Allergan, Inc, Biological Sciences, Inflammation Research Program, Irvine, California 92612, USA.
Invest Ophthalmol Vis Sci. 2012 Apr 24;53(4):2062-75. doi: 10.1167/iovs.11-9299.
The purpose of this study was to determine if autoantibodies play a role in the immunopathogenesis of experimental dry eye disease.
Dry eye was induced by exposing female C57BL/6 wild-type mice or hen egg lysozyme B-cell receptor transgenic mice to desiccating stress (subcutaneous scopolamine [0.5 mg/0.2 mL] 3 times a day, humidity < 40%, and sustained airflow) for 3 weeks, allowing sufficient time for a humoral immune response. Serum or purified IgG isolated from dry-eye mice or untreated controls was passively transferred to nude recipient mice, which were evaluated for ocular surface inflammation 3 days after transfer. To determine if complement activation contributed to serum-induced dry eye disease, cobra venom factor was used to deplete complement activity.
Autoantibodies against kallikrein 13 were identified in serum from dry-eye mice, but were undetectable in untreated controls. Autoantibody-containing serum or purified IgG from dry-eye mice was sufficient to mediate complement-dependent ocular surface inflammation. Serum or purified IgG caused marked inflammatory burden and tissue damage within the ocular surface tissues, including elevated Gr1+ neutrophil infiltration and proinflammatory cytokines/chemokines associated with goblet cell loss. Moreover, complement C3b deposition was found within the ocular surface tissues of mice receiving dry-eye serum, but not in recipients of control serum. Functionally, complement depletion attenuated the ability to transfer dry-eye-specific serum or IgG-mediated disease.
These data demonstrate for the first time a complement-dependent pathogenic role of dry-eye-specific autoantibodies, and suggest autoantibody deposition within the ocular surface tissues contributes to the predominantly T-cell-mediated immunopathogenesis of dry eye disease.
本研究旨在确定自身抗体是否在实验性干眼疾病的免疫发病机制中起作用。
通过对雌性 C57BL/6 野生型小鼠或鸡卵溶菌酶 B 细胞受体转基因小鼠进行干燥应激（每天皮下注射东莨菪碱[0.5mg/0.2mL]3 次，湿度<40%，持续气流）3 周，使体液免疫反应有足够的时间来诱导干眼。将来自干眼小鼠或未经处理对照的血清或纯化 IgG 被动转移到裸受体小鼠中，在转移后 3 天评估眼表炎症。为了确定补体激活是否导致血清诱导的干眼病，使用眼镜蛇毒因子耗尽补体活性。
在干眼小鼠的血清中鉴定出针对激肽释放酶 13 的自身抗体，但在未经处理的对照中未检测到。来自干眼小鼠的含自身抗体的血清或纯化 IgG 足以介导补体依赖性眼表炎症。血清或纯化 IgG 导致眼表面组织中的炎症负担和组织损伤明显增加，包括 Gr1+中性粒细胞浸润和与杯状细胞丢失相关的促炎细胞因子/趋化因子。此外，在接受干眼血清的小鼠的眼表面组织中发现了补体 C3b 沉积，但在接受对照血清的小鼠中没有。功能上，补体耗竭减弱了转移干眼特异性血清或 IgG 介导疾病的能力。
这些数据首次证明了干眼特异性自身抗体的补体依赖性致病作用，并表明自身抗体在眼表面组织中的沉积有助于干眼病主要以 T 细胞介导的免疫发病机制。
