Purified Serum IgG from a Patient with Anti-IgLON5 Antibody Cause Long-Term Movement Disorders with Impaired Dopaminergic Pathways in Mice

Abstract

Background: Anti-IgLON5 disease is a rare autoimmune disease of the central nervous system. It typically manifests as a chronic condition, characterized by cognitive impairments, movement disorders, and sleep disorders. The mechanisms underlying movement disorders in this disease remain poorly understood due to a lack of research. Furthermore, this disease exhibits both neuroimmune and neurodegenerative characteristics. The objective of this study is to explore the underlying mechanisms of movement disorders caused by anti-IgLON5 antibodies for the first time. Methods: Antibodies were purified from the serum of a confirmed patient of anti-IgLON5 disease. The passive transfer animal models were employed, where antibodies were continuously injected into the substantia nigra pars compacta (SNc) of the mouse midbrain using stereotactic injection to explore the mechanism of movement disorder. The effects of anti-IgLON5 antibodies on dopaminergic neurons in the SNc and neurodegeneration were examined through immunohistochemistry. Changes in neurotransmitter levels in the basal ganglia were assessed using high-performance liquid chromatography. Additionally, RNA-seq was employed to identify the differentially expressed genes associated with the short-term and long-term effects of anti-IgLON5 antibody on the SNc. Results: Mice injected with anti-IgLON5 antibodies in the SNc exhibited persistent movement impairments for up to 3 months. One week after antibody injection, the number of TH neurons significantly decreased compared to the control group, accompanied by reduced projection fibers in the basal ganglia and decreased dopamine levels. After 3 months of antibody injection, an increase in phosphorylated Tau was observed in the SNc of the midbrain. Additionally, long-term sustained activation of microglia was detected in the SNc. The differentially expressed genes of long-term effects of IgLON5 antibodies were different from their short-term effects on the SNc. Conclusion: Purified serum IgG from a patient with anti-IgLON5 antibodies can cause long-term movement disorder in mice. The movement disorders appear to be linked to the impaired dopaminergic pathway, and the increased p-Tau showed neurodegenerative changes induced by the anti-IgLON5 antibody.

IgLON5 deficiency produces behavioral alterations in a knockout mouse model

“…Our results suggest that IgLON5 has a physiological role in fine motor coordination and balance; these findings support the possibility that IgLON5 autoantibodies can interfere with IgLON5's function and may be pathogenically involved in the gait instability frequently noted in this disorder. This is also consistent with the results of a recent study of passive antibody transfer where intracerebral injections of IgLON5-IgG from patients into the nigrostriatal dopaminergic pathway of mice produced sustained motor impairment (22). Behavioral studies reported in KOs of other IgLON family members did not describe deficits in balance or motor coordination (27-30) (Table 2).…”

“…Despite the in vitro effects of IgLON5 antibodies, passive transfer experiments using cerebroventricular infusion or intracerebral injection of IgLON5-IgG have failed to reproduce the most characteristic symptoms of the disease and have been unable to demonstrate in vivo the pathogenic effects described in vitro (21,22).…”

New knowledge on anti-IgLON5 disease

“…IgLON5 belongs to the IgLON family of cell adhesion molecules [21] and like other members of the family is spontaneously shed from the cell surface of neurons, interacting with other members of the IgLON family in cis (in the same cell) and in trans (between cells). Patient's antibodies interfere with this binding, but this potential pathogenic mechanism was not specific to IgG4 [22 ]. Second, 60% of patients present the same HLA class II haplotype (DRB1Ã10 : 01-DQB1Ã05 : 01), which is infrequent in the normal population (1-3%) [ symptoms (a feature that would be unusual in a primary neurodegenerative disease ([5 && ]).…”

“…Animals receiving IgLON5-IgG exhibited memory deficits, anxiety-like behaviour and progressively accumulation of human IgG immunostaining in the area of injection but the irreversible downregulation of membrane IgLON5 clusters observed in vitro was not investigated, which is a limitation [ 25 ▪ ]. Similarly, another study that injected the purified IgG into the substantia nigra pars compacta of mice for 7 days, showed a decline in motor balance that persisted 3 months after the last infusion, dopamine decrease content in the area of injection, microglial activation, and a moderate increase of p-tau measured by western blot after three months [ 26 ▪ ].…”