Strukturella och funktionella studier av anticitrullinerade proteinantikroppar vid reumatoid artrit

Changrong Ge, Karolinska Institutet, 85 000 kronor

Bakgrund och motivering

Autoantibodies develop many years before the clinical onset of most autoimmune diseases. The molecular details that determine the specificity and roles of autoantibodies have not yet been fully elucidated. Thus, we attempt to resolve the crystal structures of the antigen-binding fragment (Fab) of human monoclonal ACPA in complex with the related citrullinated peptides by X-ray diffraction. In addition, we will further analyze their functions in animal models.

Syfte och mål

The project objectives are 1) to elucidate the structural basis by which ACPAs bind specifically to citrullinated antigens; 2) to investigate the functional (pathogenic or regulatory) roles of monoclonal ACPAs in animal models; 3) to understand the molecular mechanism governing the suppressive effects of certain monoclonal ACPAs in experimental arthritis.

Metod

All the equipment needed for the project is already within our laboratories or accessed through service center platforms (SciLife), especially for protein science facilities, including protein expression and purification, and also the crystallization platform. We also have an eligible ethical permit for doing the animal experiments in Animal House in Karolinska Institutet. We collaborate closely with Prof. Holmdahl’s lab across different subjects within RA filed in Karolinska Institutet. We also collaborate with Prof. Rene Toes in the Netherlands regarding the selection of human ACPAs from RA patients.

Betydelse för patienten 

The lack of detailed information about the interaction of ACPA with cognate antigen at the molecular level has been a bottleneck for understanding if and how ACPA are pathogenic, and our work, therefore, offers novel conceptual insight into this topic. Furthermore, the finding that certain ACPA (such as E4) could be therapeutic in the mouse models opens the door to investigating the mechanisms of how disease-specific autoantibodies can regulate disease and be developed into a project in which these could be used for the therapy of RA.