Stratégies pour le diagnostic, le pronostic et le traitement de la polyarthrite rhumatoïde fondées sur l'utilisation de peptides dérivés de la fibrine. – FIPESTRA

Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease leading to severe disability. It is the commonest autoimmune disorder and the most frequent of all chronic inflammatory joint diseases, affecting 0.5-1% of the world population. Aggressive treatment in the early phases of the disease limits joint damage and thus the resulting disability. However, the potential toxicity and the cost of the newly available treatments make the certainty of diagnosis necessary and the use of efficient prognostic criteria to identify patients with unfavourable prognoses essential. Tools to classify patients are thus required to delineate subgroups of patients with different disease outcome. Among the autoantibodies associated to RA are IgG autoantibodies directed to deiminated (‘Citrullinated’) proteins (ACPA). The detection of ACPA in the serum of RA patients has gained enormous success over the last decade. Indeed, ACPA have a very high diagnostic value. They are present in the serum of up to 80 % of patients, are very specific for the disease and are present early in its course. In addition, numerous arguments indicate that the autoimmune response to citrullinated proteins play a pathophysiological role. Therefore, in view of their highly probable important contribution to RA synovitis, autoreactive cells involved in the production of ACPA constitute highly relevant targets. However, while the infusion of anti-CD20 antibodies that results in the elimination of most B-cells has proven to be an efficient therapy for RA, currently there is no antigen-specific B-cell-targeting therapeutic strategy available. Citrullinated forms of the ?- and ?-chains of fibrin have been identified as major targets of ACPA in the synovial tissue of RA patients. Recently, it was demonstrated that immunoreactivity of ACPA on fibrin is mainly restricted to immunodominant epitopes borne by 2 15-mer peptides, ?36-50 and ?60-74, located on the central globular domain and bearing 2 and 3 citrulline residues, respectively. These peptides are conjointly able to abolish the reactivity to in vitro citrullinated fibrinogen of a highly polyclonal mixture of ACPA. The fine mapping of ACPA reactivity to these peptides using short (7-mer) overlapping peptides encompassing their sequence allowed identifying 3 major independent minimal (5-mer) epitopes referred to as the ?? epitope’, the ??? epitope’ and the ?? epitope’. Peptides bearing these epitopes constitute excellent perfectly defined ligands for ACPA that will permit totally new and original investigations towards diagnostic and therapeutic applications. The goal of this project is to develop several new epitopic peptide-based molecular tools that can be used for the early and accurate diagnosis of RA, for its prognosis, or are able to induce specific elimination of B cells exhibiting ACPA specificity, hence constitute potentially suitable tools for the development of new immunomodulatory strategies for RA treatment.