Apoptotic bodies from patients with Sjogren's disease drive atypical memory B cell and macrophage activation and autoantibody production

The impaired clearance of apoptotic cells has long been associated with systemic autoimmune diseases like Sjogrens disease (SjD), which is characterised by autoantibodies targeting antigens on apoptotic cells. However, most studies analysing human samples have used patient-derived phagocytes and in vitro generated apoptotic cells, which do not reflect the heterogeneity of patient-derived apoptotic bodies (ApoBDs). Here, we molecularly and functionally compare ApoBDs derived from patients with SjD and healthy donors. ApoBDs were increased in the circulation in SjD and induced atypical memory B cell expansion, which was attenuated by blocking B cell receptor (BCR) and Toll-like receptors (TLR) 7-9 signalling. Co-cultures of ApoBDs and B cells drove autoantibody production. Macrophages engulfing SjD ApoBDs had a distinct inflammatory profile compared to macrophages engulfing healthy control ApoBDs. These findings define patient-derived ApoBDs as immunostimulatory substrates capable of driving innate and adaptive immune responses consistent with the pathogenic features observed in SjD, hence opening a new avenue of diagnostic and therapeutic development.