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Systemic delivery of human GlyR IgG antibody induces GlyR internalization into motor neurons of brainstem and spinal cord with motor dysfunction in mice
- Source :
- Neuropathology and Applied Neurobiology, Repositorio U. El Bosque, Universidad El Bosque, instacron:Universidad El Bosque, Neuropathol Appl Neurobiol
- Publication Year :
- 2020
- Publisher :
- John Wiley and Sons Inc., 2020.
-
Abstract
- Purified IgG from a patient with progressive encephalopathy with rigidity and myoclonus (PERM) who had raised antibodies to the inhibitory glycine receptor was injected into mice together with lipopolysaccharide to open the blood–brain barrier. The mice developed a motor phenotype, indicated by falling off a rotating cylinder earlier than healthy IgG injected controls. At termination, these mice had deposits of IgG within the brainstem neurons which express glycine receptors, consistent with an antibody‐induced dysfunction of these neurons.<br />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.
- Subjects :
- Male
Myoclonus
0301 basic medicine
Lipopolysaccharide
Encephalomyelitis
Glycine receptor
Autoantigens
Mice
chemistry.chemical_compound
Receptors, Glycine
0302 clinical medicine
Internalization
antibody‐mediated autoimmune disease
media_common
Motor Neurons
Progressive encephalomyelitis with rigidity and myoclonus
medicine.anatomical_structure
Spinal Cord
Neurology
Original Article
Brainstem
Corrigendum
medicine.medical_specialty
Histology
media_common.quotation_subject
PERM
Pathology and Forensic Medicine
03 medical and health sciences
Peritoneal cavity
Stiff person syndrome
In vivo
Physiology (medical)
Internal medicine
stiff person syndrome
medicine
Animals
Humans
Animal model
Autoantibodies
Antibody-mediated autoimmune disease
animal model
Original Articles
medicine.disease
Spinal cord
Muscle Rigidity
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
chemistry
Immunoglobulin G
Neurology (clinical)
glycine receptor
030217 neurology & neurosurgery
Brain Stem
Subjects
Details
- Language :
- English
- ISSN :
- 13652990 and 03051846
- Volume :
- 47
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Neuropathology and Applied Neurobiology
- Accession number :
- edsair.doi.dedup.....ab4197cf01ad87c02067d18b11e6f474