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To the Editor:

We thank Bell and colleagues for their comments on our article on the fine specificity of the anti–citrullinated protein antibody (ACPA) response. Our report describes that the rheumatoid arthritis (RA)–associated shared epitope (SE) alleles act as “classic” immune response genes in the ACPA response (i.e., the genes first described in mice in the 1960s as the genes that control antibody production [1, 2]), since they influence the magnitude (3) as well as the fine specificity of this RA-specific antibody response. In the Discussion section of this article we note that our data point to the possibility that a peptide derived from vimentin, or a protein physically linked or structurally related to vimentin, is presented to T cells that are restricted by the HLA–DRB1 SE alleles (or the HLA–DQ alleles that are genetically linked to the SE alleles). In that respect, the data published by Hill et al (4) would be consistent with this assumption, and we are grateful to Bell and colleagues for pointing this out. However, we would also like to note that we do not exclude the possibility of a contribution of other proteins and/or other HLA molecules to explain our findings.

Furthermore, the data described by Hill et al were not obtained in humans, but in mice expressing hybrid MHC molecules consisting of the antigen-binding domains from HLA–DRA and HLA–DRB1*0401 molecules and the remaining domains from the mouse IE(d)-alpha and IE(d)-beta chains. These animals were immunized with a peptide from human vimentin that contained a leucine-to-alanine substitution. This could potentially increase its immunogenicity required for T cell activation. In addition, we would like to note that, in contrast to the statement in Bell and colleagues' letter, we did not use the exact same vimentin peptide in our study. Hill and collaborators used a peptide derived from amino acids 65–77 of human vimentin containing a single citrulline residue, whereas we used a peptide derived from amino acids 59–74 containing 3 citrulline residues. Intriguingly, in a recent publication from the authors (5), it was shown that immunization with citrullinated fibrinogen induced the formation of ACPA and the precipitation of arthritis in mice expressing the HLA SE antigen-binding groove. However, we did not detect an influence of the HLA SE alleles on the recognition of a citrullinated fibrinogen peptide. Therefore, we believe Hill and colleagues' findings in mice, although in line with our recent data, should be viewed with some caution before being cited as validation of the proposed mechanism.

  • 1
    McDevitt HO, Sela M. Genetic control of the antibody response. I. Demonstration of determinant-specific differences in response to synthetic polypeptide antigens in two strains of inbred mice. J Exp Med 1965; 122: 51731.
  • 2
    Mozes E, McDevitt HO, Jaton JC, Sela M. The genetic control of antibody specificity. J Exp Med 1969; 130: 126378.
  • 3
    Van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR. The HLA–DRB1 shared epitope alleles are primarily a risk factor for anti–cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum 2006; 54: 111721.
  • 4
    Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol 2003; 171: 53841.
  • 5
    Hill JA, Bell DA, Brintnell W, Yue D, Wehrli B, Jevnikar AM, et al. Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice. J Exp Med. E-pub ahead of print.

K. N. Verpoort MD*, A. Ioan PhD*, G. J. M. Pruijn PhD†, R. E. M. Toes PhD‡, * Leiden University Medical Center, Leiden, The Netherlands, † Radboud University, Nijmegen, The Netherlands, ‡ Leiden University Medical Center, Leiden, The Netherlands.