{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:41:35Z","timestamp":1760146895544,"version":"build-2065373602"},"reference-count":25,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T00:00:00Z","timestamp":1735516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Myasthenia Gravis Foundation of California"},{"name":"New York MG Alliance"},{"name":"UC Davis Health Ventures"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We have designed and produced 39 amino acid peptide mimics of the Torpedo and human acetylcholine receptors\u2019 (AChRs) main immunogenic regions (MIRs). These conformationally sensitive regions consist of three non-contiguous segments of the AChR \u03b1-subunits and are the target of 50\u201370% of the anti-AChR autoantibodies (Abs) in human myasthenic serum and in the serum of rats with a model of that disease, experimental autoimmune myasthenia gravis (EAMG), induced by immunizing the rats with the Torpedo electric organ AChR. These MIR segments covalently joined together bind a significant fraction of the monoclonal antibodies (mAbs) raised in rats against electric organ AChR. Many of these mAbs cross react with the rat neuromuscular AChR MIR and induce myasthenic symptoms when injected into na\u00efve rats. The human MIR mimic peptide (H39MIR) is evolutionarily related to that of the Torpedo electric organ MIR mimic peptide (T39MIR) with eight amino acid differences between the two MIR mimics. The mAbs raised to the electric organ AChR MIR cross react with the human and scores of other species\u2019 neuromuscular AChRs. However, the mAbs do not cross react with the H39MIR mimic attached to the N-terminus of an intein\u2013chitin-binding domain (H39MIR-IChBD) even though they do bind to the T39MIR-IChBD construct. To account for this difference in binding anti-MIR mAbs, each of the eight human amino acids was substituted individually into the T39MIR-IChBD, and four of them were found to weaken mAb recognition. Substituting the corresponding four Torpedo amino acids individually and in combination into the homologous positions in H39MIR-IChBD makes chimeric human MIR mimic peptides (T\/H39MIR), some of which bind anti-MIR mAbs and anti-MIR Abs from rat EAMG and human MG sera. The best mAb binding chimeric peptide constructs may potentially serve as the basis of a diagnostic anti-MIR Ab titer assay that is both prognostic and predictive of disease severity. Furthermore, the best peptides may also serve as the targeting element of a non-steroidal antigen-specific treatment of MG to remove anti-AChR MIR Abs, either as fused to the N-terminals of the human immunoglobin Fc fragment or as the targeting component of a T cell chimeric autoantibody receptor (CAAR) directed to anti-MIR memory B cells for elimination.<\/jats:p>","DOI":"10.3390\/ijms26010229","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T07:51:57Z","timestamp":1735631517000},"page":"229","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development of Peptide Mimics of the Human Acetylcholine Receptor Main Immunogenic Region for Treating Myasthenia Gravis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1654-3592","authenticated-orcid":false,"given":"Vu B.","family":"Trinh","sequence":"first","affiliation":[{"name":"Department of Neurology, Davis School of Medicine, University of California, 1515 Newton Court, Davis, CA 95618, USA"},{"name":"Biochemistry, Molecular, Cellular, and Developmental Biology Graduate Group, University of California, Davis, CA 95618, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert H.","family":"Fairclough","sequence":"additional","affiliation":[{"name":"Department of Neurology, Davis School of Medicine, University of California, 1515 Newton Court, Davis, CA 95618, USA"},{"name":"Biochemistry, Molecular, Cellular, and Developmental Biology Graduate Group, University of California, Davis, CA 95618, USA"},{"name":"Biophysics Graduate Group, University of California, Davis, CA 95618, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/j.1749-6632.1993.tb22891.x","article-title":"Effector mechanisms of myasthenic antibodies","volume":"681","author":"Richman","year":"1993","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/(SICI)1097-4598(200004)23:4<453::AID-MUS3>3.0.CO;2-O","article-title":"Acetylcholine receptors and myasthenia","volume":"23","author":"Lindstrom","year":"2000","journal-title":"Muscle Nerve"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1021\/bi00511a017","article-title":"Monoclon antibodies as probes of acetylcholine receptor structure. Binding to native receptor","volume":"20","author":"Tzartos","year":"1981","journal-title":"Biochemistry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1042\/bj2690239","article-title":"Antigenic role of single residues within the main immunogenic region of the nicotinic acetylcholine receptor","volume":"269","author":"Papadouli","year":"1990","journal-title":"Biochem. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/j.1471-4159.1990.tb13282.x","article-title":"Main immunogenic region of Torpedo electroplax and human muscle acetylcholine receptor: Localization and microheterogeneity revealed by the use of synthetic peptides","volume":"54","author":"Tzartos","year":"1990","journal-title":"J. Neurochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/j.1749-6632.1981.tb33726.x","article-title":"Monoclonal hybridoma anti-acetylcholine receptor antibodies: Antibody specificity and effect of passive transfer","volume":"377","author":"Gomez","year":"1981","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1212\/WNL.36.5.612","article-title":"Myasthenia gravis: Monoclonal antihuman acetylcholine receptor antibodies used to analyze antibody specificities and responses to treatment","volume":"36","author":"Whiting","year":"1986","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1084\/jem.141.6.1365","article-title":"Experimental autoimmune myasthenia: A model of myasthenia gravis in rats and guinea pigs","volume":"141","author":"Lennon","year":"1975","journal-title":"J. Exp. Med."},{"key":"ref_9","first-page":"568","article-title":"Experimental autoimmune myasthenia gravis","volume":"43","author":"Lennon","year":"1980","journal-title":"J. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0733-8619(18)30097-5","article-title":"Acquired myasthenia gravis. Immunopathology","volume":"12","author":"Richman","year":"1994","journal-title":"Neurol. Clin"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1073\/pnas.79.1.188","article-title":"Specificities of antibodies to acetylcholine receptors in sera from myasthenia gravis patients measured by monoclonal antibodies","volume":"79","author":"Tzartos","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1073\/pnas.77.2.755","article-title":"Monoclonal antibodies used to probe acetylcholine receptor structure: Localization of the main immunogenic region and detection of similarities between subunits","volume":"77","author":"Tzartos","year":"1980","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8635","DOI":"10.1016\/S0021-9258(19)68891-5","article-title":"Mapping of surface structures of electrophorus acetylcholine receptor using monoclonal antibodies","volume":"256","author":"Tzartos","year":"1981","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/0896-6273(95)90037-3","article-title":"Three-dimensional location of the main immunogenic region of the acetylcholine receptor","volume":"15","author":"Beroukhim","year":"1995","journal-title":"Neuron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.molimm.2013.11.005","article-title":"Structural characterization of the main immunogenic region of the Torpedo acetylcholine receptor","volume":"58","author":"Morell","year":"2014","journal-title":"Mol. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.jmb.2004.12.031","article-title":"Refined structure of the nicotinic acetylcholine receptor at 4\u00c5 resolution","volume":"346","author":"Unwin","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.molimm.2014.01.002","article-title":"Design, synthesis, and characterization of a 39 amino acid peptide mimic of the main immunogenic region of the Torpedo acetylcholine receptor","volume":"59","author":"Trinh","year":"2014","journal-title":"Mol. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1038\/nn1942","article-title":"Crystal structure of the extracellular domain of nAChR alpha1 bound to alpha-bungarotoxin at 1.94 A resolution","volume":"10","author":"Dellisanti","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"W39","DOI":"10.1093\/nar\/gki398","article-title":"SPACE: A suite of tools for protein structure prediction and analysis based on complementarity and environment","volume":"33","author":"Sobolev","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5916","DOI":"10.1016\/S0021-9258(18)60652-0","article-title":"Monoclonal antibodies to the main immunogenic region of the nicotinic acetylcholine receptor bind to residues 61-76 of the alpha subunit","volume":"263","author":"Barkas","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1136\/jnnp-2012-302705","article-title":"Antibodies against the main immunogenic region of the acetylcholine receptor correlate with disease severity in myasthenia gravis","volume":"83","author":"Masuda","year":"2012","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1038\/s41587-022-01637-z","article-title":"Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells","volume":"41","author":"Oh","year":"2023","journal-title":"Nat. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1126\/science.aaf6756","article-title":"Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease","volume":"353","author":"Ellebrecht","year":"2016","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6317","DOI":"10.1172\/JCI138416","article-title":"Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris","volume":"130","author":"Lee","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5084","DOI":"10.1016\/j.cell.2023.10.001","article-title":"Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells","volume":"186","author":"Reincke","year":"2023","journal-title":"Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/229\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:56:34Z","timestamp":1760115394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/229"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,30]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ijms26010229"],"URL":"https:\/\/doi.org\/10.3390\/ijms26010229","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,12,30]]}}}