Targeting autoimmunity in renal diseases: focus on neutrophil extracellular traps and autoreactive B-cells

Abstract

This thesis aimed to understand the humoral autoimmune response and to translate our knowledge to improve the targeting of autoimmunity in AAV and SLE patients. Our studies demonstrate that NETs have a pivotal role in both AAV and SLE patients. NETs function as autoantigens, can cause direct glomerular inflammation and can be part of immune-complexes in SLE. Importantly, AAV and SLE-induced NETs are disease specific processes that each encompassed their own unique properties. This should be taken into account when evaluating targeting of NETs in AAV and SLE. In SLE patients, NETs could be targeted through reducing the autoantibody repertoire, specifically high avidity anti-dsDNA and anti-C1q autoantibodies that drive immune complex formation. These autoantibodies were effectively targeted by combined treatment with RTX and BLM. During B-cell targeted therapy in AAV and SLE patients, the presence and reoccurrence of autoreactive B-cells and relevant autoantibodies are components of minimal residual autoimmunity (MRA), which often persists after B-cell therapy. Interestingly, both in AAV and SLE, double negative (DN) B-cells have a key role in the humoral autoimmune response and were associated with reoccurrence of autoantibodies. However, it remains to be established how MRA is associated with disease flares and to find the best way to use it as immunomonitoring tool to guide and personalize treatment.