Rheumatoid Arthritis (RA) represents a major global public health challenge with approximately 1% of the world’s population suffering from this autoimmune
musculoskeletal disease. The disease follows a variable course in which periods of remission followed by disease flare are common. As such, in the absence of a cure, patients require ongoing and very often lifelong treatment.
While environmental, genetic, and epigenetic factors have all been linked to the development of RA, a key, initiating factor in disease development is the loss of immunological tolerance to self-antigens. Dendritic cells are widely accepted as having a nonredundant role in maintaining and controlling this tolerance to self-antigen whereby the breakdown of this function is a driving force in the onset of many autoimmune diseases. Therefore, therapeutically targeting DCs in a disease setting such as RA, may provide a unique opportunity to act as a molecular switch, moving DC away from autoreactivity towards tolerance. While previous groups have explored strategies to switch immunogenic DCs to tolerogenic cells or increasing the frequency or function of regulatory cells, strategies aimed at repairing or restoring dysfunctional tolerogenic DCs in vivo have yet to be explored.
In this study we will examine the role of in vivo tolerogenic DC (TolDC) for the first time. Specifically, we will examine the frequency, function and metabolism of TolDC within the circulation in addition to synovial tissue and synovial fluid. We will determine if dysfunctional TolDC drive the initiation and progression of RA by examining patients from across the spectrum of disease from individuals at risk (IAR) of developing RA ( or pre RA) to early and established disease. Finally using unbiased computational sequencing approaches we will identify targetable pathways in RA that may restore immune tolerance, thus limiting synovial inflammation and progressing treatments to that which have more curative potential.