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... Show moreThis 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. Show less
First, we described a method to quantify NETs which has the potential to monitor autoantigen load in the setting of autoimmune diseases where NETs play a role in its pathophysiology. The use of... Show moreFirst, we described a method to quantify NETs which has the potential to monitor autoantigen load in the setting of autoimmune diseases where NETs play a role in its pathophysiology. The use of confocal microscopy with multiple z-stacks, makes it a sensitive method. We provided a context of how NETs can be quantified in SLE and AAV. We demonstrated that not all NETs are created equally and translation of NET formation to a digital quantification creates a narrow view. We showed higher ex vivo NET formation in AAV patients with active disease compared to AAV patients with an underlying infection supporting that excessive NET formation is an autoimmune phenomenon. Also, we demonstrated that the observed excessive NET formation is independent of ANCAs.In the next part of this thesis, we focused on new treatments in lupus nephritis. Most importantly, the results of the Sybiose study are shown; a phase 2 proof-of-concept study that included 15 patients with severe, refractory SLE treated with rituximab and belimumab. We showed that RTX+BLM has the ability to reduce autoantibodies, thereby indirectly reducing excessive NET formation in SLE, presumably due to the targeting of autoreactive B cells. Further, we observed a clinical response in our patients while tapering immunosuppressive medication. Show less
