Anti-IgLON5 Disease: A Cross Talk between Autoimmunity and Tauopathy

Anti-IgLON5 disease is characterized by a distinctive sleep disorder associated with a variety of neurological symptoms. The hallmark of the disease is the presence of antibodies against IgLON5, the fifth member of the IgLON family that belongs to the immunoglobulin superfamily of cell adhesion molecules predominantly expressed in the neuronal membrane. Patients with anti-IgLON5 disease are usually 60 years or older and develop a chronic course, in months, characterized by combinations of sleep problems (non-rapid eye movements (NREM) and REM parasomnias, and obstructive sleep apnea with stridor), bulbar dysfunction (dysphagia, dysarthria, central hypoventilation), and movement disorders (gait instability, chorea, craniofacial dyskinesias). Initial neuropathologic studies in a few patients showed a neuronal accumulation of hyperphosphorylated tau with predominant involvement of the tegmental nuclei of the brainstem suggesting a neurodegenerative disorder. However, a primary autoimmune pathogenesis is supported by the extracellular localization of the antigen, the robust association with the HLA-DRB1*10:01- DQB1*05:01 haplotype and the absence of hyperphosphorylated tau deposits in subsequent autopsies. Moreover, cultured rat hippocampal neurons exposed to patients’ IgLON5 antibodies show an irreversible decrease of IgLON5 clusters in the membrane and alterations in the cytoskeleton which suggest that the tauopathy might occur late in the course of the disease as a consequence of the antibody effects. Although the effect of immunotherapy is limited, early diagnosis and treatment may be associated with a better utcome.