Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients
Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by muscle weakness and caused by pathogenic autoantibodies that bind to membrane proteins at the neuromuscular junction. Most patients have autoantibodies against the acetylcholine receptor (AChR), but a subset of patients have au...
| Những tác giả chính: | , , , , , , , , , , , , , , |
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| Định dạng: | Journal article |
| Được phát hành: |
American Society for Clinical Investigation
2019
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| _version_ | 1826267694837530624 |
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| author | Takata, K Stathopoulos, P Cao, M Mané-Damas, M Fichtner, M Benotti, E Jacobson, L Waters, P Irani, S Martinez-Martinez, P Beeson, D Losen, M Vincent, A Nowak, R O'Connor, K |
| author_facet | Takata, K Stathopoulos, P Cao, M Mané-Damas, M Fichtner, M Benotti, E Jacobson, L Waters, P Irani, S Martinez-Martinez, P Beeson, D Losen, M Vincent, A Nowak, R O'Connor, K |
| author_sort | Takata, K |
| collection | OXFORD |
| description | Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by muscle weakness and caused by pathogenic autoantibodies that bind to membrane proteins at the neuromuscular junction. Most patients have autoantibodies against the acetylcholine receptor (AChR), but a subset of patients have autoantibodies against muscle-specific tyrosine kinase (MuSK) instead. MuSK is an essential component of the pathway responsible for synaptic differentiation, which is activated by nerve-released agrin. Through binding MuSK, serum-derived autoantibodies inhibit agrin-induced MuSK autophosphorylation, impair clustering of AChRs, and block neuromuscular transmission. We sought to establish individual MuSK autoantibody clones so that the autoimmune mechanisms could be better understood. We isolated MuSK autoantibody-expressing B cells from 6 MuSK MG patients using a fluorescently tagged MuSK antigen multimer, then generated a panel of human monoclonal autoantibodies (mAbs) from these cells. Here we focused on 3 highly specific mAbs that bound quantitatively to MuSK in solution, to MuSK-expressing HEK cells, and at mouse neuromuscular junctions, where they colocalized with AChRs. These 3 IgG isotype mAbs (2 IgG4 and 1 IgG3 subclass) recognized the Ig-like domain 2 of MuSK. The mAbs inhibited AChR clustering, but intriguingly, they enhanced rather than inhibited MuSK phosphorylation, which suggests an alternative mechanism for inhibiting AChR clustering. |
| first_indexed | 2024-03-06T20:58:07Z |
| format | Journal article |
| id | oxford-uuid:39f29e9c-363f-4fa6-9711-bc766f4a8fb8 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T20:58:07Z |
| publishDate | 2019 |
| publisher | American Society for Clinical Investigation |
| record_format | dspace |
| spelling | oxford-uuid:39f29e9c-363f-4fa6-9711-bc766f4a8fb82022-03-26T13:58:37ZCharacterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patientsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:39f29e9c-363f-4fa6-9711-bc766f4a8fb8Symplectic Elements at OxfordAmerican Society for Clinical Investigation2019Takata, KStathopoulos, PCao, MMané-Damas, MFichtner, MBenotti, EJacobson, LWaters, PIrani, SMartinez-Martinez, PBeeson, DLosen, MVincent, ANowak, RO'Connor, KMyasthenia gravis (MG) is a chronic autoimmune disorder characterized by muscle weakness and caused by pathogenic autoantibodies that bind to membrane proteins at the neuromuscular junction. Most patients have autoantibodies against the acetylcholine receptor (AChR), but a subset of patients have autoantibodies against muscle-specific tyrosine kinase (MuSK) instead. MuSK is an essential component of the pathway responsible for synaptic differentiation, which is activated by nerve-released agrin. Through binding MuSK, serum-derived autoantibodies inhibit agrin-induced MuSK autophosphorylation, impair clustering of AChRs, and block neuromuscular transmission. We sought to establish individual MuSK autoantibody clones so that the autoimmune mechanisms could be better understood. We isolated MuSK autoantibody-expressing B cells from 6 MuSK MG patients using a fluorescently tagged MuSK antigen multimer, then generated a panel of human monoclonal autoantibodies (mAbs) from these cells. Here we focused on 3 highly specific mAbs that bound quantitatively to MuSK in solution, to MuSK-expressing HEK cells, and at mouse neuromuscular junctions, where they colocalized with AChRs. These 3 IgG isotype mAbs (2 IgG4 and 1 IgG3 subclass) recognized the Ig-like domain 2 of MuSK. The mAbs inhibited AChR clustering, but intriguingly, they enhanced rather than inhibited MuSK phosphorylation, which suggests an alternative mechanism for inhibiting AChR clustering. |
| spellingShingle | Takata, K Stathopoulos, P Cao, M Mané-Damas, M Fichtner, M Benotti, E Jacobson, L Waters, P Irani, S Martinez-Martinez, P Beeson, D Losen, M Vincent, A Nowak, R O'Connor, K Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients |
| title | Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients |
| title_full | Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients |
| title_fullStr | Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients |
| title_full_unstemmed | Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients |
| title_short | Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients |
| title_sort | characterization of pathogenic monoclonal autoantibodies derived from muscle specific kinase myasthenia gravis patients |
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