芬兰坦佩雷大学Keijo Viiri及其合作者近期取得重要工作进展。他们研究分析了应用转谷氨酰胺酶2抑制剂预防谷蛋白诱导的乳糜泻肠道损伤后的肠道转录组学。相关研究成果2024年6月24日在线发表于《自然—免疫学》杂志上。

据介绍，转谷氨酰胺酶2（TG2）通过对饮食中的谷蛋白肽进行脱酰胺，促进抗原呈递和强烈的抗谷蛋白T细胞反应，在乳糜泻（CeD）的发病机制中发挥着关键作用。

研究人员通过对长期无谷蛋白饮食的CeD患者的十二指肠活检进行转录分析，阐明了TG2抑制剂ZED1227疗效的分子机制，这些患者在6周的谷蛋白挑战与每天100 mg ZED1227或安慰剂相结合之前和之后。在转录组水平上，口服ZED1227有效地预防了谷蛋白诱导的肠道损伤和炎症，提供了分子水平的证据，证明TG2抑制是治疗CeD的有效策略。ZED1227治疗将与粘膜形态、炎症、细胞分化和营养吸收相关的转录组特征保留到无谷蛋白饮食组的水平。近一半的谷蛋白诱导的CeD基因表达变化与上皮干扰素-γ反应有关。

此外，数据表明，脱酰胺谷蛋白诱导的适应性免疫足以为CeD的发病机制奠定基础。在样本量有限的情况下，这一研究结果还表明，CeD患者可能受益于基于基因剂量的HLA-DQ2/HLA-DQ8分层，以最大限度地消除由给谷蛋白引发的干扰素-γ诱导的粘膜损伤。

附：英文原文

Title: Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease

Author: Dotsenko, Valeriia, Tewes, Bernhard, Hils, Martin, Pasternack, Ralf, Isola, Jorma, Taavela, Juha, Popp, Alina, Sarin, Jani, Huhtala, Heini, Hiltunen, Pauliina, Zimmermann, Timo, Mohrbacher, Ralf, Greinwald, Roland, Lundin, Knut E. A., Schuppan, Detlef, Mki, Markku, Viiri, Keijo

Issue&Volume: 2024-06-24

Abstract: Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.

DOI: 10.1038/s41590-024-01867-0

Source: https://www.nature.com/articles/s41590-024-01867-0