Valine 11 and phenylalanine 13 have a greater impact on the T-cell response to citrullinated peptides than the 70–74 shared epitope of the DRB1 molecule in macaques

Abstract

ObjectivesVarious rheumatoid arthritis (RA) HLA-DRB-1 risk haplotypes have been regrouped under the shared epitope (SE) in position 70–74. The presence of Valine in position 11 (Val11) and phenylalanine in position 13 (Phe13) are also associated with RA, but it is impossible to differentiate their role compared with the SE since they are in strong linkage disequilibrium (LD) in humans. Similar to humans, certain macaques express the SE (H6). We analysed the effect of various DRB1 haplotypes on T-cell response to citrullinated peptides (Cit-P) in macaques.MethodsSix H6 and six non-H6 macaques were immunized with four Cit-P. T-cell response was assessed using Interferon γ enzyme-linked immunospot.ResultsAnimals developed a specific anti-Cit-P T-cell response. Surprisingly, H6 animals had a significantly lower T-cell response than non-H6. In macaques, the 70–74 SE and the Val11 are on separate haplotypes. Presence of Val11 was strongly associated with the anti-Cit-P T-cell response, whatever the 70–74 sequence was. This response was amplified in case of presence of Phe13.ConclusionThe absence of LD between Val11 and SE in macaques allowed us to demonstrate that the most important HLA positions to induce a T-cell response against Cit-P were Val11 and Phe13 and not the 70–74 SE.

MHC‐DRB alleles with amino acids Val11, Phe13, and the shared epitopes promote collagen‐induced arthritis and a rapid IgG1 response in Filipino cynomolgus macaques

“…We detected two susceptibility alleles with the SE, V11 and F13 in 4 of the 9 Filipino cynomolgus macaques examined in this study, whereas the set of SE, V11 and F13 epitopes was reportedly not present in the protein encoded by Mafa-DRB1 alleles in Mauritius macaques. 22 Eighteen Mafa-DRB haplotypes have been characterized in the Filipino population, and the haplotype frequency of Mafa-DRB-Hp17 and Mafa-DRB-Hp7 including Mafa-DRB1*10:05 and Mafa-DRB1*10:07 was reported at 31%. 42 We did not identify protective SE or MHC alleles in the CIA asymptomatic macaques in the present study.…”

Current Understanding of an Emerging Role of HLA-DRB1 Gene in Rheumatoid Arthritis–From Research to Clinical Practice

“…While the role of Codon 13 in RA risk is still uncertain, Val 11 and Leu 11 have been reported to strongly influence the RA risk (OR = 3.8 and OR = 1.3, respectively) [56]. Moreover, a recent experimental model in macaques has shown that Val 11 and Phe 13 positions may be even more important than SE positions in the process of inducing the T-cell response against citrullinated peptides [57]. Val 11 has also been shown to correlate with the higher incidence of anti-CCP antibodies, similarly to SE variants [58].…”

Causal risk and protective factors in rheumatoid arthritis: A genetic update

“…The collection of HLA alleles that contained within the third hyper-variable region of the DR beta-(B)1 chain a conserved amino acid motif (QKRAA) at positions 70–74, known as SE, corresponds to the main genetic risk factor for RA ranging from OR = 2.17 (CI95: 1.94–2.42) for HLA DR1 to OR = 4.44 (CI95: 4.02–4.91) for HLA-DR4 (*04.04) when the SE is associated with a valine residue at position 11 [ 69 , 70 ]. The link between ACPA and HLA-DRB1 is now elucidated through the demonstration that citrullination is mandatory for vimentine peptide binding with the strongest binding retrieved at valine 11 (DR4) and a lesser binding at SE (DR1 and DR4) explaining, when comparing DR4 and DR1 response, that DR4 possess the strongest T-cell response in vitro and a severe arthritis in transgenic mice [ [71] , [72] , [73] ]. Back to humans and when present, HLA-DRB1 valine 11 and SE contribute both and independently to RA disease severity including erosion (OR = 2.0; CI95: 1.8–2.2) but not with the formation of rheumatoid nodules [ 74 , 75 ].…”