KARIN LUNDBERG TEAM
Our research aims to increase our understanding of the pathobiology underpinning the anti-citrullinated protein/peptide antibody (ACPA) response in rheumatoid arthritis (RA). Specifically, we investigate the hypothesis that the periodontal bacterium Porphyromonas gingivalis – a major cause of chronic periodontitis – is driving disease in a subset of RA, by mediating loss of tolerance to citrullinated proteins. Furthermore, we aim to determine whether ACPA are pathogenic, and by which mechanisms.
The discovery of autoantibodies directed to citrullinated proteins/peptides (ACPA) has during the past decade increased our understanding of the specific autoimmune reactions that are thought to drive RA, and led to the development of a novel diagnostic test, the CCP ELISA assay. Present in 60%-70% of patients, anti-CCP antibodies divide RA into two disease subsets; the anti-CCP positive and the anti-CCP negative. Well-known genetic risk factors for RA, as well as the major environmental risk factor, cigarette smoking, associate with the anti-CCP positive subset only, which also demonstrates a more destructive disease course. Anti-CCP antibodies are thought to target epitopes on citrullinated proteins in the rheumatoid joint, including citrullinated α-enolase, fibrinogen, vimentin and collagen type II, and thereby drive chronic inflammation. We have previously shown that ACPA targeting citrullinated α-enolase, purified from RA patients, cross-react with citrullinated enolase from Porphyromonas gingivalis, providing a basis for a possible triggering of autoimmunity by molecular mimicry.
We hypothesise that Porphyromonas gingivalis, in the context of cigarette smoking and PAMPS (e.g. LPS), drives a local inflammation in the gingival tissue (i.e. gingivitis / periodontitis), triggering the activation of bacterial and human PAD enzymes, which in turn cause increased protein citrullination. In genetically predisposed individuals (i.e. HLA-DRB1 SE+, PTPN22+), citrulline-specific T cells become activated and mediate “help” to ACPA-specific B cells, which in response secrete ACPA. Through epitope-spreading, ACPA later cross-react with citrullinated epitopes in the joint, form immune complexes and drive a local synovial inflammation into a chronic state (i.e. RA). With epidemiological and molecular research approaches, using patient cohorts and biological materials, our research is focused on the studies of citrullinated α-enolase as a prototype citrullinated antigen, for investigating the etiology and the pathogenesis of the ACPA response in RA. The long-term ambition with our research is to develop personalised antigen-specific therapies and pre-clinical interventions.
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. Presence of autoantibodies in "seronegative" rheumatoid arthritis associates with classical risk factors and high disease activity. Arthritis Res Ther. 2020 Jul 16;22(1):170.
Sahlström P, Hansson M, Steen J, Amara K, Titcombe PJ, Forsström B, Stålesen R, Israelsson L, Piccoli L, Lundberg K, Klareskog L, Mueller DL, Catrina AI, Skriner K, Malmström V, Grönwall C. Different Hierarchies of Anti-Modified Protein Autoantibody Reactivities in Rheumatoid Arthritis. Arthritis Rheumatol. 2020 Jun 5. doi: 10.1002/art.41385.
Sherina N, Hreggvidsdottir HS, Bengtsson C, Hansson M, Israelsson L, Alfredsson L, Lundberg K. Low levels of antibodies against common viruses associate with anti-citrullinated protein antibody-positive rheumatoid arthritis; implications for disease aetiology. Arthritis Res Ther. 2017 Sep 30;19(1):219.
Schwenzer A, Jiang X, Mikuls TR, Payne JB, Sayles HR, Quirke AM, Kessler BM, Fischer R, Venables PJ, Lundberg K* and Midwood KS* (*shared last author). Identification of an immunodominant peptide from citrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis. Ann Rheum Dis. 2016 Oct;75(10):1876-83.
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. Protective effect of HLA-DRB1*13 alleles during specific phases in the development of ACPA-positive RA. Ann Rheum Dis. 2016 Oct;75(10):1891-8.
Johansson L, Sherina N, Kharlamova N, Potempa B, Larsson B, Israelsson L, Potempa J, Rantapää-Dahlqvist S, Lundberg K. Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis. Arthritis Res Ther. 2016 Sep 7;18:201.
Eriksson K, Nise L, Kats A, Luttropp E, Catrina AI, Askling J, Jansson L, Alfredsson L, Klareskog L, Lundberg K, Yucel-Lindberg T. Prevalence of Periodontitis in Patients with Established Rheumatoid Arthritis: A Swedish Population Based Case-Control Study. PLoS One. 2016 May 20;11(5):e0155956.
Reed E, Jiang X, Kharlamova N, Ytterberg AJ, Catrina AI, Israelsson L, Mathsson-Alm L, Hansson M, Alfredsson L, Rönnelid J, Lundberg K. Antibodies to carbamylated α-enolase epitopes in rheumatoid arthritis also bind citrullinated epitopes and are largely indistinct from anti-citrullinated protein antibodies. Arthritis Res Ther. 2016 May 4;18(1):96.
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. Antibodies to Porphyromonas gingivalis Indicate Interactioon between Oral Infection, Smoking, and Risk Genes in Rheumatoid Arthritis Etiology. Arthritis Rheumatol. 2016 Mar;68(3):604-13.
Kastbom A, Forslind K, Ernestam S, Geborek P, Karlsson JA, Petersson IF, Saevarsdottir S, Klareskog L, van Vollenhoven RF, Lundberg K. Changes in the anti-citrullinated peptide antibody response in relation to therapeutic outcome in early rheumatoid arthritis: results from the SWEFOT trial. Ann Rheum Dis. 2016 Feb;75(2):356-61.
Lundström SL, Cerqueira CF, Ytterberg JA, Ossipova E, Jakobsson PJ, Malmström V, Catrina A, Klareskog L, Lundberg K* and Zubarev RA* (*shared last author). IgG antibodies to cyclic citrullinated peptides comprise a specific profile both in terms of subclass and Fc-glycosylation. PLoS One. 2014 Nov 26;9(11):e113924.
Jiang X, Trouw LA, van Wesemael TJ, Shi J, Bengtsson C, Källberg H, Malmström V, Israelsson L, Hreggvidsdottir H, Verduijn W, Klareskog L, Alfredsson L, Huizinga TWJ, Toes REM, Lundberg K, van der Woude D. Anti-CarP antibodies in two large cohorts of patients with rheumatoid arthritis and their relationship to genetic risk factors, cigarette smoking and other autoantibodies. Ann Rheum Dis. 2014 Oct;73(10):1761-8.
Ossipova E, Cerqueira CF, Reed E, Kharlamova N, Israelsson N, Holmdahl R, Nandakumar KS, Engström M, Harre U, Schett G, Catrina AI, Malmström V, Sommarin Y, Klareskog L, Jakobsson PJ, Lundberg K. Affinity purified anti-citrullinated protein/peptide antibodies target antigens expressed in the rheumatoid joint. Arthritis Res Ther. 2014 Aug 12;16(4):R167.
Lundberg K, Bengtsson C, Kharlamova N, Reed E, Jiang X, Kallberg H, Pollak-Dorocic I, Israelsson L, Kessel C, Padyukov L, Holmdahl R, Alfredsson L, Klareskog L. Genetic and environmental determinants for disease risk in subsets of rheumatoid arthritis defined by the anticitrullinated protein/peptide antibody fine specificity profile. Ann Rheum Dis. 2013 May;72(5):652-8.
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. Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Nat. Genet. 2009 Dec;41(12):1319-24.
Lundberg K, Kinloch A, Fisher B, Wegner N, Wait R, Charles P, Mikuls TR, Venables PJ. Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum. 2008 Oct;58(10):3009-19.