Our research group, led by Rikard Holmdahl, aims to understand the basic pathogenic mechanisms behind autoimmune diseases and cancer. We try to identify and functionally analyse the genes that control autoimmune diseases, primarily by using animal models in which it is possible to identify genetic causes of complex diseases. With this knowledge we develop new diagnostics and vaccines for the treatment of autoimmune diseases like rheumatoid arthritis, and aim to improve immunotherapy in cancer.
Our division is located within Biomedicum, a research building that houses a large part of the experimental research conducted at Karolinska Institutet. The building opened its doors in 2018 and promotes collaboration and research across scientific boundaries.
Open Diagnostics project: JointID clinical treatment research – a new unique diagnostic test for Rheumatoid Arthritis configuration options
Find out below what the research within the division of Medical Inflammation Research (MIR) is aimed at. Also listed are examples of research projects and an overview of our collaborations and recent publications.
The aims of our research are:
We have different research projects within our division. Below, some examples of such projects.
Inflammation in cartilaginous joints occurs in many common diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and psoriasis arthritis (PsA). It is known that antibodies to modified proteins (anticitrullinated protein antibodies and rheumatoid factors) are useful for predicting and classifying RA. It has however been difficult to identify specific and useful biomarkers derived from the joint inflammation itself.
We have focused on the immune response to joint cartilage proteins, in particular type II collagen (CII). This is directed to exposed triple helical structures, as well as to structures modified e.g. by citrullination. The response is connected with the onset of the RA and provides very sensitive biomarkers for joint inflammation.
We have three main goals:
To extend the antibody kit with additional joint-related epitopes useful for diagnosing additional joint inflammatory diseases, including common diseases like OA and PsA
Prof. Rikard Holmdahl.
Prof. Inger Gjertsson, Göteborg University; Prof. Jan Kihlberg, Uppsala University
The next step in the treatment of autoimmune disease will be to prevent and cure, rather than only treating the symptoms. We focus on vaccine development to both prevent and treat rheumatoid arthritis (RA) but subsequently also other autoimmune diseases.
Vaccines have not yet been developed to any autoimmune disease, but we have several unique findings that will be tested clinically in RA. Our patent protected approach is to induce regulatory T cells by administration of a protein complex with the product of a strongly associated RA gene together with a protein fragment from collagen type II in joint cartilage that is a recognized by T cells in RA.
We have established new unique mouse strains with the human genes of interest, allowing development and validation of new vaccines not only for RA but for other autoimmune diseases as well. We have also developed new technology that allows modification of peptide structure; glycosylation and protein carrier, to develop improved personalized variants vaccines.
Prof. Rikard Holmdahl
Prof. Roman Zubarev, Division of Chemistry I and chemical proteomics platform, Karolinska Institutet; Prof. Jan Kihlberg, Uppsala University; Dr. Kajsa Wing, Division of Medical inflammation Research, Karolinska Institutet
We have identified several major causative polymorphisms in mouse and rat models of autoimmune disease and are now investigating their functional role. One of these projects concerns Ncf1, a component of the NOX2 complex, which induces reactive oxygen species (ROS).
We found that Ncf1 alleles causing low production of reactive oxygen species (ROS) is a major cause of autoimmune disease as well as being a pronounced risk behavior, explaining the natural selection. In addition ROS is likely to regulate the immune response to cancer cells.
The Ncf1 locus is highly polymorphic and has in fact not been sequenced in humans, due to copy number variation, and is therefore not included in genome wide association studies. However, we have found that copy number variation and amino acid polymorphism is strongly associated with both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).
Based on our original finding and many years of combined efforts in both experimental animals and humans we have now established a unique platform and strategy to reveal a critical part of the pathogenesis of autoimmune disease. We have established CRISPR mutated and conditionally controlled Ncf1 mouse strains.
With models for RA and SLE we have also confirmed that the pathways are conserved between mice and humans. We have preliminary evidence of direct links to major pathways, such as interferon signaling and T and B cell receptor signaling. We intent to identify the immune regulatory cells expressing Ncf1 that play a critical role in the downstream pathway of autoimmune disease such as RA and SLE, but also in cancer. Also to determine the signaling oxidative and antioxidant pathways in the regulatory Ncf1 expressing cells as well as in cells exposed to secreted ROS.
This project will provide new insights into key pathogenic mechanisms based on redox regulation, leading to autoimmune and malignant diseases.
Prof. Rikard Holmdahl
Prof. Elias Arnér, Division of Biochemistry, Karolinska Institute; Prof. Roman Zubarev, Division of Chemistry I and chemical proteomics platform, Karolinska Institute
Psoriasis vulgaris (PsV) is an immune mediated disease of the skin, which is associated in one third of the patients with the development of psoriatic arthritis (PsA). PsV is a complex chronic disease driven by adaptive and innate lymphocytes involving the IL-17/22/23 signaling pathway. It is associated with the PSORS1 locus within the major histocompatibility complex (MHC) region, containing non-classical MHC genes regulating IL-17 producing innate lymphocytes. Besides the strong influence of the MHC region, a locus with the inducible nitric oxide synthase (NOS2) gene is associated with PsV/PsA susceptibility and the NOS2 locus regulate the exposure of various reactive oxygen species (ROS). Thus, genetic evidence argues for that non-classical MHC genes involved in the innate immune responses are regulated by RNS/ROS mediated functions.
The environmental causes of the PsV/ PsA in humans is not known but some sort of environmental challenges triggering the immune system in pathogenic way is likely. And it is likely that an immune adjuvant type of exposure, mediated by infections, pollution or smoking, will trigger or promote disease. Our project is based on the unique discovery that mannan exposure could induce the development of a disease in mice mimicking PsV and PsA. In this project, we will use the MIP model to investigate PsV and PsA with the aim to develop new type of diagnostics and treatments.
The mechanisms by which mannan triggers disease is not known but is likely involving activation of inflammatory cells through CLRs. These receptors could be both inflammatory and anti-inflammatory, partially dependent on their ability to activate the NOX2 complex that could induce reactive oxygen species (ROS), protecting disease development in the MIP model. Based on this, we will use mouse strains with and without the Ncf1 mutation to determine whether the observed therapeutic effect is dependent of the proposed mechanisms of action through the NOX2 complex. We will also use the model to facilitate the development of better diagnostics for PsV and PsA, with developed a multiplex peptide-based antibody test to investigate the ongoing autoantibody responses in in autoimmune diseases.
Prof. Rikard Holmdahl
54. Michael Bonner (KI),
55. Carolin Svensson (KI)
1) Per Larsson, UU 1989, main supervisor Lars Klareskog, 2) Inga Hansson, UU 1993, main supervisor Ragnar Mattsson, 5) Jinan Li, UmeåU 2004, main supervisor Tor Ny 3) Hai Tao Yang, UU 2000, main supervisor Prof. Ulf Pettersson; 4) Ingrid Teige, LU 2004, main supervisor Prof. Shoreh Issasadeh; 6) Meirav Holmdahl, LU 2005, main supervisor Prof. Anders Grubb 7) Jenny Karlsson, LU 2005, main supervisor Prof. Shoreh Issasadeh, 8) Alexandra Treschow, LU 2005, main supervisor Prof. Shoreh Issasadeh 9) Patrick Merky, KI 2011, main supervisor Docent Johan Bäcklund; 11) Ia Khalmadze, KI 2014, main supervisor Prof. Kutty Selva Nandakumar; 12) Simon Guerad, KI 2016 main supervisor Dr Kajsa Wing:; 13) Katrin Klocke, KI 2017, main supervisor Dr Kajsa Wing; 14) Bibo Liang, SMU 2017, main supervisor Prof. Zhao Ming; 15) Dongmei Tong, SMU 2018, main supervisor Prof. Zhao Ming, 16) Mike Aoun, Main supervisor Dr Liselotte Bäckdahl, 210903 “Positional cloning of polymorphic loci that control autoreactive T cells”, Opponent: Prof. Marc K. Jenkins, University of Minnesota, USA