Targeted treatment approaches and pathogenicity of antibody subclasses in MuSK-myasthenia gravis
<p>Muscle Specific Kinase myasthenia gravis (MuSK-MG) is an autoimmune disease that impairs neuromuscular transmission leading to muscle fatigability. No targeted medications are currently available, and non-specific immunotherapies are required. MuSK initiates a phosphorylation cascade regula...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2021
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| _version_ | 1797099395948216320 |
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| author | Cao, M |
| author2 | Beeson, D |
| author_facet | Beeson, D Cao, M |
| author_sort | Cao, M |
| collection | OXFORD |
| description | <p>Muscle Specific Kinase myasthenia gravis (MuSK-MG) is an autoimmune disease that impairs neuromuscular transmission leading to muscle fatigability. No targeted medications are currently available, and non-specific immunotherapies are required. MuSK initiates a phosphorylation cascade regulating the clustering of acetylcholine receptors (AChRs) at the neuromuscular junction (NMJ). SH2 domain-containing phosphatase (SHP2) negatively regulates the pathway inhibiting MuSK activation. In MuSK-MG, monovalent IgG4 autoantibodies block MuSK phosphorylation dispersing AChR clusters. The role of the smaller population of divalent MuSK IgG1, 2 and 3 antibodies is still undefined. The aims of the study were a) to test in vitro and in vivo SHP2 inhibition by NSC-87877 evaluating its efficacy in counteracting the effects of MuSK-Abs; b) to investigate the pathogenic contribution of MuSK IgG1-3-Abs.</p>
<p>Protein phosphorylation and AChR clustering were studied in different cell lines exposed to NSC-87877, and to either patients’ purified MuSK-Ab subclasses or anti-MuSK monoclonals. NSC-87877 was tested for safety and efficacy in wild-type mice and a model of AChR deficiency syndrome. Effects of MuSK IgG1-3 were evaluated on impairment of the MuSK-Lrp4 interaction required for MuSK activation, and on the cytoskeleton activation necessary for cluster maturation. RNA transcriptomic analysis was performed to look for changes in intracellular pathways.</p>
<p>In vitro, NSC-87877 increased MuSK phosphorylation protecting AChR clusters from dispersal in the presence of all MuSK-Ab subclasses. Functional MUSK was required for the effectiveness of the drug. In vivo, no side effects were observed but the available genetice myasthenic syndrome models did not improve. Divalent MuSK antibodies activated the phosphorylation cascade but failed to sustain cluster maturation, impairing MuSK-Lrp4 interaction and cytoskeleton rearrangements. Transcriptomic analysis did not detect specific changes that could inform on the mechanisms. In conclusion, SHP2 inhibition showed promising results in vitro, although more studies are needed in vivo to evaluate its potential effectiveness. Although the exact mechanisms of MuSK IgG1-3 antibodies were not identified, the work in this thesis confirms their potential pathogenic role in MuSK-MG that requires further investigation.</p> |
| first_indexed | 2024-03-07T05:23:05Z |
| format | Thesis |
| id | oxford-uuid:df9b8b9b-0afe-46fe-965c-f4ee91b3c243 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:23:05Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:df9b8b9b-0afe-46fe-965c-f4ee91b3c2432022-03-27T09:40:38ZTargeted treatment approaches and pathogenicity of antibody subclasses in MuSK-myasthenia gravisThesishttp://purl.org/coar/resource_type/c_db06uuid:df9b8b9b-0afe-46fe-965c-f4ee91b3c243Myasthenia gravisEnglishHyrax Deposit2021Cao, MBeeson, DCossins, JWebster, RColes, ARinaldi, S<p>Muscle Specific Kinase myasthenia gravis (MuSK-MG) is an autoimmune disease that impairs neuromuscular transmission leading to muscle fatigability. No targeted medications are currently available, and non-specific immunotherapies are required. MuSK initiates a phosphorylation cascade regulating the clustering of acetylcholine receptors (AChRs) at the neuromuscular junction (NMJ). SH2 domain-containing phosphatase (SHP2) negatively regulates the pathway inhibiting MuSK activation. In MuSK-MG, monovalent IgG4 autoantibodies block MuSK phosphorylation dispersing AChR clusters. The role of the smaller population of divalent MuSK IgG1, 2 and 3 antibodies is still undefined. The aims of the study were a) to test in vitro and in vivo SHP2 inhibition by NSC-87877 evaluating its efficacy in counteracting the effects of MuSK-Abs; b) to investigate the pathogenic contribution of MuSK IgG1-3-Abs.</p> <p>Protein phosphorylation and AChR clustering were studied in different cell lines exposed to NSC-87877, and to either patients’ purified MuSK-Ab subclasses or anti-MuSK monoclonals. NSC-87877 was tested for safety and efficacy in wild-type mice and a model of AChR deficiency syndrome. Effects of MuSK IgG1-3 were evaluated on impairment of the MuSK-Lrp4 interaction required for MuSK activation, and on the cytoskeleton activation necessary for cluster maturation. RNA transcriptomic analysis was performed to look for changes in intracellular pathways.</p> <p>In vitro, NSC-87877 increased MuSK phosphorylation protecting AChR clusters from dispersal in the presence of all MuSK-Ab subclasses. Functional MUSK was required for the effectiveness of the drug. In vivo, no side effects were observed but the available genetice myasthenic syndrome models did not improve. Divalent MuSK antibodies activated the phosphorylation cascade but failed to sustain cluster maturation, impairing MuSK-Lrp4 interaction and cytoskeleton rearrangements. Transcriptomic analysis did not detect specific changes that could inform on the mechanisms. In conclusion, SHP2 inhibition showed promising results in vitro, although more studies are needed in vivo to evaluate its potential effectiveness. Although the exact mechanisms of MuSK IgG1-3 antibodies were not identified, the work in this thesis confirms their potential pathogenic role in MuSK-MG that requires further investigation.</p> |
| spellingShingle | Myasthenia gravis Cao, M Targeted treatment approaches and pathogenicity of antibody subclasses in MuSK-myasthenia gravis |
| title | Targeted treatment approaches and pathogenicity of antibody subclasses in MuSK-myasthenia gravis |
| title_full | Targeted treatment approaches and pathogenicity of antibody subclasses in MuSK-myasthenia gravis |
| title_fullStr | Targeted treatment approaches and pathogenicity of antibody subclasses in MuSK-myasthenia gravis |
| title_full_unstemmed | Targeted treatment approaches and pathogenicity of antibody subclasses in MuSK-myasthenia gravis |
| title_short | Targeted treatment approaches and pathogenicity of antibody subclasses in MuSK-myasthenia gravis |
| title_sort | targeted treatment approaches and pathogenicity of antibody subclasses in musk myasthenia gravis |
| topic | Myasthenia gravis |
| work_keys_str_mv | AT caom targetedtreatmentapproachesandpathogenicityofantibodysubclassesinmuskmyastheniagravis |