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Cryptic determinants and promiscuous sequences on human acetylcholine receptor: HLA-dependent dichotomy in T-cell
Raghavanpillai Raju1, Eric Marietta, Javier Vinasco
1Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. david.chella@mayo.edu
Human Immunology
|June 1, 2002
Summary
Human leukocyte antigen (HLA) DQ8 transgenic mice show increased susceptibility to experimental autoimmune myasthenia gravis compared to HLA DQ6 mice. This difference is linked to distinct T cell responses and epitope recognition of the acetylcholine receptor.
Area of Science:
- Immunology
- Genetics
- Neuroscience
Background:
- Myasthenia gravis (MG) is an autoimmune disease affecting neuromuscular junctions.
- Experimental autoimmune MG (EAMG) is induced by acetylcholine receptor (AChR) immunization in rodents.
- Human studies link MG susceptibility to the human leukocyte antigen (HLA) complex.
Purpose of the Study:
- To investigate the role of specific HLA class II molecules in MG development.
- To compare EAMG susceptibility in HLA DQ8 and HLA DQ6 transgenic mice.
- To map AChR epitopes and analyze T cell responses in these models.
Main Methods:
- Utilized HLA DQ8 and HLA DQ6 transgenic mice lacking endogenous mouse class II molecules.
- Mapped immunodominant and cryptic epitopes on the extracellular region of the human AChR.
- Analyzed T cell functional dichotomy upon priming with immunodominant sequences.
Main Results:
- HLA DQ8 transgenic mice exhibited increased susceptibility to EAMG compared to HLA DQ6 mice.
- Identified common and distinct AChR epitopes recognized by DQ8 and DQ6 transgenic mice.
- Observed differential T cell functional profiles in DQ8 versus DQ6 transgenic mice.
Conclusions:
- Differential peptide recognition by HLA DQ8 and HLA DQ6 molecules contributes to MG susceptibility.
- Distinct T cell functional profiles generated by HLA DQ8 and DQ6 influence disease manifestation.
- These findings provide direct experimental evidence for MHC gene influence in MG pathogenesis.