CORDIS
EU research results

CORDIS

English EN
The role of complement in the induction of autoimmunity against post-translationally modified proteins

The role of complement in the induction of autoimmunity against post-translationally modified proteins

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.
Leaflet | Map data © OpenStreetMap contributors, Credit: EC-GISCO, © EuroGeographics for the administrative boundaries

Host institution

ACADEMISCH ZIEKENHUIS LEIDEN

Address

Albinusdreef 2
2333 Za Leiden

Netherlands

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 1 999 802,50

Beneficiaries (1)

Sort alphabetically

Sort by EU Contribution

Expand all

ACADEMISCH ZIEKENHUIS LEIDEN

Netherlands

EU Contribution

€ 1 999 802,50

Project information

Grant agreement ID: 724517

Status

Ongoing project

  • Start date

    1 September 2017

  • End date

    31 August 2022

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 999 802,50

  • EU contribution

    € 1 999 802,50

Hosted by:

ACADEMISCH ZIEKENHUIS LEIDEN

Netherlands