Allele specificity of structural requirement for peptides bound to HLA-DRB1*0405 and -DRB1*0406 complexes: implication for the HLA-associated susceptibility to methimazole-induced insulin autoimmune syndrome.

Abstract

SummarySelf-peptides bound to HLA-DR4 (DRA-DRBl*0405 complex) were eluted from the purified DR4 complex, ffactionated on reverse-phase HPLC, and subjected to NH2-terminal sequencing. Seven independent sequences were obtained, and all putative peptides synthesized bound to DRBI*0405 as well as DRBI*0406 complex, which differ only at DRfl 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 DRBI*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 F, W, or Y; and N to Q or S on AAFAALANAA changed the affinity substantially between DRBI*0405 and DRBI*0406. It is noteworthy that all patients with methimazole-induced insulin autoimmune syndrome are positive for DRBI*0406 and negative for DRBI*0405. Interestingly, the quantitative structural motif identified in this study predicted that 8TSICSLYQLE 17 of human insulin cx chain may bind specifically to DRBI*0406 using its l~ motif. Indeed, DRBI*0406 complex bound sTSICSLYQLE17 with a high affinity, and in striking contrast, DRBI*0405 complex did not. Furthermore, a short-term T cell line specific to human insulin established from a DRBI*0406-bearing individual did show reactivity with a peptide fragment containing the l~ motif. Although this fragment probably exists at a very low level under normal physiological conditions due to the disulfide bond between flanking cysteine residues (6Cys-llCys), a reducing compound such as methimazole may cleave the disulfide bond in vivo and allow DRcr-DRBI*0406 complex on antigen-presenting cells to bind much of the linear fragment of insulin c~ chain, which may lead to the activation of self-insulin-specific T-helper cells.

Fine Specificity of T Cells Reactive to Human PDC-E2 163-176 Peptide, the Immunodominant Autoantigen in Primary Biliary Cirrhosis: Implications for Molecular Mimicry and Cross-Recognition Among Mitochondrial Autoantigens

“…[14][15][16][17][19][20][21][22][23][24][25] In the present study, to further analyze the TCR ligands of the PDC-E2 163-176 -reactive T cells, we investigated the response of PDC-E2 163-176 -reactive cloned T-cell lines to a panel of single amino acid-substituted peptides derived from the PDC-E2 163-176 peptide. We found that each T-cell clone had a different pattern of reactivity to a panel of these analogue peptides, indicating the presence of a variety of T-cell repertoire for a single TCR ligand such as the PDC-E2 163-176 peptide/HLA DR53 complex.…”

“…Because numerous studies have shown that not only the TCR-TCR ligand interaction but also the peptide-major histocompatibility complex (MHC) interaction are significantly down-modulated when the polarity of important residues is inverted on the antigenic peptide, each hydrophilic residue on the wild-type peptide was substituted with the minimal hydrophobic alanine, and each hydrophobic residue was substituted with the minimal neutral hydrophilic serine as described elsewhere. 20 We previously revealed that 170 E, 172 D, and 173 K are the common and essential amino acids of the PDC-E2 163-176 peptide for recognition by PDC-E2 163-176 -reactive cloned T-cell lines established from patients with PBC. 11 Furthermore, using cloned Tcell lines with specificity for the PDC-E2 163-176 peptide established from the liver of PBC patients, we recently identified a common T-cell epitope motif ExETDK, which is essential for the detection of cross-reactivity of these cloned T-cell lines to the OGDC-E2 100-113 peptide.…”

An HLA-binding-motif-aided peptide epitope library: A novel library design for the screening of HLA-DR4-restricted antigenic peptides recognized by CD4+T cells

“…Design strategy for the HLA-DRB1*0405 motif-aided peptide epitope library A binding motif for HLA-DRB1*0405-associated peptides has been elucidated by several investigators from analysis of endogenous peptides eluted from the molecule (Kinouchi et al 1994;Matsushita et al 1994;Rammensee et al 1995;Friede et al 1996). The motif is composed of nine amino acid residues of which position 1, 4, 6, and 9 (P1, P4, P6, and P9) are considered to be anchor positions as shown in Table␣ 1.…”

In Vivo Evidence That Peptide Vaccination Can Induce HLA-DR-Restricted CD4+ T Cells Reactive to a Class I Tumor Peptide

“…The amino acid sequence of the UBE2V 43-51 peptide could conform to the motif for HLA-DRB1*0403 molecules. Judging from the binding motif of HLA-DRB1*0406 molecules (16), although this motif is different by one amino acid from that of HLA-DRB1*0403 molecules, the leucine at the first t position and serine at the sixth position are thought to be the amino acids anchored to the HLA-DRB1*0403 molecules. Several researchers have reported that CD4 ϩ T cells can recognize nine or 10 aa in the context of MHC class I molecules (17,18), and long peptides recognized by both CD8 ϩ T cells and CD4 ϩ T cells have been identified (19,20).…”