Antibodies associated to Rheumatoid Arthritis (RA) had been described by indirect immunofluorescence on epithelial tissues. We confirmed their high diagnosis specificity and identified their targets as deiminated forms of (pro)filaggrin then as deiminated fibrin abundant in the inflammatory synovial tissue of patients. Those results led to immunoassays allowing detection of IgG anti-citrullinated protein autoantibodies (ACPA) that, after years of international validation, were recognized as a major diagnosis criterion for RA.
We showed that ACPA are secreted by plasma cells in the synovium and we proposed that formation of immobilized immunecomplexes on citrullinated fibrin deposits chronically generated in the inflammatory tisue by fibrinogen extravasation, polymerization and deimination by local PAD2 and PAD4 enzymes, is responsible for inducing and maintaining synovium inflammation. Using an in vitro model with human fibrinogen and macrophages, we demonstrated that ACPA do induce secretion of TNF and other proinflammatory cytokines, secretion being greatly amplified in the presence of IgM Rheumatoid Factor by forming macro-immunecomplexes.
Based on this pathopysiological model and epitopic mapping of citrullinated fibrin, we created the « Cure-RA » consortium to develop a bioimmunotherapy aiming to kill the ACPA B cells in the patients. We designed hybrids including peptides presenting immunodominant epitopes and either human Fc fragments of IgG or Fab fragments of monoclonals to plasma cell membrane antigens, to specifically target either the ACPA-positive B cells or the ACPA-secreting plasma cells, respectively.