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. Fields of science medical and health sciencesclinical medicinerheumatologymedical and health sciencesbasic medicineimmunologyimmunisationnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineimmunologyautoimmune diseasesmedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2016-COG - ERC Consolidator Grant Call for proposal ERC-2016-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution ACADEMISCH ZIEKENHUIS LEIDEN Net EU contribution € 1 999 802,50 Address ALBINUSDREEF 2 2333 ZA Leiden Netherlands See on map Region West-Nederland Zuid-Holland Agglomeratie Leiden en Bollenstreek Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 999 802,50 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all ACADEMISCH ZIEKENHUIS LEIDEN Netherlands Net EU contribution € 1 999 802,50 Address ALBINUSDREEF 2 2333 ZA Leiden See on map Region West-Nederland Zuid-Holland Agglomeratie Leiden en Bollenstreek Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 999 802,50
