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Departments of
* Cellular and Structural Biology,
Pediatrics, and
Microbiology, University of Texas Health Science Center, San Antonio, TX 78229;
Cancer Therapy and Research Center, San Antonio, TX 78229; and
¶ Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy, Toledo, OH 43606
Because it is one of the few autoimmune disorders in which the
target autoantigen has been definitively identified, myasthenia gravis
(MG) provides a unique opportunity for testing basic concepts of immune
tolerance. In most MG patients, Abs against the acetylcholine receptors
(AChR) at the neuromuscular junction can be readily identified and have
been directly shown to cause muscle weakness. T cells have also been
implicated and appear to play a role in regulating the pathogenic B
cells. A murine MG model, generated by immunizing mice with
heterologous AChR from the electric fish Torpedo
californica, has been used extensively. In these animals, Abs
cross-react with murine AChR; however, the T cells do not. Thus, to
study tolerance to AChR, a transgenic mouse model was generated in
which the immunodominant Torpedo AChR (T-AChR) 
subunit is expressed in appropriate tissues. Upon immunization, these
mice showed greatly reduced T cell responses to T-AChR and the
immunodominant -chain peptide. Limiting dilution assays suggest the
likely mechanism of tolerance is deletion or anergy. Despite this
tolerance, immunization with intact T-AChR induced anti-AChR Abs,
including Abs against the subunit, and the incidence of MG-like
symptoms was similar to that of wild-type animals. Furthermore,
evidence suggests that this B cell response to the -chain receives
help from T cells directed against the other AChR polypeptides (
,
, or 
). This model offers a novel opportunity to elucidate
mechanisms of tolerance regulation to muscle AChR and to clarify the
role of T cells in MG.
This article has been cited by other articles:
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  S. Calbo, H. Delagreverie, C. Arnoult, F.-J. Authier, F. Tron, and O. Boyer Functional Tolerance of CD8+ T Cells Induced by Muscle-Specific Antigen Expression J. Immunol., July 1, 2008; 181(1): 408 - 417. [Abstract] [Full Text] [PDF]
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N. E. Standifer, S. Stacy, E. Kraig, and A. J. Infante Discrete T Cell Populations with Specificity for a Neo-Self-Antigen Bear Distinct Imprints of Tolerance J. Immunol., March 15, 2007; 178(6): 3544 - 3550. [Abstract] [Full Text] [PDF]
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P. N. Pichurin, C.-R. Chen, G. D. Chazenbalk, H. Aliesky, N. Pham, B. Rapoport, and S. M. McLachlan Targeted Expression of the Human Thyrotropin Receptor A-Subunit to the Mouse Thyroid: Insight into Overcoming the Lack of Response to A-Subunit Adenovirus Immunization J. Immunol., January 1, 2006; 176(1): 668 - 676. [Abstract] [Full Text] [PDF]
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