Molecular dynamics of collagen peptide binding to arthritogenic autoantibodies
Abstract
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting 0.5-1% of the population, with both genetic and environmental factors contributing to its development. RA is characterized by erosive inflammation of joint tissues, progressive destruction of cartilage and bone, and pain. A key event is the loss of immunological tolerance to self-structures, e.g. to cartilage collagen type II (CII), triggering the production of signature antibodies (Ab), chemokines, cytokines and enzymes in early phases of the disease. A full understanding of RA pathogenic mechanisms is required for the development of more efficient drugs and vaccines to cure or prevent RA.
Our goal is to reveal details of the interactions between RA-specific anti-CII autoAb and anti-citrullinated protein Ab (ACPA) and their CII epitopes, and between susceptibility conferring MHCII and presented self-peptides, which are all key players in RA pathogenesis. Furthermore, we want to study the role of epitope modification and conformation, genetic predisposition and affinity maturation in recognition and response. To this purpose we perform crystallographic studies on respective MHCII or autoAb-Fab fragment complexes and molecular dynamics simulations.
