AUTOCOMPLEMENT SIGNED
The role of complement in the induction of autoimmunity against post-translationally modified proteins
Total Cost €
0EC-Contrib. €
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Project "AUTOCOMPLEMENT" data sheet
The following table provides information about the project.
| Coordinator |
ACADEMISCH ZIEKENHUIS LEIDEN
Organization address contact info |
| Coordinator Country | Netherlands [NL] |
| Total cost | 1˙999˙802 € |
| EC max contribution | 1˙999˙802 € (100%) |
| Programme |
1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC)) |
| Code Call | ERC-2016-COG |
| Funding Scheme | ERC-COG |
| Starting year | 2017 |
| Duration (year-month-day) | from 2017-09-01 to 2022-08-31 |
Partnership
Take a look of project's partnership.
| # | ||||
|---|---|---|---|---|
| 1 | ACADEMISCH ZIEKENHUIS LEIDEN | NL (LEIDEN) | coordinator | 1˙999˙802.00 |
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Project objective
In many prevalent autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) autoantibodies are used as diagnostic and prognostic tools. Several of these autoantibodies target proteins that have been post-translationally modified (PTM). Examples of such modifications are citrullination and carbamylation. The success of B cell-targeted therapies in many auto-antibody positive diseases suggests that B cell mediated auto-immunity is playing a direct pathogenic role. Despite the wealth of information on the clinical associations of these anti-PTM protein antibodies as biomarkers we have currently no insight into why these antibodies are formed. Immunization studies reveal that PTM proteins can induce antibody responses even in the absence of exogenous adjuvant. The reason why these PTM proteins have ‘autoadjuvant’ properties that lead to a breach of tolerance is currently unknown. In this proposal, I hypothesise that the breach of tolerance towards PTM proteins is mediated by complement factors that bind directly to these PTM. Our preliminary data indeed reveal that several complement factors bind specifically to PTM proteins. Complement could be involved in the autoadjuvant property of PTM proteins as next to killing pathogens complement can also boost adaptive immune responses. I plan to unravel the importance of the complement–PTM protein interaction by answering these questions: 1) What is the physiological function of complement binding to PTM proteins? 2) Is the breach of tolerance towards PTM proteins influenced by complement? 3) Can the adjuvant function of PTM be used to increase vaccine efficacy and/or decrease autoreactivity? With AUTOCOMPLEMENT I will elucidate how PTM-reactive B cells receive ‘autoadjuvant’ signals. This insight will impact on patient care as we can now design strategies to either block unwanted ‘autoadjuvant’ signals to inhibit autoimmunity or to utilize ‘autoadjuvant’ signals to potentiate vaccination.
Publications
| year | authors and title | journal | last update |
|---|---|---|---|
| 2019 |
Douwe J. Dijkstra, Jivan V. Joeloemsingh, Ingeborg M. Bajema, Leendert A. Trouw Complement activation and regulation in rheumatic disease published pages: 101339, ISSN: 1044-5323, DOI: 10.1016/j.smim.2019.101339 |
Seminars in Immunology 45 | 2020-04-24 |
| 2020 |
R. Lubbers, S. C. Oostindie, D. J. Dijkstra, P. W. H. I. Parren, M. K. Verheul, L. Abendstein, T. H. Sharp, A. Ru, G. M. C. Janssen, P. A. Veelen, E. T. J. den Bremer, B. Bleijlevens, B.â€J. Kreuk, F. J. Beurskens, L. A. Trouw Carbamylation reduces the capacity of IgG for hexamerization and complement activation published pages: 1-11, ISSN: 0009-9104, DOI: 10.1111/cei.13411 |
Clinical & Experimental Immunology 200/1 | 2020-04-15 |
| 2019 |
Arieke Suzanna Berendina Kampstra, Jacqueline Stephanie Dekkers, Mikhail Volkov, Annemarie L Dorjée, Lise Hafkenscheid, Ayla C Kempers, Myrthe van Delft, Theresa Kissel, Sanne Reijm, George M C Janssen, Peter A van Veelen, Holger Bang, Tom W J Huizinga, Leendert A Trouw, Diane van der Woude, René E M Toes Different classes of anti-modified protein antibodies are induced on exposure to antigens expressing only one type of modification published pages: 908-916, ISSN: 0003-4967, DOI: 10.1136/annrheumdis-2018-214950 |
Annals of the Rheumatic Diseases 78/7 | 2020-04-15 |
| 2020 |
Maaike Biewenga, Arantza Farina Sarasqueta, Maarten E. Tushuizen, Eveline S.M. de Jonge-Muller, Bart van Hoek, Leendert A. Trouw The role of complement activation in autoimmune liver disease published pages: 102534, ISSN: 1568-9972, DOI: 10.1016/j.autrev.2020.102534 |
Autoimmunity Reviews | 2020-04-15 |
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