Glycine receptor antibodies: pathogenic mechanisms and clinical corrlates
<p>Glycine receptor antibodies have been identified in a few patients with progressive encephalomyelitis with rigidity and myoclonus (PERM), a highly disabling disorder characterised by rigidity, spasm and brainstem symptomatology. The clinical characteristics of patients with glycine receptor...
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| その他の著者: | |
| フォーマット: | 学位論文 |
| 言語: | English |
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2014
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| _version_ | 1826284370513625088 |
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| author | Carvajal González, A |
| author2 | Vincent, A |
| author_facet | Vincent, A Carvajal González, A |
| author_sort | Carvajal González, A |
| collection | OXFORD |
| description | <p>Glycine receptor antibodies have been identified in a few patients with progressive encephalomyelitis with rigidity and myoclonus (PERM), a highly disabling disorder characterised by rigidity, spasm and brainstem symptomatology. The clinical characteristics of patients with glycine receptor antibodies have not yet been fully described and it is not clear whether GlyR-Abs are pathogenic or just an epiphenomenon.</p> <p>This study examined the clinical features and immunotherapy responses of 45 patients; characterised the GlyR-Ab pathogenicity, subunit specificity and binding to different brain region <em>in vitro</em>, and examined mice injected with GlyR-Abs to model the disease <em>in vivo</em>.</p> <p>Most of the patients were classified as PERM but some patients had symptomatology beyond the classical motor manifestations and there were four patients with tumours (thymomas and lymphomas). GlyR-Ab titres were varied in serum and CSF, but there was intrathecal synthesis in the six patients with suitable samples. Most patients were very disabled but almost all showed excellent responses to immunotherapies. The antibodies were mainly IgG1 and IgG3 subclasses, activated complement on glycine receptor-transfected HEK cells at room temperature, and caused internalisation and lysosomal degradation of the glycine receptors at 37°C. GlyR-Abs bound to rodent spinal cord and brainstem co-localising with monoclonal antibodies to GlyRα1 on the surface of neurons.</p> <p>GlyR-IgG injected intra-peritoneally led to impairment in forced walking ability, sensorimotor function and coordination. Analysis of the brain showed that animals injected with patients' IgG, but not control IgG, had antibodies bound to the brainstem, spinal cord, cerebellum and caudate, co-localising with GlyRα1 monoclonal antibody. Intra-cerebroventricular injection of GlyR-IgG caused an anxiety-like behaviour in mice but no evident motor disturbances.</p> <p>These results provide the first evidence of <em>in vitro</em> and <em>in vivo</em> pathogenicity of the GlyR-Abs, supporting the use of long term immunosuppression in these patients to provide them with a good prognosis.</p> |
| first_indexed | 2024-03-07T01:12:49Z |
| format | Thesis |
| id | oxford-uuid:8d9e92c6-6c02-4d62-b3fc-086d8dd297a5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:12:49Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:8d9e92c6-6c02-4d62-b3fc-086d8dd297a52022-03-26T22:52:19ZGlycine receptor antibodies: pathogenic mechanisms and clinical corrlatesThesishttp://purl.org/coar/resource_type/c_db06uuid:8d9e92c6-6c02-4d62-b3fc-086d8dd297a5Medical SciencesNeurologyNeuroscienceNeuroimmunologyEnglishOxford University Research Archive - Valet2014Carvajal González, AVincent, A<p>Glycine receptor antibodies have been identified in a few patients with progressive encephalomyelitis with rigidity and myoclonus (PERM), a highly disabling disorder characterised by rigidity, spasm and brainstem symptomatology. The clinical characteristics of patients with glycine receptor antibodies have not yet been fully described and it is not clear whether GlyR-Abs are pathogenic or just an epiphenomenon.</p> <p>This study examined the clinical features and immunotherapy responses of 45 patients; characterised the GlyR-Ab pathogenicity, subunit specificity and binding to different brain region <em>in vitro</em>, and examined mice injected with GlyR-Abs to model the disease <em>in vivo</em>.</p> <p>Most of the patients were classified as PERM but some patients had symptomatology beyond the classical motor manifestations and there were four patients with tumours (thymomas and lymphomas). GlyR-Ab titres were varied in serum and CSF, but there was intrathecal synthesis in the six patients with suitable samples. Most patients were very disabled but almost all showed excellent responses to immunotherapies. The antibodies were mainly IgG1 and IgG3 subclasses, activated complement on glycine receptor-transfected HEK cells at room temperature, and caused internalisation and lysosomal degradation of the glycine receptors at 37°C. GlyR-Abs bound to rodent spinal cord and brainstem co-localising with monoclonal antibodies to GlyRα1 on the surface of neurons.</p> <p>GlyR-IgG injected intra-peritoneally led to impairment in forced walking ability, sensorimotor function and coordination. Analysis of the brain showed that animals injected with patients' IgG, but not control IgG, had antibodies bound to the brainstem, spinal cord, cerebellum and caudate, co-localising with GlyRα1 monoclonal antibody. Intra-cerebroventricular injection of GlyR-IgG caused an anxiety-like behaviour in mice but no evident motor disturbances.</p> <p>These results provide the first evidence of <em>in vitro</em> and <em>in vivo</em> pathogenicity of the GlyR-Abs, supporting the use of long term immunosuppression in these patients to provide them with a good prognosis.</p> |
| spellingShingle | Medical Sciences Neurology Neuroscience Neuroimmunology Carvajal González, A Glycine receptor antibodies: pathogenic mechanisms and clinical corrlates |
| title | Glycine receptor antibodies: pathogenic mechanisms and clinical corrlates |
| title_full | Glycine receptor antibodies: pathogenic mechanisms and clinical corrlates |
| title_fullStr | Glycine receptor antibodies: pathogenic mechanisms and clinical corrlates |
| title_full_unstemmed | Glycine receptor antibodies: pathogenic mechanisms and clinical corrlates |
| title_short | Glycine receptor antibodies: pathogenic mechanisms and clinical corrlates |
| title_sort | glycine receptor antibodies pathogenic mechanisms and clinical corrlates |
| topic | Medical Sciences Neurology Neuroscience Neuroimmunology |
| work_keys_str_mv | AT carvajalgonzaleza glycinereceptorantibodiespathogenicmechanismsandclinicalcorrlates |