TY - JOUR
T1 - Mapping myasthenia gravis-associated T cell epitopes on human acetylcholine receptors in HLA transgenic mice
AU - Yang, Huan
AU - Goluszko, Elzbieta
AU - David, Chella
AU - Okita, David K.
AU - Conti-Fine, Bianca
AU - Chan, Teh Sheng
AU - Poussin, Mathilde A.
AU - Christadoss, Premkumar
PY - 2002
Y1 - 2002
N2 - 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 F1 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 (α320-337, α304-322, and α419-437), of which the response to α320-337 was the most intense. DR3 transgenic mice also responded to this sequence very strongly. H-AChR- and α320-337 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, IgG2b, and IgG2c Ab's and reduced IL-2 and IFN-γ secretion by H-AChR- and peptide α320-337-specific lymphocytes. Finally, we show that DQ8 imparts susceptibility to EAMG and responsiveness to an epitope within the sequence α320-337 as a dominant trait.
AB - 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 F1 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 (α320-337, α304-322, and α419-437), of which the response to α320-337 was the most intense. DR3 transgenic mice also responded to this sequence very strongly. H-AChR- and α320-337 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, IgG2b, and IgG2c Ab's and reduced IL-2 and IFN-γ secretion by H-AChR- and peptide α320-337-specific lymphocytes. Finally, we show that DQ8 imparts susceptibility to EAMG and responsiveness to an epitope within the sequence α320-337 as a dominant trait.
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U2 - 10.1172/JCI14255
DO - 10.1172/JCI14255
M3 - Article
C2 - 11956249
AN - SCOPUS:0036124028
SN - 0021-9738
VL - 109
SP - 1111
EP - 1120
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -