Myasthenia gravis AChR antibodies inhibit function of rapsyn-clustered AChRs
| Autor: | Fritz Zimprich, Wei Wei Liu, Judith Cossins, Inga Koneczny, Richard D. Webster, Hakan Cetin, Akiko Nagaishi, Susan Maxwell, Angela Vincent, David Beeson |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Patch-Clamp Techniques animal structures Adolescent Muscle Proteins Neuromuscular junction Cell Line Young Adult 03 medical and health sciences 0302 clinical medicine Fluoxetine Myasthenia Gravis medicine Humans Receptors Cholinergic Patch clamp Receptor Aged Autoantibodies 030304 developmental biology Acetylcholine receptor 0303 health sciences biology Chemistry Autoantibody Middle Aged Bungarotoxins musculoskeletal system medicine.disease Molecular biology Myasthenia gravis Electrophysiological Phenomena Psychiatry and Mental health medicine.anatomical_structure Microscopy Fluorescence Neuromuscular biology.protein Female Surgery Neurology (clinical) Antibody tissues 030217 neurology & neurosurgery Intracellular |
| Zdroj: | Journal of Neurology, Neurosurgery, and Psychiatry |
| ISSN: | 1468-330X 0022-3050 |
| Popis: | ObjectiveDirect inhibition of acetylcholine receptor (AChR) function by autoantibodies (Abs) is considered a rare pathogenic mechanism in myasthenia gravis (MG), but is usually studied on AChRs expressed in cell lines, rather than tightly clustered by the intracellular scaffolding protein, rapsyn, as at the intact neuromuscular junction. We hypothesised that clustered AChRs would provide a better target for investigating the functional effects of AChR-Abs.MethodsAcetylcholine-induced currents were measured using whole-cell patch clamping and a fast perfusion system to assess fast (ResultsThe maternal AChR-Ab positive plasmas reduced fetal AChR currents, but not adult AChR currents, by >80% within 100 s. Only 2/11 AChR-Ab positive sera inhibited AChR currents in unclustered AChRs, but 6/11 AChR-Ab positive sera compared with none of the 10 AChR-Ab negative sera (p=0.0020) inhibited rapsyn-clustered AChR currents, and current inhibition by the AChR-Ab positive sera was greater when the AChRs were clustered (p=0.0385). None of the sera had detectable effects on desensitisation or recovery from desensitisation.ConclusionThese results show that antibodies can inhibit AChR function rapidly and demonstrate the importance of clustering in exploring pathogenic disease mechanisms of MG Abs. |
| Databáze: | OpenAIRE |
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