Faleiro Rebecca, Liu Ji, Karunarathne Deshapriya, Edmundson Aleksandra, Winterford Clay, Nguyen Tam Hong, Simms Lisa A, Radford-Smith Graham, Wykes Michelle
Molecular Immunology Laboratory QIMR Berghofer Medical Research Institute Herston QLD Australia.
Gut Health Laboratory QIMR Berghofer Medical Research Institute Herston QLD Australia.
Clin Transl Immunology. 2019 Jul 25;8(7):e01071. doi: 10.1002/cti2.1071. eCollection 2019.
Crohn's disease (CD) is characterised by inflammation, predominantly associated with ilea. To investigate the basis for this inflammation in patients with CD, we examined dendritic cells (DC) which are pivotal for maintenance of immunological tolerance in the gut.
Ileal biopsies and blood DCs from CD patients and controls were examined by microscopy and flow cytometry for PD-L1 and PD-L2 expression, as PD-L1 has been implicated in colitis but the contribution of PD-L2 is less clear. studies, of blood samples from CD patients, were used to demonstrate a functional role for PD-L2 in disease pathogenesis.
Quantitative microscopy of CD11c DCs in inflamed and noninflamed ilea from CD patient showed > 75% loss of these cells from the villi, lamina propria and Peyer's patches compared with non-CD controls. Given this loss of DCs from ilia of CD patients, we hypothesised DCs may have migrated to the blood as these patients can have extra-intestinal symptoms. We thus examined blood DCs from CD patients by flow cytometry and found significant increases in PD-L1 and PD-L2 expression compared with control samples. Microscopy revealed an aggregated form of PD-L2 expression, known to drive Th1 immunity, in CD patients but not in controls. functional studies with PD-L2 blockade confirmed PD-L2 contributes significantly to the secretion of pro-inflammatory cytokines known to cause disease pathogenesis.
Taken together, this study shows that PD-L2 can influence the progression of CD and blockade of PD-L2 may have therapeutic potential.
克罗恩病（CD）的特征为炎症，主要累及回肠。为研究CD患者炎症的基础，我们检测了对维持肠道免疫耐受起关键作用的树突状细胞（DC）。
通过显微镜检查和流式细胞术检测CD患者及对照的回肠活检组织和血液DC中PD-L1和PD-L2的表达，因为PD-L1与结肠炎有关，但PD-L2的作用尚不清楚。对CD患者的血样进行研究，以证明PD-L2在疾病发病机制中的功能作用。
对CD患者发炎和未发炎回肠中的CD11c DC进行定量显微镜检查发现，与非CD对照相比，这些细胞在绒毛、固有层和派尔集合淋巴结中的损失超过75%。鉴于CD患者回肠中DC的这种损失，我们推测DC可能已迁移至血液中，因为这些患者可能有肠外症状。因此，我们通过流式细胞术检测了CD患者的血液DC，发现与对照样本相比，PD-L1和PD-L2的表达显著增加。显微镜检查显示，CD患者中存在已知可驱动Th1免疫的PD-L2聚集表达形式，而对照中未发现。用PD-L2阻断剂进行的功能研究证实，PD-L2对已知导致疾病发病机制的促炎细胞因子的分泌有显著贡献。
综上所述，本研究表明PD-L2可影响CD的进展，阻断PD-L2可能具有治疗潜力。
