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Publication : Mapping myasthenia gravis-associated T cell epitopes on human acetylcholine receptors in HLA transgenic mice.

First Author  Yang H Year  2002
Journal  J Clin Invest Volume  109
Issue  8 Pages  1111-20
PubMed ID  11956249 Mgi Jnum  J:76086
Mgi Id  MGI:2178516 Doi  10.1172/JCI14255
Citation  Yang H, et al. (2002) Mapping myasthenia gravis-associated T cell epitopes on human acetylcholine receptors in HLA transgenic mice. J Clin Invest 109(8):1111-20
abstractText  Susceptibility to myasthenia gravis (MG) is positively linked to expression of HLA-DQ8 and DR3 molecules and negatively linked to expression of the DQ6 molecule. To elucidate the molecular basis of this association, we have induced experimental autoimmune MG (EAMG) in mice transgenic for HLA-DQ8, DQ6, and DR3, and in DQ8xDQ6 and DQ8xDR3 F(1) transgenic mice, by immunization with human acetylcholine receptor (H-AChR) in CFA. Mice expressing transgenes for one or both of the HLA class II molecules positively associated with MG (DQ8 and DR3) developed EAMG. T cells from DQ8 transgenic mice responded well to three cytoplasmic peptide sequences of H-AChR (alpha320-337, alpha304-322, and alpha419-437), of which the response to alpha320-337 was the most intense. DR3 transgenic mice also responded to this sequence very strongly. H-AChR- and alpha320-337 peptide-specific lymphocyte responses were restricted by HLA class II molecules. Disease resistance in DQ6 transgenic mice was associated with reduced synthesis of anti-AChR IgG, IgG(2b), and IgG(2c) Ab's and reduced IL-2 and IFN-gamma secretion by H-AChR- and peptide alpha320-337-specific lymphocytes. Finally, we show that DQ8 imparts susceptibility to EAMG and responsiveness to an epitope within the sequence alpha320-337 as a dominant trait.
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