Mercanoglu Baris, Schraps Nina, Giannou Anastasios D, Neuburg Elena, Kempski Jan, Wagener Christoph, Melling Nathaniel, Bockhorn Maximilian, Hackert Thilo, Wolters-Eisfeld Gerrit
Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Sci Rep. 2025 Apr 2;15(1):11306. doi: 10.1038/s41598-025-96060-0.
Altered O-glycosylation is a key contributor to various pathophysiological processes. Notably, the expression of the Tn antigen is primarily attributed to dysfunction of the chaperone Cosmc, while the overexpression of polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) has also been implicated in numerous diseases. We generated a transgenic mouse model with conditional Cosmc-knockout and simultaneous overexpression of polypeptide N-acetylgalactosaminyltransferase 2 (GalNT2) mediated by the pancreas-specific transcription factor 1a (Ptf1a)-Cre mouse strain to investigate the effect of Tn antigen overexpression on the pancreas in vivo. Histopathological examination of the transgenic pancreas revealed a chronic pancreatitis phenotype with interlobular fibrosis and focal necrosis after only a few weeks as a result of Tn antigen overexpression. In the later stages, there was a progressive loss of pancreatic parenchyma with consecutive exocrine pancreatic insufficiency and malnutrition in the transgenic mice. Flow cytometric analyses have also confirmed that significant infiltration of immune cells occurs in the course of pancreatitis. In the transgenic mouse model presented here, we demonstrated that overexpression of the Tn antigen in the pancreas results in chronic pancreatitis, highlighting the pathophysiological importance of truncated O-glycosylation.
O-糖基化改变是多种病理生理过程的关键促成因素。值得注意的是，Tn抗原的表达主要归因于伴侣蛋白Cosmc功能障碍，而多肽N-乙酰半乳糖胺基转移酶（GalNAc-Ts）的过表达也与多种疾病有关。我们构建了一种转基因小鼠模型，该模型通过胰腺特异性转录因子1a（Ptf1a）-Cre小鼠品系介导条件性Cosmc基因敲除并同时过表达多肽N-乙酰半乳糖胺基转移酶2（GalNT2），以研究Tn抗原过表达对胰腺的体内影响。对转基因胰腺的组织病理学检查显示，由于Tn抗原过表达，仅几周后就出现了伴有小叶间纤维化和局灶性坏死的慢性胰腺炎表型。在后期，转基因小鼠胰腺实质逐渐丧失，继而出现外分泌性胰腺功能不全和营养不良。流式细胞术分析也证实，在胰腺炎过程中会发生免疫细胞的大量浸润。在此展示的转基因小鼠模型中，我们证明胰腺中Tn抗原的过表达会导致慢性胰腺炎，突出了截短型O-糖基化的病理生理重要性。
