Nephrology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Spain.
IDIBELL, Barcelona, Spain.
RMD Open. 2024 Nov 13;10(4):e004660. doi: 10.1136/rmdopen-2024-004660.
The PD-1 axis promotes protection against autoimmunity. Immune checkpoint (IC) molecules performance in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unknown. This study aims to assess the IC pathway's role in the AAV's pathophysiology.
We recruited 88 AAV from our centre as a discovery cohort (acute=42, remission=46) and 30 patients from another institution for external validation (acute=16, remission=14).Serum, urine and peripheral blood mononuclear cells (PBMCs) were collected. In vitro IC molecules production by lymphocytes was studied with and without MPO/PR3 antigen stimulus. Cell culture supernatant (SN) was obtained by centrifugation. PD-1, PD-L1 and PD-L2 concentrations were assessed in serum (s), urine (u) and SN of AAV and healthy controls (HC) using a multiplex assay. PD-1 and PD-L1's expression was analysed in six diagnostic kidney biopsies.
uPD-1 and uPD-L2's concentration was lower in AAV than HC (p<0.0001, p=0.0075). Acute patients exhibited lower uPD-L2 levels compared with those in remission (p=0.036). Similarly, PBMCs showed reduced PD-1 production than HC (stimulated group p=0.04, unstimulated p=0.0074). Furthermore, patients with inflammatory renal lesions had fewer PD-1-positive interstitial cells/staining intensity compared with those with sclerotic lesions. Contradictorily, sPD-1 and sPD-L1's concentration was higher in AAV than HC (p=0.007, p<0.0001) with acute patients exhibiting elevated sPD-1 levels compared with those in remission (p=0.0051). Serum and urine findings were confirmed in the validation cohort.
Results in urine, SN and histology suggest IC pathway abolition during acute disease restored in remission and contribute to understand PD-1 axis's role in AAV proposing it as a new biomarker of disease activity.
PD-1 轴促进自身免疫保护。免疫检查点 (IC) 分子在抗中性粒细胞胞质抗体相关性血管炎 (AAV) 中的作用尚不清楚。本研究旨在评估 IC 通路在 AAV 病理生理学中的作用。
我们招募了来自我们中心的 88 例 AAV 作为发现队列（急性期=42 例，缓解期=46 例），并从另一家机构招募了 30 例患者进行外部验证（急性期=16 例，缓解期=14 例）。收集血清、尿液和外周血单核细胞（PBMC）。研究了淋巴细胞在有和没有 MPO/PR3 抗原刺激时的 IC 分子产生情况。通过离心获得细胞培养上清液（SN）。使用多重分析评估 AAV 和健康对照（HC）血清（s）、尿液（u）和 SN 中的 PD-1、PD-L1 和 PD-L2 浓度。分析了六例诊断性肾活检的 PD-1 和 PD-L1 表达。
与 HC 相比，AAV 的 uPD-1 和 uPD-L2 浓度较低（p<0.0001，p=0.0075）。急性期患者的 uPD-L2 水平低于缓解期患者（p=0.036）。同样，与 HC 相比，PBMC 产生的 PD-1 减少（刺激组 p=0.04，未刺激组 p=0.0074）。此外，与硬化性病变相比，有炎症性肾病变的患者间质细胞的 PD-1 阳性细胞/染色强度较少。相反，与 HC 相比，AAV 的 sPD-1 和 sPD-L1 浓度较高（p=0.007，p<0.0001），且急性期患者的 sPD-1 水平高于缓解期患者（p=0.0051）。验证队列证实了血清和尿液结果。
尿液、SN 和组织学结果表明，急性期疾病中 IC 通路的消除在缓解期得到恢复，并有助于了解 PD-1 轴在 AAV 中的作用，提出其作为疾病活动的新生物标志物。
