Influence of HLA–DR genes on the production of rheumatoid arthritis–specific autoantibodies to citrullinated fibrinogen

Abstract

Objective Antibodies directed against citrullinated fibrinogen are highly specific for rheumatoid arthritis (RA). This study was undertaken to test whether RA‐associated HLA–DR alleles are associated with anti–citrullinated fibrinogen in RA patient sera and whether replacement of arginyl by citrullyl residues on fibrinogen peptides modifies their binding to HLA–DR molecules and their recognition by T cells. Methods Antikeratin, antifilaggrin, and anti–citrullinated fibrinogen antibodies were assayed in RA patients who had undergone HLA–DR typing. Direct assays were performed to investigate binding of citrullinated or native fibrinogen peptides (encompassing the entire α‐ and β‐chains of fibrinogen) to purified HLA–DR molecules. T cell proliferative responses to citrullinated or native fibrinogen peptides were measured in RA patients and controls. Results HLA–DRB1*0404 was associated with anti–citrullinated fibrinogen in RA sera (P = 0.002). For the RA‐associated alleles HLA–DRB1*0401 and HLA–DR1, there was a nonsignificant trend toward association (P = 0.07). Multiple peptides from the α‐ and β‐chains of fibrinogen bound many HLA–DR alleles; DRB1*0404 was the best fibrinogen peptide binder. Citrullination did not influence fibrinogen peptide binding to HLA–DR or fibrinogen peptide recognition by T cells. Peripheral blood T cells that recognized native or citrullinated fibrinogen peptides were common in RA patients but not in healthy controls. Conclusion The RA‐associated HLA–DRB1*0404 allele is also associated with production of antibodies to citrullinated fibrinogen. DRB1*0401 and DRB1*01 tend to be associated with anti–citrullinated fibrinogen, but this is not statistically significant. Citrullination of fibrinogen peptide does not influence peptide–DR–T cell interaction. Finally, T cell proliferation in response to citrullinated or uncitrullinated fibrinogen peptides is frequent in RA patients and very infrequent in controls.

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

“…As indicated, the hypothesis that T cells recognizing citrullinated antigens provide help to autoreactive, ACPAspecific B cells needs further confirmation (20)(21)(22). Alternatively, the T cells could react to a noncitrullinated epitope included in the protein complex that is recognized by ACPAϩ B cells (3).…”

“…First, the exact nature of the antigens that drive this process is unknown. Moreover, the specific presence of these TCR alterations in ACPAϩ RA synovitis does not necessarily imply that the antigen should be citrullinated (3,(20)(21)(22).…”

“…One study demonstrated that a citrullinated peptide of vimentin binds with higher affinity than its native counterpart to HLA-DRB1*0401, *0404, and *0101 but not other HLA-DRB1 alleles (20), a theory supported by T cell reactivity to citrullinated epitopes in HLA-DR4-transgenic mice immunized with citrullinated human fibrinogen (21). In contrast, however, extensive studies with fibrinogen peptides could not confirm that citrullination influences the HLA-DR binding or the T cell reactivity in human RA (22). Alternatively, T cells may recognize a noncitrullinated epitope of a protein complex in which a distinct citrullinated part is recognized by the B cell receptor, allowing adequate antigen-specific collaboration between T cells and B cells (3).…”

Shared genetics in coeliac disease and other immune-mediated diseases

“…The HLA genes responsible for these other diseases can have different structural motifs that bind different epitope triggers [22,30]. For example, it is well known that the haplotypes DRB1*0301-DQA1*0501-DQB1*0201, DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB*0302 and DRB1*0402-DQA1* 0301-DQB1*0302 carry a high risk for T1D in Caucasian populations (Table 1) [31].…”

“…For example, it is well known that the haplotypes DRB1*0301-DQA1*0501-DQB1*0201, DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB*0302 and DRB1*0402-DQA1* 0301-DQB1*0302 carry a high risk for T1D in Caucasian populations (Table 1) [31]. In the case of RA, the major alleles are HLA-DRB1*0401, DRB1*0404, DRB1*0405 and DRB1*0408 [30]. However, in some populations, such as the Spanish and Indians, DQ8 and DR4 have been found to be predominantly associated with RA with an increased frequency of DQ7 amongst affected individuals [32].…”