Structural Superimposition

Abstact

Anti-IgLON5 disease is a rare neuro-immunological disorder characterized by autoantibodies targeting the neuronal adhesion molecule IgLON5, as well as profound brain dysfunction and tau pathology. Despite its severe clinical manifestations, the molecular basis of antibody recognition and its contribution to disease pathogenesis is poorly understood. Here, we characterize the B cell receptor repertoire of a patient with anti-IgLON5 disease, revealing marked diversity and no evidence of dominant clonal expansion. We isolate a human monoclonal IgG4 antibody that binds IgLON5 with high affinity and determine the structure of its Fab in complex with IgLON5 using cryo-electron microscopy. Biochemical and structural analyses show that antibody binding preserves IgLON5 adhesive interfaces while remaining compatible with clustering of IgLON5 on the cell surface. Analysis of the germline-reverted precursor suggests that IgLON5 recognition is already present before affinity maturation and is strengthened by somatic mutations that stabilize antigen binding. 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.