To unravel how autophagy deficiencies, a process orchestrated by the complex assembly and interaction of numerous proteins, encoded by ATG-related genes, contribute to the dysregulated immune response in iTTP. Exploiting these abnormalities by measuring autophagosome formation and autophagic activity in vivo is crucial to get insights and develop pharmacologic interventions strategies as novel therapies for iTTP as wells as various autoimmune diseases. To decide which autophagy pathway plays a role in iTTP, we investigate the relative mRNA expression levels of key autophagy-related (ATG) genes known to be involved in other autoimmune disease and inflammation in dendritic cells (DCs), B-and T-cells. Additionally specialized autophagy pathways are analyzed as well (a) mitophagy (p62 with NIX), (b) aggrephagy (p62 with NBRL and OPTIN), and (c) chaperone-mediated autophagy (LAMP2A9). Enriched or reduced formation of autophagosome in immune cells, most likely causing accumulation of abnormal proteins leading to defective survival of T- and B-cells in vitro cultures are assessed. Using experimental autophagy inhibitors/activators the impact of blocking or activating autophagy pathways on the systemic inflammation and self-antigen presentation in the acute or remission state of iTTP. As a potential new treatment option for iTTP patients, we will evaluate the effect of P140 peptide (Lupuzor, clinical trial phase IIa, Immunopharm, 2018), known to rescue in mouse model of lupus (MRP/lpr) the autoantigen processing in self-reactive B- and T-cells in immune cells in vitro. Lupuzor as an adjunct therapy with the first-line treatment and possibly in the future with B-cell and autoantibody targeted therapies should improve substantially the outcome of the severe cases of iTTP.
