Design, synthesis, and characterization of a 39 amino acid peptide mimic of the main immunogenic region of the Torpedo acetylcholine receptor

Trinh, Vu B.; Foster, Alex J.; Fairclough, Robert H.

doi:10.1016/j.molimm.2014.01.002

Cited by 8 publications

(5 citation statements)

References 24 publications

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“…Using this methodology, we successfully isolated a clone of nAChR Abs against MIR, B12L from human MG samples and clearly demonstrated its pathogenicity in an EAMG model. In recent studies, blocking pathogenic antibodies against autoantigens using blocking antibodies [ 66 , 67 ] and depleting antigen-specific antibodies [ 68 ] were suggested as new concepts for MG therapy. Therefore, B12L could be a promising target molecule for MG therapy in the future.…”

Section: Discussionmentioning

confidence: 99%

Analysis of peripheral B cells and autoantibodies against the anti-nicotinic acetylcholine receptor derived from patients with myasthenia gravis using single-cell manipulation tools

Makino¹,

Nakamura

Terakawa

et al. 2017

PLoS ONE

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The majority of patients with myasthenia gravis (MG), an organ-specific autoimmune disease, harbor autoantibodies that attack the nicotinic acetylcholine receptor (nAChR-Abs) at the neuromuscular junction of skeletal muscles, resulting in muscle weakness. Single cell manipulation technologies coupled with genetic engineering are very powerful tools to examine T cell and B cell repertoires and the dynamics of adaptive immunity. These tools have been utilized to develop mAbs in parallel with hybridomas, phage display technologies and B-cell immortalization. By applying a single cell technology and novel high-throughput cell-based binding assays, we identified peripheral B cells that produce pathogenic nAChRAbs in patients with MG. Although anti-nAChR antibodies produced by individual peripheral B cells generally exhibited low binding affinity for the α-subunit of the nAChR and great sequence diversity, a small fraction of these antibodies bound with high affinity to nativestructured nAChRs on cell surfaces. B12L, one such Ab isolated here, competed with a rat Ab (mAb35) for binding to the human nAChR and thus considered to recognize the main immunogenic region (MIR). By evaluating the Ab in in vitro cell-based assays and an in vivo rat passive transfer model, B12L was found to act as a pathogenic Ab in rodents and presumably in humans.These findings suggest that B cells in peripheral blood may impact MG pathogenicity. Our methodology can be applied not only to validate pathogenic Abs as molecular target of MG treatment, but also to discover and analyze Ab production systems in other human diseases.

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Section: Discussionmentioning

confidence: 99%

Analysis of peripheral B cells and autoantibodies against the anti-nicotinic acetylcholine receptor derived from patients with myasthenia gravis using single-cell manipulation tools

Makino¹,

Nakamura

Terakawa

et al. 2017

PLoS ONE

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“…Binding between the Fc-III mimetic of DCAF and the Fc region of the antibody was examined to confirm whether this interaction blocks the binding of the Fc region with the Fc receptor or complement protein. Synthesis of DCAF4 was achieved by conjugating the Fc-III-4C tag and pep 4—a 39-mer antigenic peptide12 that was selected to inhibit Ab 4—the commercial antibody mAb35 that blocks the acetylcholine receptor (AChR) and induces myasthenia gravis . The ELISA assay for the C1q protein, which initiates the complement cascade, showed that Ab 4 directly interacts with C1q, which is consistent with a previous study13 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Development of a dual-functional conjugate of antigenic peptide and Fc-III mimetics (DCAF) for targeted antibody blocking

et al. 2019

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“…An alternative antigen-specific approach is to target the B cells that are secreting the auto-Abs. This approach is currently under study in both AChR-MG and in MuSK-MG, through the use of either genetically engineered Abs or genetically engineered T cells that target the pathogenic autoimmune B cells (155,156).…”

Section: Future Treatments: Antigen-specific Agentsmentioning

confidence: 99%

Muscle-Specific Kinase Myasthenia Gravis

Borges

Richman

2020

Front. Immunol.

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Thirty to fifty percent of patients with acetylcholine receptor (AChR) antibody (Ab)negative myasthenia gravis (MG) have Abs to muscle specific kinase (MuSK) and are referred to as having MuSK-MG. MuSK is a 100 kD single-pass post-synaptic transmembrane receptor tyrosine kinase crucial to the development and maintenance of the neuromuscular junction. The Abs in MuSK-MG are predominantly of the IgG4 immunoglobulin subclass. MuSK-MG differs from AChR-MG, in exhibiting more focal muscle involvement, including neck, shoulder, facial and bulbar-innervated muscles, as well as wasting of the involved muscles. MuSK-MG is highly associated with the HLA DR14-DQ5 haplotype and occurs predominantly in females with onset in the fourth decade of life. Some of the standard treatments of AChR-MG have been found to have limited effectiveness in MuSK-MG, including thymectomy and cholinesterase inhibitors. Therefore, current treatment involves immunosuppression, primarily by corticosteroids. In addition, patients respond especially well to B cell depletion agents, e.g., rituximab, with long-term remissions. Future treatments will likely derive from the ongoing analysis of the pathogenic mechanisms underlying this disease, including histologic and physiologic studies of the neuromuscular junction in patients as well as information derived from the development and study of animal models of the disease.

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Design, synthesis, and characterization of a 39 amino acid peptide mimic of the main immunogenic region of the Torpedo acetylcholine receptor

Cited by 8 publications

References 24 publications

Analysis of peripheral B cells and autoantibodies against the anti-nicotinic acetylcholine receptor derived from patients with myasthenia gravis using single-cell manipulation tools

Analysis of peripheral B cells and autoantibodies against the anti-nicotinic acetylcholine receptor derived from patients with myasthenia gravis using single-cell manipulation tools

Development of a dual-functional conjugate of antigenic peptide and Fc-III mimetics (DCAF) for targeted antibody blocking

Muscle-Specific Kinase Myasthenia Gravis

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