Background & Aims

Significant progress has been made since the first report of inflammatory bowel disease (IBD) in 1859, after decades of research that have contributed to the understanding of the genetic and environmental factors involved in IBD pathogenesis. Today, a range of treatments is available for directed therapy, mostly targeting the overactive immune response. However, the mechanisms by which the immune system contributes to disease pathogenesis and progression are not fully understood. One challenge hindering IBD research is the heterogeneous nature of the disease and the lack of understanding of how immune cells interact with one another in the gut mucosa. Introduction of a technology that enables expansive characterization of the inflammatory environment of human IBD tissues may address this gap in knowledge.

Methods

We used the imaging mass cytometry platform to perform highly multiplex image analysis of IBD and healthy deidentified intestine sections (6 Crohn’s disease compared to 6 control ileum; 6 ulcerative colitis compared to 6 control colon). The acquired images were graded for inflammation severity by analysis of adjacent H&E tissue sections. We assigned more than 300,000 cells to unique cell types and performed analyses of tissue integrity, epithelial activity, and immune cell composition.

Results

The intestinal epithelia of patients with IBD exhibited increased proliferation rates and expression of HLA-DR compared to control tissues, and both features were positively correlated with the severity of inflammation. The neighborhood analysis determined enrichment of regulatory T cell interactions with CD68⁺ macrophages, CD4⁺ T cells, and plasma cells in both forms of IBD, whereas activated lysozyme C⁺ macrophages were preferred regulatory T cell neighbors in Crohn’s disease but not ulcerative colitis.

Conclusions

Altogether, our study shows the power of imaging mass cytometry and its ability to both quantify immune cell types and characterize their spatial interactions within the inflammatory environment by a single analysis platform.

中文翻译：

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炎症性肠病患者肠道组织切片的高度复用图像分析

背景与目标

自 1859 年首次报告炎症性肠病 (IBD) 以来，在经过数十年的研究有助于了解 IBD 发病机制中涉及的遗传和环境因素后，取得了重大进展。今天，有一系列治疗方法可用于定向治疗，主要针对过度活跃的免疫反应。然而，免疫系统促进疾病发病机制和进展的机制尚不完全清楚。阻碍 IBD 研究的一个挑战是该疾病的异质性以及对免疫细胞如何在肠粘膜中相互作用的认识不足。引入一种能够广泛表征人类 IBD 组织炎症环境的技术可能会弥补这一知识差距。

方法

我们使用成像质谱流式细胞术平台对 IBD 和健康的去识别肠道切片进行高度多重图像分析（6 个克罗恩病与 6 个对照回肠相比；6 个溃疡性结肠炎与 6 个对照结肠相比）。通过分析相邻的 H&E 组织切片，对获取的图像进行炎症严重程度分级。我们将超过 300,000 个细胞分配给独特的细胞类型，并对组织完整性、上皮活性和免疫细胞组成进行了分析。

结果

与对照组织相比，IBD 患者的肠上皮细胞表现出更高的增殖率和 HLA-DR 表达，并且这两个特征与炎症的严重程度呈正相关。邻域分析确定了两种形式的 IBD 中调节性 T 细胞与 CD68 ⁺巨噬细胞、CD4 ⁺ T 细胞和浆细胞相互作用的富集，而活化的溶菌酶 C ⁺巨噬细胞是克罗恩病而非溃疡性结肠炎中首选的调节性 T 细胞邻居。

结论

总而言之，我们的研究展示了成像质谱流式细胞术的强大功能及其通过单一分析平台量化免疫细胞类型和表征它们在炎症环境中的空间相互作用的能力。