Use of T cell receptor/HLA-DRB1*04 molecular modeling to predict site-specific interactions for the DR shared epitope associated with rheumatoid arthritis

Abstract

These results suggest a structural mechanism in which specific TCR recognition and possibly Vbeta selection are directly influenced by the disease-associated MHC polymorphisms.

HLA-DRB1 alleles encoding the “shared epitope” are associated with susceptibility to developing rheumatoid arthritis whereas HLA-DRB1 alleles encoding an aspartic acid at position 70 of the β-chain are protective in Mexican mestizos

“…In fact, antigenic peptides, with negatively charged residues, are efficiently bound by SEϩ alleles [34]. On the other hand, Penzotti et al [35] have suggested that the hydrogen bonding network around SE residues at ␤70 and ␤71 is intimately involved in direct T cell receptor (TCR) contact, and that interaction alone may be sufficient for TCR activation. In view of the fact that the aspartic acid at ␤70 from DRB1*07, DRB1*08, and DRB1*11 has a different charge, this can influence either the kind of peptide that can be bound to HLA molecule or TCR activation.…”

Genetic susceptibility and immune-mediated destruction in beryllium-induced disease

“…The deeper P4 pocket could potentially enable direct access of beryllium to the MHC molecule in the absence of peptide, although this remains an active area of investigation. In regard to HLA-DP, and particularly the DPb position 69, Penzotti et al [59] have suggested that the analogous position in HLA-DR4 could interact directly with the TCR. Thus, it remains possible that the negatively charged aspartic acid (D) at position 96 of the TCR Vb3 chain could interact with the negatively charged glutamic acid (E) at position 69 of the DPb chain through an intermediary beryllium moiety [13,14].…”

T cell responses to a human cartilage autoantigen in the context of rheumatoid arthritis–associated and nonassociated HLA–DR4 alleles

“…Accordingly, it has been proposed that the consensus sequence could influence the binding of arthritogenic peptides as well as the selection of a potentially autoreactive CD4ϩ TCR repertoire during thymic maturation. Support for this hypothesis comes from direct peptide-binding studies (11), from pool sequencing of natural peptide ligands eluted from HLA-DR molecules (12), from experiments examining the influence of DR␤-chain mutants on both peptide binding and allorecognition by TCR (13), and from molecular modeling and crystallographic studies (14)(15)(16). These studies also predict that negatively charged residues would be preferred at position 4 of peptides binding to DR*0401, and positive residues would be preferred at this position for epitopes binding to DR*0402 molecules.…”