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

Objective.To use molecular modeling tools to analyze the potential structural basis for the genetic association of rheumatoid arthritis (RA) with the major histocompatibility complex (MHC) "shared epitope," a set of conserved amino acid residues in the third hypervariable region of the DRP chain.Methods. Homology model building techniques were used to construct molecular models of the arthritis-associated DRB1*0404 molecule and a T cell receptor (TCR) from T cell clone EM025, which is specific for DR4 molecules containing the shared epitope sequence. Interactive graphics techniques were used to orient the TCR on the DR molecule, guided by surface complementarity analysis.Results. The predicted TCR-MHC-peptide complex involved multiple interactions and specificity for the shared epitope. TCR residues CDRlP D30, CDR2P N51, and CDR3P Q97 were positioned to potentially participate in hydrogen bond interactions with the shared epitope DRP residues Q70 and R71.Conclusion. These results suggest a structural mechanism in which specific TCR recognition and possibly V, selection are directly influenced by the diseaseassociated MHC polymorphisms.The interaction of specific T cell receptors (TCR), major histocompatibility complex (MHC) molecules, and peptides forms the structural basis for the principal antigen-specific activation event involving T

Genetics of rheumatoid arthritis: Is there a pattern predicting extraarticular manifestations?

“…Although this may in part be explained by differences in the overall frequency of individual alleles (e.g., 0401), it could be that 0401/0401 is more important in some ExRA subsets, such as vasculitis and severe internal organ disease, and 0401/0404 in others, such as nodules (44). The only difference between 0401 and 0404 is the Lys‐Arg substitution in position 71, which has been suggested to be particularly important in peptide binding (88) and in direct HLA–DR–TCR interaction (89). This could lead to a different T‐cell repertoire after thymic maturation in 0401/0404 patients compared with those with 0401/0401.…”

Metal-Induced Diffuse Lung Disease

“…It is possible that the situation will be different in MHCII molecules with Glu 69 (i.e., the carboxylate will be surface exposed). Penzotti and colleagues 39 have suggested that the analogous position in HLA-DR4 could directly interact with the TCR. One wonders whether the invariant negatively charged aspartic acid (D) at position 96 of the TCR b-chain that we have identified in CD4 þ T cell expansions in the lungs of CBD patients could directly interact with the carboxylate of Glu 69 of HLA-DP2 through an intermediary Be 2 þ moiety.…”