PLOTTING THE DEVELOPMENT OF AUTOREACTIVE B CELLS IN AUTOIMMUNE DISEASE

Autoimmune diseases affect more than 5% of the world’s population. They are often debilitating and chronic, posing significant challenges to patients and Society. For many of these diseases, the underlying mechanisms are poorly understood.

Our goal is to build a comprehensive picture of the development of autoreactive B cells in rheumatoid arthritis (RA), which play a central role as evidenced by the success with B cell-depletion therapy.

We hypothesise thatautoreactive B cells are generated during bone marrow (BM) B-cell development due to defective antibody repertoire selection and that autoreactive naïve B cells are activated by autoantigen(s), initiating immune responses that give rise to recirculating autoreactive memory B cells (MBCs), creating a vicious circle.

To test this, we focused on B-cell development and MBCs in RA.

We have found that Tbet+ MBCs correlate with joint destruction in RA and will now investigate the remaining MBCs, their potential function and correlations with clinical parameters.

We have generated a new B-cell development scheme and will investigate antibody repertoire selection and whether either is defective in RA. The BM is host to many cell types that require unique environments for their survival. We will determine the spatial localisation of B cells in healthy BM and investigate whether RA BM is different.

Knowledge gained from our studies may lead to new therapeutics, eg targeting specific B cells, in individuals who develop RA.