We are a mixed team of pre-clinical and clinical researchers performing translational research of autoimmune diseases, with a special focus on rheumatoid arthritis (RA). We are investigating the early phases of RA development using a large spectrum of molecular techniques and with direct access to national registers and clinical samples.
We are aiming to understand how genes, environment and life style factors interact and contribute to development of autoimmunity outside the joints (such as at mucosal sites and the immune system) that only in a second stage leads to chronic joint inflammation and tissue destruction. We want to understand why and when the disease actually starts. Rheumatologists are today focusing on diagnosis and
treatment of relatively late stages of the disease, when chronic inflammation has already developed. We want to change this so we can interfere much more earlier during disease development. RA is the only autoimmune disease where different stages of disease development (from autoimmunity generation to disease onset) are well characterized. This gives unique possibilities to test different strategies for disease prevention.
Recent results in our group have largely contribute to a new hypothesis for RA development. According to this hypothesis, RA starts with break of tolerance at mucosal sites, especially in the respiratory mucosa. Airborne pollutants such as smoking induce local modifications of proteins by so called citrullination which leads to immune activation and antibody production, the so-called antibodies against citrullinated proteins (ACPA). These reactions mature over time and gradually induce pain and joint inflammation. Our current work hypothesis is that ACPA are responsible for this gradual development. We have shown that osteoclasts are dependent on citrullination (the same process taking place in smoke-exposed respiratory mucosa) for their physiological development and express citrullinated proteins on their cell surface. As such ACPA can bind to osteoclasts with osteoclast activation and release of Interleukin (IL)-8. This leads in turn to bone loss, pain and subclinical inflammation. We are currently developing our work hypothesis by testing the effects of a broad spectrum of patient-derived ACPAs in cell and animal models. We have also taken the first step towards clinical studies by initiating a double-blind placebo-controlled study using an osteoclasts-blocking agent to treat pain and prevent arthritis development in individuals bearing ACPA and having a risk to develop RA.
Our work will contribute to:
(1). Detailed knowledge on the mechanisms responsible for disease progression that can result in new therapeutic strategies,
(2). Improved identification of individuals at risk for developing RA and discovery of biomarkers for disease progression that are essential for therapy selection with right drug and at the right timepoint,
(3). Development of new animal models mirroring human disease development that can be used to test new therapeutic strategies and
(4). More specific and early treatment which open the possibilities for disease prevention.
Bence Rethi, PhD, associate professor
Karin Lundberg, PhD, associate professor
Aleksandra Antovic, MD, PhD, associate professor
Aase Hah Hensvold, MD, PhD, senior postdoc
Katerina Chatzidionysiou, MD, PhD, senior postdoc
Erik af Klint, MD, PhD senior resercher
Heidi Wähämaa, PhD, lab manager
Meng Sun, PhD, lab coordinator
Akilan Krishnamurthy, PhD, lab coordinator
Vijay Joshua, PhD, senior postodoc
Koji Sakuraba, MD, PhD, postdoc
Alexandra Circiumaru, MD, PhD student
Malena Loberg Haarhaus, MD, PhD student
Yogan Kisten, MSc, PhD student
Charlotte de Vries, BSc, PhD student
Marianne Engström, lab engineer
Malin Bodin, research nurse
Sofia Geschwind, research nurse
Anticitrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts.
Sun M, Rethi B, Krishnamurthy A, Joshua V, Circiumaru A, Hensvold AH, et al
Ann. Rheum. Dis. 2019 12;78(12):1621-1631
Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis.
Catrina AI, Svensson CI, Malmström V, Schett G, Klareskog L
Nat Rev Rheumatol 2017 Feb;13(2):79-86
The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting.
Malmström V, Catrina AI, Klareskog L
Nat. Rev. Immunol. 2017 01;17(1):60-75
How well do ACPA discriminate and predict RA in the general population: a study based on 12 590 population-representative Swedish twins.
Hensvold AH, Frisell T, Magnusson PK, Holmdahl R, Askling J, Catrina AI
Ann. Rheum. Dis. 2017 Jan;76(1):119-125
Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis.
Reynisdottir G, Olsen H, Joshua V, Engström M, Forsslund H, Karimi R, et al
Ann. Rheum. Dis. 2016 09;75(9):1722-7
Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss.
Krishnamurthy A, Joshua V, Haj Hensvold A, Jin T, Sun M, Vivar N, et al
Ann. Rheum. Dis. 2016 Apr;75(4):721-9
Mechanisms involved in triggering rheumatoid arthritis.
Catrina AI, Joshua V, Klareskog L, Malmström V
Immunol. Rev. 2016 Jan;269(1):162-74
Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation.
Ytterberg AJ, Joshua V, Reynisdottir G, Tarasova NK, Rutishauser D, Ossipova E, et al
Ann. Rheum. Dis. 2015 Sep;74(9):1772-7
Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins.
Hensvold AH, Magnusson PK, Joshua V, Hansson M, Israelsson L, Ferreira R, et al
Ann. Rheum. Dis. 2015 Feb;74(2):375-80
Klareskog L, Catrina AI, Paget S
Lancet 2009 Feb;373(9664):659-72