A role for B-cells in Osteoarthritis

Osteoarthritis (OA) is the most common musculoskeletal disease and a leading cause of disability worldwide, affecting knees, hands and hips. It is considered an age-related disease. Despite OA being investigated using numerous approaches including imaging, genetic and cellular/molecular technologies, its pathogenesis remains poorly understood. Inflammatory responses are recognised as driving some processes associated with age (i.e., inflammageing) and are increasingly recognised as part of OA. Increased frequencies/levels of autoantibodies (AutoAbs) have been associated with ageing. In OA, AutoAbs are also frequently observed beyond ageing and with extended specificities, notably including post-translational modified (PTM) antigens resulting from inflammatory processes in the soft tissue in joints (synovitis), which has also been proposed to act as a niche for B-cell differentiation, favouring the generation of AutoAbs. Disturbances in subsets of B-cell homeostasis in OA patients have also been evidenced. My project proposed to better understand the pathology of OA by distinguishing age-associated changes in AutoAb production from those that are OA-specific and investigate B-cell capacities for differentiation and antibody production in ageing versus OA. My thesis provides evidence that ageing has limited effects on the capacity of healthy B-cells to differentiate into plasma cells with T-cell help, while T-cell independent differentiation showed multiple age-related changes suggesting better capacities in the elderly. OA further exacerbated these age-related changes, in particular with increased antibody production. OA synovial cell culture provided better support for B-cell survival (i.e., “niche” effect) and favoured antibody production. A high proportion of AutoAbs for PTM-antigens was observed in OA synovial fluid while only small frequencies were observed in the circulation, suggesting differences between local/joint and systemic disease. T-cell independent B-cell differentiation preferentially occurs with non-protein antigens. My results therefore associate a more prevalent AutoAb production to synovitis related PTM-antigens in OA with increased capacity for T-cell independent B-cell differentiation, while synovitis itself can contribute to plasma cell survival.