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Anti-MuSK autoantibodies block binding of collagen Q to MuSK
- Publication Year :
- 2011
- Publisher :
- Lippincott Williams & Wilkins, 2011.
-
Abstract
- Objective: Muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) accounts for 5%–15% of autoimmune MG. MuSK mediates the agrin-signaling pathway and also anchors the collagenic tail subunit (ColQ) of acetylcholinesterase (AChE). The exact molecular target of MuSK–immunoglobulin G (IgG), however, remains elusive. As acetylcholine receptor (AChR) deficiency is typically mild and as cholinesterase inhibitors are generally ineffective, we asked if MuSK-IgG interferes with binding of ColQ to MuSK. Methods: We used 3 assays: in vitro overlay of the human ColQ-tailed AChE to muscle sections of Colq−/− mice; in vitro plate-binding assay to quantitate binding of MuSK to ColQ and to LRP4; and passive transfer of MuSK-IgG to mice. Results: The in vitro overlay assay revealed that MuSK-IgG blocks binding of ColQ to the neuromuscular junction. The in vitro plate-binding assay showed that MuSK-IgG exerts a dose-dependent block of MuSK binding to ColQ by but not to LRP4. Passive transfer of MuSK-IgG to mice reduced the size and density of ColQ to ∼10% of controls and had a lesser effect on the size and density of AChR and MuSK. Conclusions: As lack of ColQ compromises agrin-mediated AChR clustering in Colq −/− mice, a similar mechanism may lead to AChR deficiency in MuSK-MG patients. Our experiments also predict partial AChE deficiency in MuSK-MG patients, but AChE is not reduced in biopsied NMJs. In humans, binding of ColQ to MuSK may be dispensable for clustering ColQ, but is required for facilitating AChR clustering. Further studies will be required to elucidate the basis of this paradox.
- Subjects :
- medicine.medical_specialty
Muscle Proteins
Neuromuscular junction
Receptor tyrosine kinase
chemistry.chemical_compound
Mice
Internal medicine
COLQ
medicine
Animals
Receptors, Cholinergic
Antibodies, Blocking
Cholinesterase
Acetylcholine receptor
Autoantibodies
Mice, Knockout
biology
Receptor Protein-Tyrosine Kinases
Articles
medicine.disease
Acetylcholinesterase
Molecular biology
In vitro
Myasthenia gravis
Myasthenia Gravis, Autoimmune, Experimental
Endocrinology
medicine.anatomical_structure
chemistry
biology.protein
Neurology (clinical)
Binding Sites, Antibody
Collagen
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....919e997ce15027bbdd722c2f2e1691d0