Identifying therapeutic targets that could transform Rheumatoid Arthritis from disease remission into cure

Studentship strategic priority area: Basic and Clinical Research

Background. Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that disables joints (synovitis) and shortens lifespan. Currently ~50% of patients achieve therapeutic remission of inflammation.

However, those patients still have ongoing autoimmunity (autoreactive T/B-cells) that eventually induces flares of diseases and prevents cure. In this project we want to understand why immune-tolerance is not restored in remission. Dendritic cells (DC) are the only known cell-type that can reset adaptive immunity towards immune-tolerance.

Using scRNAseq/flow-cytometry we found that synovial tissue (ST) CD1cpos in remission are more similar to healthy DCs than to active RA DCs. However, they lack many of the healthy DCs tolerogenic-pathways, suggesting impaired tolerogenic functions. Molecular drivers of this remission DC phenotype are unknown.

One plausible explanation is that epigenetic changes in long-lived synovial stromal cells (synovial fibroblasts) due to prior inflammation may drive the differentiation of DC precursors into a phenotype that is not able to induce tolerance. Thus, we hypothesize that the phenotype and functional differences between ST DCs in RA in remission and health contribute to the maintenance of autoimmunity in remission and is driven by epigenetic changes in synovial fibroblasts.

Understanding these may provide novel therapeutic targets for an ambitious step-change from remission to cure. We will address this with two aims:

Aim1. To compare the molecular mechanisms by which remission synovial-tissue CD1cposDC drive autologous T-cell responses with those driven by healthy synovial-tissue DCs. Aim2. To investigate the role of synovial fibroblasts in the emergence of remission CD1cposDC phenotypes

We will provide molecular insight into the lack of immune-conversion from autoimmunity to tolerance in RA patients in disease remission and will establish the role of SF in determining the phenotype of DCs found in RA in remission tissue.