NATURAL PEPTIDE LIGAND MOTIFS OF 2 HLA MOLECULES ASSOCIATED WITH MYASTHENIA-GRAVIS

The peptide motifs of two HLA molecules, B8 and DR3(17), which are ass ociated with autoimmune diseases including myasthenia gravis, were det ermined from natural peptide pools using Edman degradation. The majori ty of HLA-B8 ligands are nonamers preferentially terminated by leucine . As a characteristic feature of the HLA-B8 motif, there is a high deg ree of conservation of positively charged amino acids at position 3 an d 5, exclusively lysine at position 3, and lysine or arginine at posit ion 5. Additional evidence for this allele-specific motif is the prese nce of these features in several viral peptides recognized by HLA-B8 r estricted T cells. The DR3(17) motif is characterized by four conserve d anchor-like positions ordered in an almost symmetrical arrangement, as has been found for DR1 and DR5 motifs. A first hydrophobic/aromatic anchor three to four residues apart from the N-terminus (at relative position 1) appears to be a common feature of DR ligands. The second a nchor is an aspartate at relative position 4, which is likely to be th e DR3(17)-specific contact site in the groove. Two additional conserve d positions closer to the C-terminus are occupied by charged amino aci ds at relative position 6 and by hydrophobic/aromatic residues at posi tions 8, 9, or 10. Eight individual naturally processed DR17 ligands w ere sequenced and were found to be derived from exogenous proteins and cytoplasmic membrane receptors. These natural peptides conform well t o the determined motif. A single exchange of the anchor-like positions in a model peptide abrogated binding to DR17+ cells. On the basis of the DR17 motif, peptides from the acetylcholine receptor (AChR), the a utoimmune target in myasthenia gravis, were selected that should conta in candidate epitopes for AChR-specific T helper cells. Several peptid e sequences which were reported to activate T cells from DR3+ individu als were among this collection.