Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan.
Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba 274-8510, Japan.
Int J Mol Sci. 2021 Sep 19;22(18):10125. doi: 10.3390/ijms221810125.
Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by dysfunction of salivary and lacrimal glands, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Autoantibodies, such as anti-SSA and anti-SSB antibodies, are hallmarks and important diagnostic factors for SS. In our previous study, we demonstrated that SS-like xerostomia was observed in SATB1 conditional knockout (SATB1cKO) mice, in which the floxed SATB1 gene was specifically deleted in hematopoietic cells as early as 4 weeks of age. In these mice, autoantibodies were not detected until 8 weeks of age in SATB1cKO mice, although exocrine gland function reached its lowest at this age. Therefore, other markers may be necessary for the diagnosis of SS in the early phase. Here, we found that mRNA expression of the () gene and the IFN-responsive () gene is upregulated in the salivary glands of SATB1cKO mice after 3 and 4 weeks of age, respectively. We detected l-kynurenine (l-KYN), an intermediate of l-tryptophan (l-Trp) metabolism mediated by IDO, in the serum of SATB1cKO mice after 4 weeks of age. In addition, the upregulation of IDO expression was significantly suppressed by the administration of IFN-γ neutralizing antibodies in SATB1cKO mice. These results suggest that the induction of IFN-dependent IDO expression is an initial event that occurs immediately after the onset of SS in SATB1cKO mice. These results also imply that serum l-KYN could be used as a marker for SS diagnosis in the early phases of the disease before autoantibodies are detectable.
干燥综合征（SS）是一种慢性自身免疫性疾病，其特征为唾液腺和泪腺功能障碍，导致口干（口干）和干燥性角结膜炎（干眼症）。自身抗体，如抗 SSA 和抗 SSB 抗体，是 SS 的标志和重要诊断因素。在我们之前的研究中，我们证明了 SATB1 条件性敲除（SATB1cKO）小鼠中观察到类似于 SS 的口干，其中 floxed SATB1 基因早在 4 周龄时就在造血细胞中特异性缺失。在这些小鼠中，尽管在外分泌腺功能在这个年龄达到最低水平，但直到 8 周龄才检测到自身抗体。因此，其他标志物可能是 SS 早期诊断所必需的。在这里，我们发现 SATB1cKO 小鼠的唾液腺中，在 3 周和 4 周龄后，基因和 IFN 反应性基因的 mRNA 表达分别上调。我们在 SATB1cKO 小鼠的血清中检测到 l-犬尿氨酸（l-KYN），这是 IDO 介导的 l-色氨酸（l-Trp）代谢的中间产物。此外，在 SATB1cKO 小鼠中，IFN-γ中和抗体的给药显著抑制了 IDO 表达的上调。这些结果表明，IFN 依赖性 IDO 表达的诱导是 SATB1cKO 小鼠 SS 发病后立即发生的初始事件。这些结果还暗示，在可检测到自身抗体之前，血清 l-KYN 可作为 SS 早期诊断的标志物。
