Immunological Interaction of HLA-DPB1 and Proteinase 3 in ANCA Vasculitis is Associated with Clinical Disease Activity.

BACKGROUND

PR3-ANCA vasculitis has a genetic association with HLA-DPB1. We explored immunologic and clinical features related to the interaction of HLA-DPB1*04:01 with a strongly binding PR3 peptide epitope (PR3).

METHODS

Patients with ANCA vasculitis with active disease and disease in remission were followed longitudinally. Peripheral blood mononuclear cells from patients and healthy controls with HLA-DPB104:01 were tested for HLA-DPB104:01 expression and interaction with a PR3 peptide identified and assays. Tetramers (HLA/peptide multimers) identified autoreactive T cells RESULTS: The HLA-DPB104:01 genotype was associated with risk of relapse in PR3-ANCA (HR for relapse 2.06; 95% CI, 1.01 to 4.20) but not in myeloperoxidase (MPO)-ANCA or the combined cohort. predictions of HLA and PR3 peptide interactions demonstrated strong affinity between ATRLFPDFFTRVALY (PR3) and HLA-DPB104:01 that was confirmed by competitive binding studies. The interaction was tested in flow cytometry studies of labeled peptide and HLA-DPB1*04:01-expressing cells. We demonstrated PR3 specific autoreactive T cells using synthetic HLA multimers (tetramers). Patients in long-term remission off therapy had autoantigenic peptide and HLA interaction comparable to that of healthy volunteers.

CONCLUSIONS

The risk allele HLA-DPB104:01 has been associated with PR3-ANCA, but its immunopathologic role was unclear. These studies demonstrate that HLA-DPB104:01 and PR3 initiate an immune response. Autoreactive T cells specifically recognized PR3 presented by HLA-DPB1*04:01. Although larger studies should validate these findings, the pathobiology may explain the observed increased risk of relapse in our cohort. Moreover, lack of HLA and autoantigen interaction observed during long-term remission signals immunologic nonresponsiveness.