holger Bang, Aase H Hensvold, Monika Hansson, Linda Mathsson-Alm, Lena Israelsson, Vijay Joshua, Anna Svärd, Ragnhild Stålesen, Philip J Titcombe, Johanna Steen, Luca Piccoli, Natalia Sherina, Cyril CLAVEL, Elisabet Svenungsson, Iva Gunnarsson, Saedis Saevarsdottir, Alf Kastbom, Guy Serre, Lars Alfredsson, Vivianne Malmström, Johan Rönnelid, Anca I Catrina, Karin Lundberg, Lars Klareskog. Front Immunol. 2021 May 20;12:627986. doi: 10.3389/fimmu.2021.627986.
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 Jul 16;22(1):170. doi: 10.1186/s13075-020-02191-2.
A cross-sectional investigation into the association between P. 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 5;11:1759720X19883152.
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, ReedE, Maassen H, Kwakkenbos MJ, Bakker AQ, Klareskog L, Malmström V, de Vries N, Toes REM, Lundberg K, Spits H, Baeten DL. Arthritis Rheumatol. 2019 Mar;71(3):340-350. doi: 10.1002/art.40739.
Anticitrullinated protein/peptide antibody multiplexing defines an extended group of ACPA-positive RA 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 Feb;77(2):203-211.
Low levels of antibodies against common viruses associate with anti-citrullinated protein antibody-positive rheumatoid arthritis; implications for disease aetiology. Sherina N, Hreggvidsdottir HS, Bengtsson C, Hansson M, Israelsson L, Alfredsson L, Lundberg K. Arthritis Res Ther. 2017 Sep 30;19(1):219.
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(1):201. doi: 10.1186/s13075-016-1100-4.
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. doi: 10.1002/art.39491.
Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Mahdi H, Fisher B, Källberg H, Plant D, Malmström V, Rönnelid J, Charles P, Ding B, Alfredsson L, Padyukov L, Symmons DP, Venables PJ, Klareskog L, Lundberg K. Nat. Genet. 2009 Dec;41(12):1319-24. doi: 10.1038/ng.480.
Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Lundberg K, Kinloch A, Fisher B, Wegner N, Wait R, Charles P, Mikuls TR, Venables PJ. Arthritis Rheum. 2008 Oct;58(10):3009-19. doi: 10.1002/art.23936.