Objetivo 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. Ámbito científico medical and health sciencesclinical medicinerheumatologymedical and health sciencesbasic medicineimmunologyimmunisationnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineimmunologyautoimmune diseasesmedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines Programa(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Tema(s) ERC-2016-COG - ERC Consolidator Grant Convocatoria de propuestas ERC-2016-COG Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-COG - Consolidator Grant Institución de acogida ACADEMISCH ZIEKENHUIS LEIDEN Aportación neta de la UEn € 1 999 802,50 Dirección ALBINUSDREEF 2 2333 ZA Leiden Países Bajos Ver en el mapa Región West-Nederland Zuid-Holland Agglomeratie Leiden en Bollenstreek Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 1 999 802,50 Beneficiarios (1) Ordenar alfabéticamente Ordenar por aportación neta de la UE Ampliar todo Contraer todo ACADEMISCH ZIEKENHUIS LEIDEN Países Bajos Aportación neta de la UEn € 1 999 802,50 Dirección ALBINUSDREEF 2 2333 ZA Leiden Ver en el mapa Región West-Nederland Zuid-Holland Agglomeratie Leiden en Bollenstreek Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 1 999 802,50