Faucher Pauline, Beuvon Frédéric, Fignani Daniela, Sebastiani Guido, Afonso Georgia, Zhou Zhicheng, Dousset Bertrand, Boitard Christian, Dotta Francesco, Mallone Roberto, Larger Etienne
Institut Cochin, CNRS, Inserm, Université de Paris, Paris, France.
Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires de Paris Centre-Université de Paris, Paris, France.
Diabetologia. 2021 Dec;64(12):2731-2740. doi: 10.1007/s00125-021-05563-8. Epub 2021 Sep 14.
AIMS/HYPOTHESIS: We report the case of a woman who underwent a partial pancreatectomy for a serous cystadenoma when aged 56 years. She had been diagnosed with diabetes 6 years before and had Hashimoto's thyroiditis. Despite positive anti-GAD autoantibodies (GADA) and previous surgery, she was transiently weaned off long-acting insulin. Blood glucose levels remained well controlled with low-dose long-acting insulin. Insulin needs eventually increased 8 years after surgery, in conjunction with anti-zinc transporter 8 (ZnT8) seroconversion and decreasing residual C-peptide. We hypothesised that the surgical pancreas specimens and blood autoimmune T cell responses may provide correlates of this indolent clinical course.
Beta and alpha cell area and insulitis were quantified on pancreas head tissue sections obtained at surgery. Blood T cell responses against beta cell antigens were analysed by enzyme-linked immunospot.
Pancreas sections displayed reduced beta cell and normal alpha cell area (0.27% and 0.85% of section area, respectively). High-grade insulitis was observed, mostly in insulin-containing islets, with a peri-insulitis pattern enriched in T cells positive for regulatory forkhead box protein 3 (FOXP3). In vitro challenge with beta cell antigens of circulating T cells collected 4 and 9 years after surgery revealed dominant and persistent IL-10 responses; IFN-γ responses increasing at 9 years, after anti-ZnT8 seroconversion, was observed.
CONCLUSIONS/INTERPRETATION: Despite persistent GADA and the histopathological finding of insulitis and decreased beta cell area 6 years after diabetes diagnosis, glycaemic control was maintained with low-dose insulin up to 8 years after surgery. Regulated T cell responses towards beta cell antigens and FOXP3-positive peri-insulitis suggest spontaneous long-term regulation of islet autoimmunity after substantial beta cell loss, and eventual autoimmune progression upon anti-ZnT8 seroconversion.
目的/假设：我们报告了一例56岁女性因浆液性囊腺瘤接受部分胰腺切除术的病例。她6年前被诊断出患有糖尿病，并患有桥本甲状腺炎。尽管存在抗谷氨酸脱羧酶自身抗体（GADA）阳性且曾接受手术，但她曾短暂停用长效胰岛素。血糖水平通过低剂量长效胰岛素得以良好控制。术后8年胰岛素需求最终增加，同时出现抗锌转运体8（ZnT8）血清转化以及残余C肽减少。我们推测手术切除的胰腺标本和血液自身免疫性T细胞反应可能与这种隐匿的临床病程相关。
对手术时获取的胰头组织切片进行β细胞和α细胞面积以及胰岛炎的定量分析。通过酶联免疫斑点法分析血液中针对β细胞抗原的T细胞反应。
胰腺切片显示β细胞面积减少而α细胞面积正常（分别占切片面积的0.27%和0.85%）。观察到重度胰岛炎，主要存在于含胰岛素的胰岛中，呈现出富含调节性叉头框蛋白3（FOXP3）阳性T细胞的胰岛周围炎模式。术后4年和9年采集的循环T细胞经β细胞抗原体外刺激后显示出占主导且持续的白细胞介素-10反应；在抗ZnT8血清转化后9年观察到γ干扰素反应增加。
结论/解读：尽管糖尿病诊断6年后持续存在GADA以及胰岛炎的组织病理学表现和β细胞面积减少，但术后长达8年血糖控制通过低剂量胰岛素得以维持。对β细胞抗原的调节性T细胞反应以及FOXP3阳性胰岛周围炎表明，在大量β细胞丢失后胰岛自身免疫存在自发的长期调节，而抗ZnT8血清转化后最终出现自身免疫进展。
