A new study, led by CRC 1160 member Marta Rizzi (B02), relates classic disease markers – such as dysfunctional B cell differentiation – to a pathway triggered by non-apoptotoc signaling from the FAS proteinFAS is a molecular switch between EF and GC fate. Enhanced mTOR and EF response explain the susceptibility to autoimmunity in ALPS and the rational to therapeutically target mTOR signaling pathway. Spleen and lymph node of ALPS-FAS patients have expanded extrafollicular B cell compartments, small germinal centers and very low switched memory cells. ALPS-FAS B cells isolated from the secondary lymphoid organs are strongly activated in PI3K-mTOR and BCR signaling pathways. Modeling in vitro B cell activation, Rizzi found that FAS signaling specifically modulates CD40 indced mTOR activation, this function is impaired in ALPS B cells. Mechanistically, FAS modulates PTEN nuclear exclusion with involvement of DAXX and caspase-8.
The study’s findings have been published in Science Immunology and are available here.
