Structural basis of IgLON5 autoantibody recognition in autoimmune encephalitis

Anti-IgLON5 disease is a rare neurological disorder at the interface of autoimmunity and neurodegeneration. It is characterized by autoantibodies against the neuronal adhesion molecule IgLON5 and is associated with profound brain dysfunction and tau pathology. Despite its severe clinical manifestations, the molecular basis of antibody recognition and its contribution to disease pathogenesis remain unclear. Here, we profile the B cell receptor repertoire of a patient with anti-IgLON5 disease and identify a highly polyclonal response lacking dominant clonal expansion. We isolate a human monoclonal IgG4 antibody that binds IgLON5 with high affinity and determine its structure in complex with IgLON5 by cryo–electron microscopy. Biochemical and structural analyses show that antibody binding preserves IgLON5 adhesion interfaces while promoting higher-order clustering of IgLON5 dimers. These findings provide mechanistic insight into autoantibody recognition of neuronal surface proteins and establish a framework for understanding antibody-mediated neurodegeneration in anti-IgLON5 disease.