Immuno-suppressive Peptides for a Human T Cell Clone Autoreactive to a Unique Acetylcholine Receptor α Subunit Peptide Presented by the Disease-Susceptible HLA-DQ6 in Infant-Onset Myasthenia Gravis

Abstract

ABSTRACT: Infant-onset myasthenia gravis, an autoimmune disease specific to Asians predominantly affects neuromuscular junctions in ocular muscles. An AChRα peptide (p71–91) specific autoreactive CD4 +αβ T cell clone was established by stimulating PBMC from a patient heterozygous for two disease-susceptible HLA- DR9-DQ9 and DR13-DQ6 haplotypes with a mixture of overlapping peptides covering AChRα. The T cell clone recognized the AChRα peptide in the context of the HLA-DQ6 molecule and produced a large amount of IFN-γ and a trace amount of IL-4. A part (p75–83) of the core epitope of the autoantigenic peptide (p75–87) is encoded for by an exon P3A of the AChRα gene which can be alternatively spliced. The T cell clone responded to the recombinant AChRα protein with a P3A exon product, but not without a P3A exon product. We investigated responses of the T cell clone to 114 analogue peptides carrying single residue substitutions of the core AChRα peptide. The majority of analogues substituted at residues Phe-77, Leu-80 and Asn-82 stimulated proliferation of the T cell clone. Conversely, the majority of analogue peptides substituted at either Gln-81 or Glu-83 did not stimulate proliferative responses, and all exhibited strong or intermediate inhibitory effects on proliferative responses of the T cell clone to the wild type peptide, possibly by TCR antagonism. Thus, an HLA class II allele specific to Asians may directly control susceptibility to the Asians-specific type of myasthenia gravis. Analogues of the auto-antigenic AChRα peptide may prove effective for new immunosuppressive therapy.