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_225–239).

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-DPB1*04:01 were tested for HLA-DPB1*04:01 expression and interaction with a PR3 peptide identified via in silico and in vitro assays. Tetramers (HLA/peptide multimers) identified autoreactive T cells in vitro.

The HLA-DPB1*04:01 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. In silico predictions of HLA and PR3 peptide interactions demonstrated strong affinity between ATRLFPDFFTRVALY (PR3_225–239) and HLA-DPB1*04:01 that was confirmed by in vitro competitive binding studies. The interaction was tested in ex vivo flow cytometry studies of labeled peptide and HLA-DPB1*04:01-expressing cells. We demonstrated PR3_225–239 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.

The risk allele HLA-DPB1*04:01 has been associated with PR3-ANCA, but its immunopathologic role was unclear. These studies demonstrate that HLA-DPB1*04:01 and PR3_225–239 initiate an immune response. Autoreactive T cells specifically recognized PR3_225–239 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.

PR3-ANCA 血管炎与 HLA-DPB1 具有遗传相关性。_{我们探索了与 HLA-DPB1*04:01 与强结合 PR3 肽表位 (PR3 225–239}​​ )相互作用相关的免疫学和临床特征。

对患有活动性疾病和缓解期疾病的 ANCA 血管炎患者进行纵向随访。测试了带有 HLA-DPB1*04:01 的患者和健康对照的外周血单核细胞的 HLA-DPB1*04:01 表达以及与通过计算机和体外测定鉴定的 PR3 肽的相互作用。四聚体（HLA/肽多聚体）在体外鉴定出自身反应性 T 细胞。

HLA-DPB1*04:01 基因型与 PR3-ANCA 中的复发风险相关（复发 HR 2.06；95% CI，1.01 至 4.20），但与髓过氧化物酶 (MPO)-ANCA 或联合队列中的复发风险无关。HLA 和 PR3 肽相互作用的计算机预测表明 ATRLFPDFFTRVALY (PR3 _225–239​​ ) 和 HLA-DPB1*04:01 之间具有很强的亲和力，这一点已通过体外竞争性结合研究得到证实。在标记肽和表达 HLA-DPB1*04:01 的细胞的离体流式细胞术研究中测试了这种相互作用。我们使用合成 HLA 多聚体（四聚体）展示了 PR3 _{225-239特异性自身反应性 T 细胞。}长期缓解治疗的患者的自身抗原肽和 HLA 相互作用与健康志愿者相当。

风险等位基因 HLA-DPB1*04:01 与 PR3-ANCA 相关，但其免疫病理学作用尚不清楚。这些研究表明 HLA-DPB1*04:01 和 PR3 _225-239会启动免疫反应。自身反应性 T 细胞特异性识别HLA-DPB1*04:01 呈递的PR3 _{225–239 ​​。}尽管更大规模的研究应该验证这些发现，但病理学可以解释我们队列中观察到的复发风险增加。此外，长期缓解期间观察到的 HLA 和自身抗原相互作用的缺乏表明免疫无反应。