QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, November 4, 2009, 29(44):13898-13908; doi:10.1523/JNEUROSCI.2833-09.2009

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Luo, J. Articles by Lindstrom, J. PubMed PubMed Citation Articles by Luo, J. Articles by Lindstrom, J. Pubmed/NCBI databases Medline Plus Health Information Myasthenia Gravis

 Previous Article  |  Next Article 

Neurobiology of Disease
Main Immunogenic Region Structure Promotes Binding of Conformation-Dependent Myasthenia Gravis Autoantibodies, Nicotinic Acetylcholine Receptor Conformation Maturation, and Agonist Sensitivity

Jie Luo,¹ Palmer Taylor,² Mario Losen,³ Marc H. de Baets,³ G. Diane Shelton,⁴ and Jon Lindstrom¹

¹Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104-6074, ²Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093-0650, ³Neuroimmunology Group, Department of Neuroscience, School of Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands, and ⁴Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, California 92093-0709

Correspondence should be addressed to Dr. Jon M. Lindstrom, Department of Neuroscience, University of Pennsylvania Medical School, 217 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104-6074. Email: jslkk{at}mail.med.upenn.edu

The main immunogenic region (MIR) is a conformation-dependent region at the extracellular apex of 1 subunits of muscle nicotinic acetylcholine receptor (AChR) that is the target of half or more of the autoantibodies to muscle AChRs in human myasthenia gravis and rat experimental autoimmune myasthenia gravis. By making chimeras of human 1 subunits with 7 subunits, both MIR epitopes recognized by rat mAbs and by the patient-derived human mAb 637 to the MIR were determined to consist of two discontiguous sequences, which are adjacent only in the native conformation. The MIR, including loop 1 67–76 in combination with the N-terminal helix 1 1–14, conferred high-affinity binding for most rat mAbs to the MIR. However, an additional sequence corresponding to 1 15–32 was required for high-affinity binding of human mAb 637. A water soluble chimera of Aplysia acetylcholine binding protein with the same 1 MIR sequences substituted was recognized by a majority of human, feline, and canine myasthenia gravis sera. The presence of the 1 MIR sequences in 1/7 chimeras greatly promoted AChR expression and significantly altered the sensitivity to activation. This reveals a structural and functional, as well as antigenic, significance of the MIR.

---

Received June 15, 2009; revised Sept. 3, 2009; accepted Sept. 7, 2009.

Correspondence should be addressed to Dr. Jon M. Lindstrom, Department of Neuroscience, University of Pennsylvania Medical School, 217 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104-6074. Email: jslkk{at}mail.med.upenn.edu

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help