Scholand Kaitlin K, Galletti Jeremias, Haap Wolfgang, Santos-Ferreira Tiago, Ullmer Christoph, de Paiva Cintia S
Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States.
Department of BioSciences, Rice University, Houston, Texas, United States.
Invest Ophthalmol Vis Sci. 2024 Jul 1;65(8):26. doi: 10.1167/iovs.65.8.26.
CD25KO mice are a model of Sjögren disease (SjD) driven by autoreactive T cells. Cathepsin S (CTSS) is a protease crucial for major histocompatibility complex class II presentation that primes T cells. We investigated if a diet containing CTSS inhibitor would improve autoimmune signs in CD25KO mice.
Four-week female CD25KO mice were randomly chosen to receive chow containing a CTSS inhibitor (R05461111, 262.5 mg/kg chow) or standard chow for 4 weeks. Cornea sensitivity was measured. Inflammatory score was assessed in lacrimal gland (LG) histologic sections. Flow cytometry of LG and ocular draining lymph nodes (dLNs) investigated expression of Th1 and Th17 cells. Expression of inflammatory, T- and B-cell, and apoptotic markers in the LG were assessed with quantitative PCR. The life span of mice receiving CTSS inhibitor or standard chow was compared. CD4+ T cells from both groups were isolated from spleens and adoptively transferred into RAG1KO female recipients.
Mice receiving CTSS inhibitor had better cornea sensitivity and improved LG inflammatory scores. There was a significant decrease in the frequency of CD4+ immune cells and a significant increase in the frequency of CD8+ immune cells in the dLNs of CTSS inhibitor mice. There was a significant decrease in Th1 and Th17 cells in CTSS inhibitor mice in both LGs and dLNs. Ifng, Ciita, and Casp8 mRNA in CTSS inhibitor mice decreased. Mice that received the CTSS inhibitor lived 30% longer. Adoptive transfer recipients with CTSS inhibitor-treated CD4+ T cells had improved cornea sensitivity and lower inflammation scores.
Inhibiting CTSS could be a potential venue for the treatment of SjD in the eye and LG.
CD25基因敲除小鼠是由自身反应性T细胞驱动的干燥综合征（SjD）模型。组织蛋白酶S（CTSS）是一种对主要组织相容性复合体II类呈递至关重要的蛋白酶，该呈递过程可启动T细胞。我们研究了含有CTSS抑制剂的饮食是否会改善CD25基因敲除小鼠的自身免疫症状。
随机选择4周龄的雌性CD25基因敲除小鼠，使其接受含有CTSS抑制剂（R05461111，262.5毫克/千克食物）的食物或标准食物，持续4周。测量角膜敏感性。在泪腺（LG）组织切片中评估炎症评分。通过流式细胞术检测LG和眼引流淋巴结（dLN）中Th1和Th17细胞的表达。用定量PCR评估LG中炎症、T细胞、B细胞和凋亡标志物的表达。比较接受CTSS抑制剂或标准食物的小鼠的寿命。从两组小鼠的脾脏中分离出CD4+ T细胞，并过继转移到RAG1基因敲除的雌性受体小鼠体内。
接受CTSS抑制剂的小鼠角膜敏感性更好，LG炎症评分有所改善。CTSS抑制剂处理的小鼠的dLN中，CD4+免疫细胞频率显著降低，CD8+免疫细胞频率显著增加。CTSS抑制剂处理的小鼠的LG和dLN中，Th1和Th17细胞均显著减少。CTSS抑制剂处理的小鼠中Ifng、Ciita和Casp8 mRNA水平降低。接受CTSS抑制剂的小鼠寿命延长了30%。接受CTSS抑制剂处理的CD4+ T细胞过继转移的受体小鼠角膜敏感性提高，炎症评分降低。
抑制CTSS可能是治疗眼部和LG干燥综合征的一个潜在途径。
