Yeh S, de Paiva C S, Hwang C S, Trinca K, Lingappan A, Rafati J K, Farley W J, Li D-Q, Pflugfelder S C
Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA.
Br J Ophthalmol. 2009 Sep;93(9):1260-4. doi: 10.1136/bjo.2008.153700. Epub 2009 May 7.
BACKGROUND/AIMS: Patients with autoimmune polyendocrinopathy-candiasis-ectodermal dystrophy (APECED) develop severe keratoconjunctivitis, corneal scarring and visual loss, but the precise pathogenesis is unknown. This study evaluated the ocular surface immune cell environment, conjunctival goblet cell density and response to desiccating environmental stress of the autoimmune regulatory (Aire) gene knockout murine model of APECED.
Aire-deficient and wild type (WT) mice were subjected to desiccating stress from a drafty, low-humidity environment and pharmacological inhibition of tear secretion for 5 days. Immune cell populations (CD4(+), CD8(+), CD11b(+), CD45(+)) and goblet cell density were measured in ocular surface tissues and meibomian glands, and compared with baseline values.
Greater CD4(+) T cell populations were observed in the conjunctival epithelium of Aire-deficient mice (p<0.001) compared with WT. Aire-deficient mice also had greater numbers of CD4(+), CD8(+), and CD11b(+) cells in the peripheral cornea at baseline and following desiccating stress. The meibomian glands of Aire-deficient mice demonstrated greater CD4(+), CD8(+), CD45(+) and CD11b(+) cells at baseline (p<0.001) and following desiccating stress. Conjunctival goblet cell density was lower at baseline and following desiccating stress in Aire-deficient compared with WT mice (p<0.001).
Aire-deficiency leads to infiltration of CD4(+) and CD8(+) T cells on the ocular surface and meibomian glands, which is accompanied by goblet cell loss. Desiccating stress promotes this proinflammatory milieu. Immune-mediated mechanisms play a role in the severe blepharitis and keratoconjunctivitis in the murine model of APECED.
背景/目的：自身免疫性多内分泌腺病-念珠菌病-外胚层营养不良（APECED）患者会出现严重的角结膜炎、角膜瘢痕形成和视力丧失，但其确切发病机制尚不清楚。本研究评估了APECED的自身免疫调节（Aire）基因敲除小鼠模型的眼表免疫细胞环境、结膜杯状细胞密度以及对干燥环境应激的反应。
将Aire缺陷型和野生型（WT）小鼠置于通风、低湿度的干燥环境中，并进行为期5天的泪液分泌药理学抑制。测量眼表组织和睑板腺中的免疫细胞群体（CD4(+)、CD8(+)、CD11b(+)、CD45(+)）和杯状细胞密度，并与基线值进行比较。
与WT相比，Aire缺陷型小鼠结膜上皮中的CD4(+) T细胞群体更多（p<0.001）。在基线和干燥应激后，Aire缺陷型小鼠周边角膜中的CD4(+)、CD8(+)和CD11b(+)细胞数量也更多。Aire缺陷型小鼠的睑板腺在基线时（p<0.001）和干燥应激后显示出更多的CD4(+)、CD8(+)、CD45(+)和CD11b(+)细胞。与WT小鼠相比，Aire缺陷型小鼠在基线和干燥应激后的结膜杯状细胞密度较低（p<0.001）。
Aire缺陷导致眼表和睑板腺中CD4(+)和CD8(+) T细胞浸润，并伴有杯状细胞丢失。干燥应激促进了这种促炎环境。免疫介导机制在APECED小鼠模型的严重睑缘炎和角结膜炎中起作用。
