Health & Environmental Research Online (HERO)


Print Feedback Export to File
1090791 
Journal Article 
ALLELE SPECIFICITY OF STRUCTURAL REQUIREMENT FOR PEPTIDES BOUND TO HLA-DRB1-ASTERISK-0405 AND HLA-DRB1-ASTERISK-0406 COMPLEXES - IMPLICATION FOR THE HLA-ASSOCIATED SUSCEPTIBILITY TO METHIMAZOLE-INDUCED INSULIN AUTOIMMUNE SYNDROME 
Matsushita, S; Takahashi, K; Motoki, M; Komoriya, K; Ikagawa, S; Nishimura, Y 
1994 
Yes 
Journal of Experimental Medicine
ISSN: 0022-1007
EISSN: 1540-9538 
180 
3 
English 
Self-peptides bound to HLA-DR4 (DRA-DRB1(*)0405 complex) were eluted from the purified DR4 complex, fractionated on reverse-phase HPLC, and subjected to NH2-terminal sequencing. Seven independent sequences were obtained, and all putative peptides synthesized bound to DRB1(*)0405 as well as DRB1(*)0406 complex, which differ only at DR beta residues 37, 57, 74, and 86. Binding assay using analogue peptides of a DR4 binder GSTVFDNLPNPE revealed that FxxLxN is an important anchor motif necessary for binding (where x is any amino acid), which was common to DRB1(*)0405 and 0406. Determination of the binding affinity of 60 synthetic AAFAALANAA-based analogue peptides showed that substituting F to W or C; L to E W, or Y; and N to Q or S on AAFAALANAA changed the affinity substantially between DRB1(*)0405 and DRB1(*)0406. It is noteworthy that all patients with methimazole-induced insulin autoimmune syndrome are positive for DRB1(*)0406 and negative for DRB1(*)0405. Interestingly, the quantitative structural motif identified in this study predicted that (8)TSICSLYQLE(17) of human insulin alpha chain may bind specifically to DRB1(*)0406 using its (10)IxxLxQ(15) motif. Indeed, DRB1(*)0406 complex bound (8)TSICSLYQLE(17) with a high affinity, and in striking contrast, DRB1(*)0405 complex did not. Furthermore, a short-term T cell line specific to human insulin established from a DRB1(*)0406-bearing individual did show reactivity with a peptide fragment containing the (10)IxxLxQ(15) motif. Although this fragment probably exists at a very low level under normal physiological conditions due to the disulfide bond between flanking cysteine residues ((6)Cys-(11)Cys), a reducing compound such as methimazole may cleave the disulfide bond in vivo and allow DR alpha-DRB1(*)0406 complex on antigen-presenting cells to bind much of the linear fragment of insulin a chain, which may lead to the activation of self-insulin-specific T-helper cells.