Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
J Hepatol. 2021 Jan;74(1):48-57. doi: 10.1016/j.jhep.2020.06.044. Epub 2020 Jul 11.
BACKGROUND & AIMS: In autoimmune hepatitis (AIH), the imbalance between regulatory T cells (Tregs) and T-helper type 17 (Th17) cells has been linked to low levels of CD39, an ectoenzyme that hydrolyses ATP, ultimately generating immunosuppressive adenosine. Upregulation of CD39 results from activation of aryl hydrocarbon receptor (AHR), which mediates toxin responses to modulate T-cell immunity. In this study, we investigated whether altered AHR signalling underlies defective CD39 expression and function in AIH Tregs and Th17 cells, therefore contributing to regulatory/effector cell imbalance.
Tregs and Th17 cells, obtained from the peripheral blood of 49 patients with AIH and 21 healthy individuals (HI), were tested for response to endogenous and exogenous AHR ligands.
When compared to those of HI, AIH-derived Tregs and Th17 cells displayed impaired responses to AHR activation, reflected by impaired upregulation of CD39, delayed increase in ectoenzymatic activity, and defective Treg suppressive function. These impairments resulted, at least in part, from heightened levels of AHRR and Erα in Tregs and high HIF-1α in Th17 cells, and were reverted upon molecular blockade. Importantly, in AIH-derived Tregs, the binding affinity of AHR was higher for Erα than ARNT.
In AIH, high levels of AHRR and HIF-1α inhibit AHR signalling in Tregs and Th17 cells. AHR non-canonical binding to Erα further amplifies the lack of effective CD39 upregulation. Blockade of these inhibitory and/or non-canonical activation pathways represents a potential therapeutic approach to restore CD39 and immunohomeostasis in AIH.
In patients with autoimmune hepatitis, the imbalance between regulatory T cells and T helper type-17 cells is linked to dysfunction of the aryl hydrocarbon receptor pathway, resulting from aberrant inhibition or non-canonical activation. These alterations impair Treg- and Th17 cell-induced upregulation of CD39, an ectoenzyme key to immunoregulation. Blockade of excessive inhibition or non-canonical activation of the aryl hydrocarbon receptor pathway might represent a novel therapeutic strategy to control inflammation while restoring immune balance in autoimmune hepatitis.
在自身免疫性肝炎（AIH）中，调节性 T 细胞（Tregs）和辅助性 T 细胞 17（Th17）之间的失衡与 CD39 水平降低有关，CD39 是一种水解三磷酸腺苷（ATP）的细胞外酶，最终产生免疫抑制腺苷。CD39 的上调源于芳烃受体（AHR）的激活，该受体介导毒素反应以调节 T 细胞免疫。在这项研究中，我们研究了 AIH Tregs 和 Th17 细胞中 AHR 信号转导的改变是否是 CD39 表达和功能缺陷的基础，从而导致调节/效应细胞失衡。
从 49 例 AIH 患者和 21 名健康个体（HI）的外周血中获得 Tregs 和 Th17 细胞，检测其对内源性和外源性 AHR 配体的反应。
与 HI 相比，AIH 来源的 Tregs 和 Th17 细胞对 AHR 激活的反应受损，表现为 CD39 的上调受损、细胞外酶活性的增加延迟以及 Treg 抑制功能缺陷。这些损伤至少部分是由于 Tregs 中 AHRR 和 Erα 水平升高和 Th17 细胞中 HIF-1α 升高所致，并在分子阻断后得到逆转。重要的是，在 AIH 来源的 Tregs 中，AHR 对 Erα 的结合亲和力高于 ARNT。
在 AIH 中，AHRR 和 HIF-1α 水平升高抑制 Tregs 和 Th17 细胞中的 AHR 信号转导。AHR 对 Erα 的非经典结合进一步放大了 CD39 有效上调的缺失。阻断这些抑制性和/或非经典激活途径可能是恢复 AIH 中 CD39 和免疫稳态的潜在治疗方法。
在自身免疫性肝炎患者中，调节性 T 细胞与辅助性 T 细胞 17 之间的失衡与芳烃受体途径的功能障碍有关，这是由于异常抑制或非经典激活所致。这些改变损害了 Treg 和 Th17 细胞诱导的 CD39 上调，CD39 是免疫调节的关键细胞外酶。阻断芳烃受体途径的过度抑制或非经典激活可能是一种新的治疗策略，可在控制炎症的同时恢复自身免疫性肝炎中的免疫平衡。
