Systemic delivery of human GlyR IgG antibody induces GlyR internalization into motor neurons of brainstem and spinal cord with motor dysfunction in mice.
AIMS
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a life-threatening condition often associated with highly raised serum antibodies to glycine receptors (GlyRs); these bind to the surface of large neurons and interneurons in rodent brain and spinal cord sections and, in vitro, inhibit function and reduce surface expression of the GlyRs. The effects in vivo have not been reported.


METHODS
Purified plasma IgG from a GlyR antibody-positive patient with PERM, and a healthy control (HC), was injected daily into the peritoneal cavity of mice for 12 days; lipopolysaccharide (LPS) to open the blood-brain barrier, was injected on days 3 and 8. Based on preliminary data, behavioural tests were only performed 48 h post-LPS on days 5-7 and 10-12.


RESULTS
The GlyR IgG injected mice showed impaired ability on the rotarod from days 5 to 10 but this normalized by day 12. There were no other behavioural differences but, at termination (d13), the GlyR IgG-injected mice had IgG deposits on the neurons that express GlyRs in the brainstem and spinal cord. The IgG was not only on the surface but also inside these large GlyR expressing neurons, which continued to express surface GlyR.


CONCLUSIONS
Despite the partial clinical phenotype, not uncommon in passive transfer studies, the results suggest that the antibodies had accessed the GlyRs in relevant brain regions, led to antibody-mediated internalization and increased GlyR synthesis, compatible with the temporary loss of function.
['Carvajal-González|A|A|0000-0003-3649-1326', 'Jacobson|L|L|', 'Clover|L|L|', 'Wickremaratchi|M|M|', 'Shields|S|S|', 'Lang|B|B|', 'Vincent|A|A|0000-0003-2395-8695']
D000818:Animals D001323:Autoantibodies D001324:Autoantigens D001933:Brain Stem D004679:Encephalomyelitis D006801:Humans D007074:Immunoglobulin G D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009046:Motor Neurons D009127:Muscle Rigidity D009207:Myoclonus D018009:Receptors, Glycine D013116:Spinal Cord
Progressive encephalomyelitis with rigidity and myoclonus PERM glycine receptor animal model antibody-mediated autoimmune disease stiff person syndrome