– BATMAN

Sjogren disease (SjD) is a chronic, systemic B-cell-driven autoimmune disease with an increased risk of non-Hodgkin lymphoma (NHL) development. The abnormal B cell activation resulting from the interplay of T cell-dependent and independent responses is a hallmark of SjD linked with disease severity and evolution to lymphoma. A mechanistic understanding of which ‘targetable’ pathways steer this evolution is required to optimise and tailor treatment. Multiple lines of evidence point towards the key role of lymphocyte-specific transcription coactivator BOB1 in the progression from autoimmunity to lymphoid malignancy. BOB1 is required for T cell-dependent immune responses and germinal centre formation. Its dysregulation is proposed to contribute to the pathogenesis of various autoimmune diseases and lymphomagenesis. Our recent studies demonstrate that selective targeting BOB1 i) suppresses B cell proliferation, activation, differentiation, and antigen-specific responses in vitro and in vivo; ii) downmodulates class switch recombination and immunoglobulin production; ii) reduces cell growth, IgM production and differentiation of malignant B cells. We propose that BOB1 controls the maturation of the immune responses, and its strong activation in the context of autoimmune inflammation fosters the transition from autoimmune sialadenitis to lymphoma. BATMAN aims to unravel the role of BOB1 in the progression from autoimmunity to lymphoma using analyses of primary human tissue obtained from SjD patients with and without NHL, functional in vitro, ex vivo, and in vivo experimental models, novel selective BOB1 inhibitors, conditional genomic deletions, and comprehensive structural and molecular imaging approaches. This translational multidisciplinary project aims to establish a path towards stratified medicine by defining immunological correlates associated with the transition from autoimmunity to lymphoma and validating BOB1 as a novel therapeutic target and biomarker in SjD.