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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
  1. Samuel Bitoun1,
  2. Pierre Roques2,
  3. Bernard Maillere3,
  4. Roger Le Grand2,
  5. Xavier Mariette1
  1. 1 Rheumatology Department, Hôpitaux Universitaires Paris-Sud-Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Sud- CEA-INSERM U1184 'Immunology of viral infections and autoimmune diseases', Le Kremlin-Bicêtre, France
  2. 2 IDMIT Infrastructure, CEA - Université Paris Sud 11 - INSERM U1184, Immunology of viral infections and autoimmune diseases, Fontenay-Aux-Roses, France
  3. 3 iBiTecS, Service d'Ingenierie Moleculaire des Proteines (SIMOPRO), Labex LERMIT, Labex VRI, CEA, Gif Sur Yvette, France
  1. Correspondence to Professor Xavier Mariette, Service de Rhumatologie, Hôpitaux Universitaires Paris-Sud 78, rue du Général Leclerc - 94270, Le Kremlin-Bicêtre, France; xavier.mariette{at}


Objectives Various 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.

Methods Six H6 and six non-H6 macaques were immunized with four Cit-P. T-cell response was assessed using Interferon γ enzyme-linked immunospot.

Results Animals 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.

Conclusion The 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.

  • rheumatoid arthritis
  • gene polymorphism
  • t cell

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  • Handling editor Josef S Smolen

  • Contributors SB, PR, RLG, BM and XM designed the study, supervised the experimental design and the data analysis. SB and PR made the experiments.SB performed statistical analysis. SB and XM wrote the original draft of the manuscript, and all authors reviewed and edited the manuscript, and provided final approval of the version to be published.

  • Funding The research leading to these results was supported by the Labex in Research on Medication and Therapeutic Innovation (LERMIT) (ANR10). The IDMIT infrastructure is supported by the French government 'Programme d’Investissements d’Avenir' (PIA), under grant ANR-11-INBS- 0008. SB was supported by two PhD grants from Société Française de Rhumatologie and INSERM.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The macaque study was approved by the regional animal care and ethics committee (Comité Régional d’Ethique sur l’Expérimentation Animale Île de France Sud, Fontenay-Aux-Roses, France; decision #A15_016). The CEA Institute was approved as compliant with ETS123 recommendations for animal breeding (European Union Directive 2010/63/EU, September 22, 2010) and with Standards for Human Care and Use of Laboratory Animals (Animal Welfare Assurance, OLAW no. #A5826-01). The study was also approved by the French Department of Education and Research (MENESR; study no. 2015070114504151v3) as defined in French law 'décret 2013-118 from 2013 Feb 1st'.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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