A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis

Abstract

A comprehensive structural portrait of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in rheumatoid arthritis.

A Comparative Analysis of the Peptide Repertoires of HLA–DR Molecules Differentially Associated With Rheumatoid Arthritis

“…Different studies have analyzed the peptide pools of several of these HLA-DR molecules (19,21,(35)(36)(37), but not in a comparative manner. The identification of structural features of the peptides bound to differentially RAassociated alleles is required to define the putative target of the T cell immune response generated by RA-related molecules.…”

10 Years of GWAS Discovery: Biology, Function, and Translation

“…111 Through the use of amino acid imputation and association studies, this ''shared epitope'' sequence was extended, 112 and this information used to provide a molecular explanation for the propensity of peptides with citrullinated component amino acids to induce disease. 113 HLA variants have long been known to be major determinants of severe immunologically mediated adverse drug reactions. For example, toxicity to the anti-retroviral abacavir is largely restricted to HLA-B57 carriers.…”

A Molecular Analysis of the Shared Epitope Hypothesis: Binding of Arthritogenic Peptides to DRB1*04 Alleles

“…We measured binding of native and citrullinated forms of vimentin [66][67][68][69][70][71][72][73][74][75][76][77][78] and a-enolase [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] and noncitrullinated type II collagen [258][259][260][261][262][263][264][265][266][267][268][269][270][271][272] to 88 class II alleles on Luminex beads (which includes alleles of many varying degrees of susceptibility and resistance). We expressed DRB1*04:01, *04:02, and *08:01 in T2 cells and mutated DRB1*04:01 at positions 67, 70, 71, 74, and 86 to corresponding residues in DRB1*04:02, *04:03, *04:04, *04:05, and *08:01.…”

“…The most susceptible allele, DRB1*04:01, preferentially bound citrullinated vimentin [66][67][68][69][70][71][72][73][74][75][76][77][78] and citrullinated a-enolase [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] over the native forms. DRB1*04:02 exhibited no preference for citrullinated peptides, and *08:01 preferred native peptides.…”

“…This observation was confirmed by James et al (20), suggesting that the critical amino acids in susceptibility alleles might initiate RA by preferential binding of citrullinated peptides over their native forms. To test this hypothesis over a broad spectrum of HLA alleles, we measured the binding of native and citrullinated forms of vimentin [66][67][68][69][70][71][72][73][74][75][76][77][78] and a-enolase [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] as well as the immunodominant peptide type II collagen [258][259][260][261][262][263][264][265][266][267][268][269][270][271][272] to 88 different HLA-DRB1, DPB1, and DQB1 protein alleles. We then performed site-directed mutagenesis of DRB1*04:01 residues at positions 67, 70, 71, 74, and 86 to the corresponding residues in *04:02, *04:03, *04:04, *04:05, and *08:01 to determine the potential role of each position in the binding of these arthritogenic peptides.…”