Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands.
Inflamm Bowel Dis. 2024 Nov 4;30(11):2146-2161. doi: 10.1093/ibd/izae103.
Perianal fistulas are a debilitating complication of Crohn's disease (CD). Due to unknown reasons, CD-associated fistulas are in general more difficult to treat than cryptoglandular fistulas (non-CD-associated). Understanding the immune cell landscape is a first step towards the development of more effective therapies for CD-associated fistulas. In this work, we characterized the composition and spatial localization of disease-associated immune cells in both types of perianal fistulas by high-dimensional analyses.
We applied single-cell mass cytometry (scMC), spectral flow cytometry (SFC), and imaging mass cytometry (IMC) to profile the immune compartment in CD-associated perianal fistulas and cryptoglandular fistulas. An exploratory cohort (CD fistula, n = 10; non-CD fistula, n = 5) was analyzed by scMC to unravel disease-associated immune cell types. SFC was performed on a second fistula cohort (CD, n = 10; non-CD, n = 11) to comprehensively phenotype disease-associated T helper (Th) cells. IMC was used on a third cohort (CD, n = 5) to investigate the spatial distribution/interaction of relevant immune cell subsets.
Our analyses revealed that activated HLA-DR+CD38+ effector CD4+ T cells with a Th1/17 phenotype were significantly enriched in CD-associated compared with cryptoglandular fistulas. These cells, displaying features of proliferation, regulation, and differentiation, were also present in blood, and colocalized with other CD4+ T cells, CCR6+ B cells, and macrophages in the fistula tracts.
Overall, proliferating activated HLA-DR+CD38+ effector Th1/17 cells distinguish CD-associated from cryptoglandular perianal fistulas and are a promising biomarker in blood to discriminate between these 2 fistula types. Targeting HLA-DR and CD38-expressing CD4+ T cells may offer a potential new therapeutic strategy for CD-related fistulas.
肛周瘘是克罗恩病（CD）的一种使人衰弱的并发症。由于未知原因，CD 相关的瘘通常比非 CD 相关的（隐窝腺源性）瘘更难治疗。了解免疫细胞的特征是为 CD 相关瘘开发更有效的治疗方法的第一步。在这项工作中，我们通过高维分析来描述这两种类型的肛周瘘中与疾病相关的免疫细胞的组成和空间定位。
我们应用单细胞质谱流式细胞术（scMC）、光谱流式细胞术（SFC）和成像质谱流式细胞术（IMC）来分析 CD 相关的肛周瘘和隐窝腺源性瘘的免疫细胞组成。通过 scMC 分析一个探索性队列（CD 瘘，n=10；非 CD 瘘，n=5），以揭示与疾病相关的免疫细胞类型。SFC 对第二个瘘队列（CD，n=10；非 CD，n=11）进行了全面表型分析，以全面表型分析与疾病相关的辅助性 T 细胞（Th）。我们使用 IMC 对第三个队列（CD，n=5）进行了研究，以研究相关免疫细胞亚群的空间分布/相互作用。
我们的分析表明，与隐窝腺源性瘘相比，CD 相关瘘中明显富集了具有 Th1/17 表型的活化 HLA-DR+CD38+效应 CD4+T 细胞。这些细胞表现出增殖、调节和分化的特征，也存在于血液中，并与瘘管中的其他 CD4+T 细胞、CCR6+B 细胞和巨噬细胞共定位。
总的来说，增殖的活化 HLA-DR+CD38+效应 Th1/17 细胞将 CD 相关与隐窝腺源性肛周瘘区分开来，是血液中区分这两种瘘类型的有前途的生物标志物。针对 HLA-DR 和 CD38 表达的 CD4+T 细胞可能为 CD 相关瘘提供一种新的潜在治疗策略。
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