Translational Rheumatology

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.

Members

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

Selected publications

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

Rheumatoid arthritis.
Klareskog L, Catrina AI, Paget S
Lancet 2009 Feb;373(9664):659-72