Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
J Oral Pathol Med. 2022 Aug;51(7):674-677. doi: 10.1111/jop.13330. Epub 2022 Jul 12.
Oral and ocular dryness due to reduced saliva and tear production, exocrine gland inflammation, and autoantibodies to multiple cellular proteins are the cardinal features of Sjögren's Disease. Among the autoantibody specificities, anti-Ro52 is linked with higher disease severity. We have previously reported that mice immunized with recombinant Ro52 developed IgG deposits in salivary and lacrimal glands and showed reduced saliva and tear production. Furthermore, passive transfer of sera from Ro52-immunized mice rapidly induced glandular dysfunction without immune cell infiltration in recipient mice.
To identify mechanisms driving antibody-mediated salivary gland dysfunction, hyperimmune rabbit antiserum to mouse Ro52 was passively transferred into NZM2758 female mice, pretreated with alum adjuvant. Alum-pretreated mice given hyperimmune rabbit antiserum to maltose-binding protein served as controls. Antibody deposition and its distribution in the salivary glands were studied by immunofluorescence staining for rabbit IgG, nerve fibers, and endothelial cells. The nCounter inflammation panel was used to determine differentially expressed genes in the salivary gland.
Rabbit IgG deposits were detected in salivary glands of anti-Ro52 immune sera recipients. The rabbit IgG was present on the endothelial cells in small blood vessels, and it did not co-localize with nerve fibers. Ingenuity pathway analysis of the gene expression dataset predicted the canonical vascular endothelial growth factor (VEGF) pathway as the most activated and Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) as the most inhibited pathway in the salivary glands of anti-Ro52 sera recipients.
Our study suggests that autoantibody deposition on salivary gland endothelial cells might play a critical role in the pathogenesis of Sjögren's Disease.
由于唾液和泪液产生减少、外分泌腺炎症以及针对多种细胞蛋白的自身抗体，导致口干和眼干，这是干燥综合征的主要特征。在自身抗体特异性中，抗 Ro52 与更高的疾病严重程度相关。我们之前报道过，用重组 Ro52 免疫的小鼠在唾液腺和泪腺中产生 IgG 沉积，并表现出唾液和泪液产生减少。此外，来自 Ro52 免疫小鼠的被动转移血清可在受体小鼠中迅速诱导腺体功能障碍，而不伴有免疫细胞浸润。
为了确定驱动抗体介导的唾液腺功能障碍的机制，将高免疫兔抗 Ro52 血清被动转移到用明矾佐剂预处理的 NZM2758 雌性小鼠中。用高免疫兔抗麦芽糖结合蛋白血清预处理的小鼠作为对照。通过免疫荧光染色检测兔 IgG、神经纤维和内皮细胞，研究抗体在唾液腺中的沉积及其分布。使用 nCounter 炎症面板确定唾液腺中差异表达的基因。
在抗 Ro52 免疫血清受体的唾液腺中检测到兔 IgG 沉积。兔 IgG 存在于小血管的内皮细胞上，与神经纤维不共存。对基因表达数据集的 ingenuity 通路分析预测，经典的血管内皮生长因子 (VEGF) 通路是抗 Ro52 血清受体的唾液腺中最活跃的通路，而磷酸酶和张力蛋白同源物缺失 10 号染色体（PTEN）是最受抑制的通路。
我们的研究表明，自身抗体在唾液腺内皮细胞上的沉积可能在干燥综合征的发病机制中起关键作用。
