Acetylcholine receptor peptide recognition in HLA DR3-transgenic mice: in vivo responses correlate with MHC-peptide binding.
HLA DR3 is an MHC molecule that reportedly predisposes humans to myasthenia gravis (MG). Though MG is an Ab-mediated autoimmune disease, CD4+ T cells are essential for the generation of high-affinity Abs; hence the specificities of autoreactive CD4+ T cells are important. In this study we report the HLA DR3-restricted T cell determinants on the extracellular region sequence of human acetylcholine receptor alpha subunit. We find two promiscuous determinants on this region 141-160 and 171-190 as defined by their immunogenicity in HLA DR3-, HLA DQ8-, and HLA DQ6-transgenic mice in the absence of endogenous mouse class II molecules. We also studied the minimal determinants of these two regions by truncation analysis, and the MHC binding affinity of a set of overlapping peptides spanning the complete sequence region of human acetylcholine receptor alpha subunit. One of the peptide sequences strongly immunogenic in HLA DR3-transgenic mice also had the highest binding affinity to HLA DR3. Identification of T cell determinants restricted to an MHC molecule known to predispose to MG may be an important step toward the development of peptide-based immunomodulation strategies for this autoimmune disease.
Raju
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Division of Immunology, St. Luke's Medical Center, 2900 West Oklahoma Avenue, Milwaukee, WI 53215, USA. raju_55902@yahoo.com
Spack
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David
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D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D020022:Genetic Predisposition to Disease; D015803:HLA-DR3 Antigen / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011950:Receptors, Cholinergic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017384:Sequence Deletion
D015803:HLA-DR3 Antigen; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011950:Receptors, Cholinergic