MIR - Current research and publications
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.
Main research goals
The aims of our research are:
- To identify and functionally analyse the genes that control animal models for chronic inflammatory diseases, mainly using models for rheumatoid arthritis.
- To use the animal models not only for understanding the basic mechanism of autoimmune disease and for developing new diagnostic, preventive and therapeutic strategies.
- To understand the role of MHC class II genes in explaining the immune specificity of autoimmune disease.
We have different research projects within our division. Below, three examples of such projects can be found.
Diagnostics project: JointID clinical treatment research – a new unique diagnostic test for Rheumatoid Arthritis
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 develop a multiplex antibody diagnostic kit with post-translationally modified (citrullinated, carbamoylated, nitrosylated, oxidized and glycosylated) and conformational protein epitopes. These epitopes are selected to be of importance for development of arthritis in animal models. The purpose is to allow diagnosis of RA before disease onset and to help in determination of the type of therapy. The assay will also be used to select RA patients suitable for vaccination.
- To develop a diagnostic kit to identify T cells specific for glycosylated CII. It will be used to predict and monitor vaccination effects of pre-RA and RA patients.
- 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
- Swedish Foundation for Strategic Research (SSF) 2015 – 2020 (Dnr: RB13-0156, 35,000,000 SEK)
Vaccine project: Developing vaccines to cure autoimmune diseases
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
- Swedish Science Council (VR), 2018-2022, (Dnr. 2017-06104, 19,000,000 SEK)
- Familjen Erling-Perssons Stiftelse, 2018-2020 (2017-10-09, 9,000,000 SEK)
Ncf1 project: Changing the view on autoimmune disease based on positional cloning of the Ncf1 gene
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
- Knut och Alice Wallenbergs Stiftelse, 2020 – 2024 (Dnr KAW 2019.0059, 36,500,000 SEK)
Details about the project funding: "Genfynd kan bana väg för vaccin mot autoimmuna sjukdomar"
- Swedish Science Research Council (VR), 2020-2024 (Dnr. 2019-01209, 9,000,000 SEK)
EU MSCA project COSMIC: Combatting disorders of adaptive Immunity with systems medicine (COSMIC)
Grant no: 765158
Period: 2018 – 2021
Budget: 486,710 euro
Marie Curie fellows
Alexander KrämerMC Fellow
Project title: Identification of VDJ repertoire related to arthritis in humans.
Ana CoelhoMC Fellow
Project title: Identification of VDJ repertoire related to arthritis in mouse.
Medical Inflammation Research PhD exchange programme
The Medical Inflammation Research PhD exchange programme is a medical and PhD education including a 2-years’ international high-level research training, established by Xi’an Jiaotong University Health Science Center, in collaboration with the Division of Medical Inflammation Research at Karolinska Institutet.
PhD students apply at Xi’an Jiaotong University to be part of the Medical Inflammations Research PhD exchange programme. Students are matched with supervisors within Karolinska Institutet for their 2-year stay.
Exchange programme responsible
Prof. Rikard Holmdahl
Angel Yao Mattisson
Prior supervisors within the programme:
- Ass Prof. Stephen Malin, MedS
- PhD Yibo He, PhD Mike Aoun, Vilma Urnonaviciute, Dr Liselotte Bäckdahl, Prof. Rikard Holmdahl, MIR MBB
- Dr Qing Cheng, Dr Markus Dagnell, Prof. Elias Arnér, Biochemistry, MBB
- Dr. Dhifaf Sarhan, Labmed
- Dr. Joanna Rorbach, MolMet, MBB
- Dr. Mikael Adner, MTC
- Dr. Craig Wheelock, MBB
- Dr. Susanna Lundström, MBB
- Partner in network for Cancer Redox - targeting redox pathways for improved cancer therapy, Coord. Prof. Elias Arnér, Biochemistry, Karolinska Institute, Supported by Knut och Alice Wallenbergs Stiftelse, 2016 – 2021 (Dnr. 2015.0063)
- Partner in network for A new unique diagnostics test for Rheumatoid Arthritis, Coord Prof. Inger Gjertsson, Göteborg university, supported by Swedish Research council, 2017 – 2019 (Dnr 2016-00288)
- Longstanding collaboration with Xian Jiaotong university and the 2nd affiliated hospital in Xian, China.
- Cooperation with Fraunhofer research institute in Frankfurt Am Main.
- Guangdong province team project with Southern Medical university in Guangzhou, China
- Cooperation project with Prof. Gregg Fields, Florida Atlantic University, funded by NIH 2021-2023 (KR-K210)
- Cooperation with BioInvent international AB, Lund
- Cooperation with Sichuan University, West China Hospital in Chendu, China
Selected recent publications
- Holmdahl R, Sareila O, Olsson L, Bäckdahl L, Wing K: Ncf1 polymorphism reveals oxidative regulation of autoimmune chronic inflammation, Immunol Rev 2016
- Winter S, Hultqvist Hopkins M, Laulund F, Holmdahl R: A Reduction in Intracellular Reactive Oxygen Species Due to a Mutation in NCF4 Promotes Autoimmune Arthritis in Mice. Antiox Redox Signal 2016
- Yau ACY, Tuncel J, Haag S, Norin U, Houtman M, Padyukov L, Holmdahl R: Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis. Proc Natl Acad Sci USA; 2016
- Pfeifle R, Rothe T, Ipseiz N, Scherer HU, Culemann S, Harre U, Ackermann JA, Seefried M, Kleyer A, Uderhardt S, Haugg B, Hueber AJ, Daum P, Heidkamp GF, Ge C, Böhm S, Lux A, Schuh W, Magorivska I, Nandakumar KS, Lönnblom E, Becker C, Dudziak D, Wuhrer M, Rombouts Y, Koeleman, CA, Toes R, Winkler, TH, Holmdahl R, Herrmann M, Blüml S, Nimmerjahn F, Schett G, and Krönke G: Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nat Immunol. 2017
- Ge C, Tong D, Liang B, Lönnblom, E, Schneider N, Hagert C, Viljanen J, Ayoglu B, Stawikowska R, Nilsson P, Fields GB, Skogh T, Kastbom A, Kihlberg J, Burkhardt H, Dobritzsch D, Holmdahl R: Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage JCI Insight 2017
- OlssonLM, JohanssonÅC, GullstrandB, JönsenA, SaevarsdottirS, RönnblomL, LeonardD, WetteröJ, SjöwallC, SvenungssonE, GunnarssonI, BengtssonAA, HolmdahlR: A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus. Ann Rheum Dis 2017
- Raposo B, Merky P, Yamada H, Urbonaviciute V, Lundqvist C, Niaudet C, Kyewski B, Ekwall O, Holmdahl R*, Bäcklund J* (*=shared senior authors): T cells specific for posttranslational modifications escape intrathymic tolerance induction, Nature Com 2018
- Zhong J, Scholz T, Yau ACY, Guerard S, Hüffmeier U, Burkhardt H, Holmdahl R: Mannan-induced NOS2 in macrophages enhances IL-17-driven psoriatic arthritis through innate lymphocytes. Sci Adv 2018
- Ge C, Xu, B, Liang B, Lönnblom E, Lundström SL, Zubarev RA, Ayoglu B, Nilsson P, Skogh T, Kastbom A, Malmström V, Klareskog L, Toes REM, Rispens T, Dobritzsch D, Holmdahl R: Structural basis of cross-reactivity of anti-citrullinated protein antibodies. Arthritis Rheumatol 2019
- FarinottiAB, WigerbladG, NascimentoD, BasDB, UrbinaCM, NandakumarKS, Sandor K, XuB, AbdelmoatyS, HuntMA, Ängeby-MöllerK, BaharpoorA, SinclairJ, JardemarkK, LannerJT, KhmaladzeI, BormLE, ZhangL, WermelingF, CraggMS, LengqvistJ, Chabot-DoréAJ, DiachenkoL, BelferI, CollinM, KultimaK, HeymanB, JimenezJMA, CodeluppiS, HolmdahlR*, Svensson CI* (*shared senior and corresponding authors): Cartilage binding antibodies induce pain through immune complex mediated stimulation of neurons. J Exp Med 2019.
- Ge C, HolmdahlR: The structure, specificity and function of antibodies to citrullinated protein antigens. Nature Rev Rheumatol 2019
- UrbonaviciuteV, LuoH, SjöwallC, BengtssonA, HolmdahlR: Low production of reactive oxygen species drives pathogenesis of systemic lupus erythematosus. Trend Mol Med 2019
- Henriquez-Olguin C, Knudsen JR, Raun SH, Li Z, Dalbram E, Treebak JT, Sylow L, Holmdahl R, Richter EA, Jaimovich E, Jensen TE: Cytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise. Nature Com, 2019.
- Bäckdahl L, Aoun M, Norin U, Holmdahl R: Positional cloning of Clec4b - a novel regulator of bystander activation of auto-reactive T cells. PLOS Gen 2020
- ZhuW, LönnblomE, FörsterM, JohannessonM, Tao P, MengL, LuS, HolmdahlR: Natural polymorphism of Ym1 regulates pneumonitis through alternative activation of macrophages. Science Adv, 2020
- Fernandez LahoreG, RaposoB, LagerquistM, OhlssonC, SabatierP, XuB, AounM, JamesJ, Cai X, ZubarevRA, NandakumarKS, HolmdahlR: Vitamin D3 receptor polymorphisms regulate T cells and T cell dependent inflammatory diseases. PNAS, 2020
- NorinU, RintischC, MengL, ForsterF, EkmanD, TuncelJ, KlockeK, BäcklundJ, YangM, BonnerMY, ShchetynskyK, BergquistM, GjertssonI, HubnerN, BäckdahlL, HolmdahlR: Identification of a mutation in the SH3gl1 gene demonstrate a new T cell mediated regulatory mechanism of autoimmune disease. Nature Com 2021
- Fernandez LahoreG, Förster M, Johannesson, M, SabatierP, Lönnblom E, AounM, He Y, NandakumarKS, ZubarevRA, HolmdahlR: Polymorphism in estrogen receptor binding site causes CD2-dependent sex bias in T cell autoimmune diseases. Nature Com 2021
- Kissel T, Ge C, Hafkenscheid L, Slot LM, Cavallari M, Kwekkeboom JC, He Y, van Schie KA, Vergroesen RD, Kampstra ASB, Reijm S, Stoeken-Rijsbergen G, Heitman LH, Xu B, Pruijn GJM, Wuhrer M, Rispens T, Huizinga TWJ, Scherer HU, Reth M, Holmdahl R*, Toes REM* (shared corresponding and senior authorship): N-linked glycosylation of the immunoglobulin variable 1 domain affects antigen binding and autoreactive B-cell activation. Sci Adv 2021