Department of Surgery, University Hospital Regensburg, Regensburg 93053, Germany.
Institute of Pathology, University of Regensburg, Regensburg 93053, Germany.
EBioMedicine. 2024 Jun;104:105184. doi: 10.1016/j.ebiom.2024.105184. Epub 2024 Jun 4.
The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) incurs substantial morbidity, mortality and healthcare costs. Detection and clinical intervention at early stages of disease improves prognosis; however, we are currently limited by a lack of reliable diagnostic tests for population screening and monitoring responses to therapy. To address this unmet need, we investigated human invariant Natural Killer T cell (iNKT) activation by fat-loaded hepatocytes, leading to the discovery that circulating soluble CD46 (sCD46) levels accurately predict hepatic steatosis.
sCD46 in plasma was measured using a newly developed immuno-competition assay in two independent cohorts: Prospective living liver donors (n = 156; male = 66, female = 90) and patients with liver tumours (n = 91; male = 58, female = 33). sCD46 levels were statistically evaluated as a predictor of hepatic steatosis.
Interleukin-4-secreting (IL-4) iNKT cells were over-represented amongst intrahepatic lymphocytes isolated from resected human liver samples. IL-4 iNKT cells preferentially developed in cocultures with a fat-loaded, hepatocyte-like cell line, HepaRG. This was attributed to induction of matrix metalloproteases (MMP) in fat-loaded HepaRG cells and primary human liver organoids, which led to indiscriminate cleavage of immune receptors. Loss of cell-surface CD46 resulted in unrepressed differentiation of IL-4 iNKT cells. sCD46 levels were elevated in patients with hepatic steatosis. Discriminatory cut-off values for plasma sCD46 were found that accurately classified patients according to histological steatosis grade.
sCD46 is a reliable clinical marker of hepatic steatosis, which can be conveniently and non-invasively measured in serum and plasma samples, raising the possibility of using sCD46 levels as a diagnostic method for detecting or grading hepatic steatosis.
F.B. was supported by the Else Kröner Foundation (Award 2016_kolleg.14). G.G. was supported by the Bristol Myers Squibb Foundation for Immuno-Oncology (Award FA-19-009). N.S. was supported by a Wellcome Trust Fellowship (211113/A/18/Z). J.A.H. received funding from the European Union's Horizon 2020 research and innovation programme (Award 860003). J.M.W. received funding from the Else Kröner Foundation (Award 2015_A10).
代谢功能障碍相关脂肪性肝病（MASLD）的患病率不断上升，导致发病率、死亡率和医疗保健费用大幅增加。在疾病早期发现并进行临床干预可改善预后；然而，目前我们缺乏可靠的诊断检测方法来进行人群筛查和监测治疗反应。为了满足这一未满足的需求，我们研究了脂肪负荷的肝细胞对人天然杀伤 T 细胞（iNKT）的激活作用，发现循环可溶性 CD46（sCD46）水平可准确预测肝脂肪变性。
使用新开发的免疫竞争测定法在两个独立队列中测量血浆中的 sCD46：前瞻性活体供肝者（n=156；男性=66，女性=90）和肝肿瘤患者（n=91；男性=58，女性=33）。统计评估 sCD46 水平作为肝脂肪变性的预测因子。
从切除的人肝样本中分离的肝内淋巴细胞中，IL-4 分泌型（IL-4）iNKT 细胞过度表达。IL-4 iNKT 细胞在与脂肪负荷的肝细胞样细胞系 HepaRG 的共培养物中优先发育。这归因于脂肪负荷的 HepaRG 细胞和原代人肝类器官中基质金属蛋白酶（MMP）的诱导，这导致免疫受体的无差别切割。细胞表面 CD46 的缺失导致 IL-4 iNKT 细胞不受抑制的分化。肝脂肪变性患者的 sCD46 水平升高。发现用于区分脂肪变性患者的 sCD46 检测的区分截断值，可根据组织学脂肪变性等级准确地对患者进行分类。
sCD46 是肝脂肪变性的可靠临床标志物，可方便地从血清和血浆样本中进行非侵入性测量，这增加了使用 sCD46 水平作为检测或分级肝脂肪变性的诊断方法的可能性。
F.B. 得到了艾尔·克罗纳基金会（2016 年奖）的支持。G.G. 得到了百时美施贵宝免疫肿瘤学基金会（FA-19-009 奖）的支持。N.S. 得到了惠康信托基金会奖学金（211113/A/18/Z）的支持。J.A.H. 获得了欧盟地平线 2020 研究和创新计划的资助（860003 奖）。J.M.W. 得到了艾尔·克罗纳基金会（2015 年 A10 奖）的支持。
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