Serena G, Yan S, Camhi S, Patel S, Lima R S, Sapone A, Leonard M M, Mukherjee R, Nath B J, Lammers K M, Fasano A
Massachusetts General Hospital and Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Boston, MA, USA.
Graduate Program in Life Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
Clin Exp Immunol. 2017 Mar;187(3):490-506. doi: 10.1111/cei.12911. Epub 2017 Jan 12.
Coeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (T ) are CD4 CD25 forkhead box protein 3 (FoxP3 ) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 Δ2, cannot properly down-regulate the Th17-driven immune response. As the active state of CD has been associated with impairments in T cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 Δ2 isoform over FL, while both isoforms were expressed similarly in non-coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate-producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)-γ and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial-derived metabolites.
乳糜泻（CD）是一种由麸质引发的自身免疫性肠病，其特征是小肠中存在强烈的1型辅助性T细胞（Th1）/Th17免疫反应。调节性T细胞（Treg）是CD4+CD25+叉头框蛋白3（FoxP3+）细胞，可调节免疫反应。与全长FoxP3（FL）相反，可变剪接异构体FoxP3Δ2不能正常下调由Th17驱动的免疫反应。由于CD的活跃状态与T细胞功能受损有关，我们旨在确定FoxP3异构体之间的失衡是否可能与该疾病相关。活动性CD患者的肠道活检显示，FOXP3Δ2异构体的表达相对于FL有所增加，而在非乳糜泻对照受试者（HC）中，两种异构体的表达相似。与我们在肠道中看到的情况相反，HC受试者的外周血单个核细胞（PBMC）中异构体之间并未表现出相同的平衡。因此，我们推测肠道微环境可能在调节可变剪接中发挥作用。据报道，活动性患者的促炎性肠道微环境中富含产丁酸细菌，而高浓度的乳酸已被证明是该疾病临床前期的特征。我们发现，干扰素（IFN）-γ和丁酸盐的组合可触发HC受试者中FoxP3异构体之间的平衡，而CD患者中则不会出现这种情况。此外，我们报告乳酸会增加CD患者中两种异构体的表达。总的来说，这些发现突出了CD中FoxP3异构体比例的重要性，并首次将可变剪接过程与微生物衍生的代谢产物建立了机制联系。
