Phuc V T-D, Kang M G, Kim H, Ko Y K, Acharya S, Kim E B, Park J-Y, Chang S-H, Kim H-J, Yoon H-J, Choi Y
Department of Immunology and Molecular Microbiology in Dental Science, Seoul National University School of Dentistry, Seoul, Republic of Korea.
University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh, Vietnam.
J Dent Res. 2025 Mar;104(3):320-329. doi: 10.1177/00220345241304760. Epub 2024 Dec 23.
Oral lichen planus (OLP) is a chronic T cell-mediated inflammatory mucosal disease of unknown etiology. The lack of suitable animal models has hampered understanding of its etiopathogenesis. This study aimed to clarify the contribution of bacterial infection and zinc deficiency (ZD) in OLP pathogenesis by developing a murine model. Infection of human oral keratinocytes with OLP-isolated 7.2 in the presence of a zinc chelator increased the intracellular survival of , likely due to the mitigation of zinc poisoning. C57BL/6 female mice were subjected to either a standard diet or a zinc-deficient diet for 1 mo. Their labial mucosa was then microdamaged through scratching, followed by oral administration of 7.2. Scratching alone triggered bacterial translocation to the epithelium and lamina propria, upregulated , increased immune responses in the cervical lymph nodes, and amplified CD4 T-cell recruitment to labial mucosae. All these responses were intensified by infection, showing a strong synergism with ZD that shifted the Th cells infiltrating the labial mucosa in response to infection from Th1 to Th17 dominance. Repeated scratching plus infection amplified T-cell recruitment, even without ZD, leading to patchy lymphocytic infiltration, characterized by the presence of colloid bodies and disrupted basement membranes. Interestingly, Th1 blockade with anti-IFNγ and anti-IL-12 antibodies during infection hindered bacterial clearance in the epithelium and caused intense T-cell infiltration, epithelial degeneration and necrosis with colloid bodies, basement membrane destruction, and epithelial detachment, similar to erosive OLP lesions. This suggests that the Th1/IFNγ pathway may not be a suitable therapeutic target for OLP. In conclusion, OLP-like histopathology in the oral mucosa was induced through infection when combined with ZD, repeated epithelial microdamage, or Th1 blockade. This animal model provides a valuable platform for exploring specific hypotheses related to OLP pathogenesis and potential therapeutic targets.
口腔扁平苔藓（OLP）是一种病因不明的慢性T细胞介导的炎症性黏膜疾病。缺乏合适的动物模型阻碍了对其发病机制的理解。本研究旨在通过建立一种小鼠模型来阐明细菌感染和锌缺乏（ZD）在OLP发病机制中的作用。在锌螯合剂存在的情况下，用OLP分离株7.2感染人口腔角质形成细胞可增加其细胞内存活率，这可能是由于锌中毒的减轻。将C57BL/6雌性小鼠分为标准饮食组或缺锌饮食组1个月。然后通过刮擦对其唇黏膜造成微损伤，随后口服7.2。单独刮擦可引发细菌向上皮和固有层的移位，上调相关指标，增加颈部淋巴结的免疫反应，并扩大CD4 T细胞向唇黏膜的募集。所有这些反应在感染后均增强，显示出与ZD有强烈的协同作用，使因感染而浸润唇黏膜的Th细胞从Th1优势转变为Th17优势。即使没有ZD，反复刮擦加感染也会扩大T细胞募集，导致斑片状淋巴细胞浸润，其特征为存在胶样小体和基底膜破坏。有趣的是，在感染期间用抗IFNγ和抗IL-12抗体阻断Th1会阻碍上皮内细菌清除，并导致强烈的T细胞浸润、上皮变性和坏死伴胶样小体形成、基底膜破坏和上皮脱落，类似于糜烂性OLP病变。这表明Th1/IFNγ途径可能不是OLP的合适治疗靶点。总之，当与ZD、反复上皮微损伤或Th1阻断相结合时，通过感染可诱导口腔黏膜出现类似OLP的组织病理学变化。该动物模型为探索与OLP发病机制相关的特定假说和潜在治疗靶点提供了一个有价值的平台。
