Strukturella och funktionella studier av anticitrullinerade proteinantikroppar vid reumatoid artrit.

Changrong Ge, Karolinska Institutet, 125000

Bakgrund och motivering

Although autoantibodies arise years before onset of autoimmune diseases, their exact roles and binding specificities remain poorly defined. Resolving the molecular details of autoantibody interactions is key to clarifying their functions and pathogenic mechanisms. We will elucidate the structural basis of antigen recognition by disease-specific autoantibodies in rheumatoid arthritis (ACPAs) and delineate their impacts in vivo using animal models.

Syfte och mål

This project aims to elucidate fundamental molecular aspects of autoantibody-antigen interactions in rheumatoid arthritis pathogenesis. Specifically, we will:

Determine the structural basis of ACPA binding specificity using X-ray crystallography of ACPA Fabs bound to citrullinated peptide antigens

Delineate the functional roles of monoclonal ACPAs using animal models of arthritis

Elucidate the molecular mechanisms underlying immunosuppressive effects of select ACPAs in vivo

By integrating structural and functional analyses, we will gain conceptual insights into autoantibody recognition, functionality, and therapeutic regulation.

Metod

We are well-equipped to carry out the proposed structural and immunology studies, with all necessary infrastructure either within our laboratories or available through campus core facilities. For protein science and structural work, we have access to protein production, purification, and crystallization platforms through SciLife services. We also have an active ethical permit to perform the required animal experiments using the facilities of the Animal House at Karolinska Institutet. We will leverage long-standing collaborations with leaders in the field, including the Holmdahl lab at Karolinska Institutet across different rheumatoid arthritis research areas, as well as with the Toes lab to obtain well-characterized ACPAs from patient samples.

Betydelse för patienten

This project has significant potential to transform our understanding of autoantibody mediated mechanisms in rheumatoid arthritis. By revealing how ACPAs recognize antigens and modulate disease, we can elucidate their roles in pathogenesis. Excitingly, our findings may pave the way for leveraging regulatory ACPAs as innovative therapeutics. Overall, this work will provide conceptual and practical advances regarding the origins and impacts of autoreactive B cells in rheumatoid arthritis.