Acetylcholine Receptor Peptide Recognition in HLA DR3-Transgenic Mice: In Vivo Responses Correlate with MHC-Peptide Binding

• Published in: The Journal of immunology (1950) Vol. 167; no. 2; pp. 1118 - 1124
• Main Authors: Raju, Raghavanpillai, Spack, Edward G, David, Chella S
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.07.2001
• Subjects: Amino Acid Sequence; Animals; Female; Genetic Predisposition to Disease; histocompatibility antigen HLA; HLA-DR3 Antigen - genetics; HLA-DR3 Antigen - metabolism; Humans; Immunodominant Epitopes - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Molecular Sequence Data; Myasthenia Gravis, Autoimmune, Experimental - genetics; Myasthenia Gravis, Autoimmune, Experimental - immunology; Peptide Fragments - genetics; Peptide Fragments - immunology; Peptide Fragments - metabolism; Protein Binding - genetics; Protein Binding - immunology; Receptors, Cholinergic - genetics; Receptors, Cholinergic - immunology; Receptors, Cholinergic - metabolism; Sequence Deletion
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.2.1118

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.