Natural peptide ligand motifs of two HLA molecules associated with myasthenia gravis

• Published in: International immunology 1993-10, Vol.5 (10), p.1229-1237
• Main Authors: Malcherek, Georg, Falk, Kirsten, Rötzschke, Olaf, Rammensee, Hans-Georg, Stevanović, Stefan, Gnau, Volker, Jung, Günther, Melms, Arthur
• Format: Article
• Language: English
• Subjects: acetylcholine receptor; Amino Acid Sequence; Animals; Autoimmunity (experimental aspects and models); Biological and medical sciences; Cell Line; flow cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; HLA-B8; HLA-B8 Antigen - metabolism; HLA-DR3; HLA-DR3 Antigen - metabolism; Humans; Ligands; Mice; Molecular Sequence Data; Myasthenia Gravis - immunology; Peptides - metabolism; pool sequencing; Receptors, Cholinergic - immunology; Sequence Alignment
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/5.10.1229

The peptide motifs of two HLA molecules, B8 and DR3(17), which are associated with autoimmune diseases including myasthenia gravls, were determined from natural peptide pools using Edman degradation. The majority of HLA-B8 liganda are nonamere preferentially terminated by leucine. As a characteristic feature of the HLA-B8 motif, there is a high degree of conservation of positively charged amlno acids at position 3 and 5, exclusively lysine at position 3, and lysine or arglnine at position 5. Additional evidence for this allele-specific motif is the presence of these features in several viral peptldes recognized by HLA-B8 restricted T cells. The DR3(17) motif is characterized by four conserved 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 liganda. The second anchor is an aspartate at relative position 4, which is likely to be the DR3(17)-speclfIc contact site in the groove. Two additional conserved positions closer to the C-terminus are occupied by charged amino acids at relative position 6 and by hydrophobic/aromatic residues at positions 8, 9, or 10. Eight individual naturally processed DR17 ligands were sequenced and were found to be derived from exogenousiproteins and cytoplasmic membrane receptors. These natural peptldes conform well to 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, peptldes from the acetylcholine receptor(AChR), the autoimmune target in myasthenia gravls, were selected that should contain candidate epitopes for AChR-speclflc T helper cells. Several peptide sequences which were reported to activate T cells from DR3+ individuals were among this collection.