R. Raju et al., Acetylcholine receptor peptide recognition in HLA DR3-transgenic mice: In vivo responses correlate with MHC-peptide binding, J IMMUNOL, 167(2), 2001, pp. 1118-1124
HLA DR3 is an MHC molecule that reportedly predisposes humans to myasthenia
gravis (MG). Though MG is an Ab-mediated autoimmune disease, CD4(+) T cell
s are essential for the generation of high-affinity Abs; hence the specific
ities of autoreactive CD4(+) T cells are important. In this study we report
the HLA DR3-restricted T cell determinants on the extracellular region seq
uence of human acetylcholine receptor a subunit. We find two promiscuous de
terminants on this region 141-160 and 171-190 as defined by their immunogen
icity in HLA DR3-, HLA DQ8-, and HLA DQ6-transgenic mice in the absence of
endogenous mouse class II molecules. We also studied the minimal determinan
ts of these two regions by truncation analysis, and the MHC binding affinit
y of a set of overlapping peptides spanning the complete sequence region of
human acetylcholine receptor a subunit. One of the peptide sequences stron
gly immunogenic in HLA DR3-transgenic mice also had the highest binding aff
inity to HLA DR3. Identification of T cell determinants restricted to an MH
C molecule known to predispose to MG may be an important step toward the de
velopment of peptide-based immunomodulation strategies for this autoimmune
disease.