Anti-IgLON5 antibodies cause progressive behavioral and neuropathological changes in mice

Anti-IgLON5 disease is a recently described neurological disorder, characterized by sleep disorders, progressive gait instability, brainstem dysfunction, and cognitive impairment [1]. The biological hallmark of this disease is the presence of antibodies against IgLON5, a neuronal cell adhesion molecule whose function is not fully understood [2]. Whether the primary underlying pathophysiology of anti-IgLON5 disease is degenerative or autoimmune is unclear. Postmortem examinations have suggested a novel tauopathy with neuronal loss, predominantly involving the hypothalamus, tegmentum of the brainstem, hippocampus, and cerebellum [3]. However, a recent case report demonstrated that tauopathy was not always present in autopsy [4]. Despite the neurodegenerative features, a strong association of the disease with the HLA-DRB1*10:01-DQB1*05:01 haplotype and the presence of an antibody against a neuronal surface antigen supported an immune-mediated pathogenesis [5].

Cellular investigations of the potential pathogenic role of patients’ antibodies using cultured neurons showed that the antibodies cause damage to the neuronal cytoskeleton and lead to the internalization of surface IgLON5, which are irreversible in the long term after the removal of antibodies [6, 7]. Moreover, patient antibodies also result in dystrophic neurites and axonal swelling [7]. Collectively, these studies suggest antibody-mediated pathogenesis, providing a link between autoimmunity and neurodegeneration. However, whether patient-derived anti-IgLON5 antibodies can induce disease symptoms in vivo remains to be determined.

Passive immunization is ideal for investigating the pathogenicity of a given neuronal autoantibody, including behavioral changes and molecular synaptic abnormalities [8]. We therefore purified immunoglobulin G (IgG) autoantibodies from one patient with anti-IgLON5 disease and established two independent passive-transfer animal models. The short-term and long-term effects of anti-IgLON5 antibodies on mouse behaviors were examined at different time points from day 1 and day 30 after injections. The ventricle is a commonly chosen injection site in animal models of autoimmune encephalitis and increases parenchymal antibody binding [9, 10]. In addition, human antibodies can preferentially bind to the hippocampus during ventricular perfusion due to the close spatial relationship between the hippocampus and the ventricle. Our patient’s PET/MR also indicated damaged metabolism in the temporal lobe, so we selected the hippocampus for local injection of antibodies. Our results thus identify a unique immune-neuronal interaction that may underlie characteristic disease symptoms. To our knowledge, this is the innovative study of anti-IgLON5 antibodies are causative for the disease symptoms in vivo.

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