Department of Pediatric Cardiology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Pediatric and Adolescent Clinic, Fürth, Germany.
Thorac Cardiovasc Surg. 2021 Dec;69(S 03):e10-e20. doi: 10.1055/s-0041-1723781. Epub 2021 Feb 19.
Protein-losing enteropathy (PLE) is a severe complication of the Fontan circulation. There is increasing discussion about whether lymphatic dysregulation is involved as pathomechanism of PLE. This investigation focuses on the interplay between alteration of lymphatic cells and immunologic pathway alterations.
Micro-ribonucleic acid (miRNA) expression profiling was performed in 49 patients ( = 10 Fontan patients with PLE, = 30 Fontan patients without PLE, and = 9 patients with dextro-transposition of the great arteries (dTGA). miRNA pathway analysis was performed to identify significantly enriched pathways. To determine lymphocyte populations and subtypes multiparameter flow cytometry was used.
miRNAs pathway analysis of Fontan patients with PLE revealed 20 significantly changed networks of which four of the ten largest were associated with immunologic processes. This finding is supported by significant T cell deficiency with decreased CD4+ count ( = 0.0002), altered CD4 +/CD8+ ratio, and significantly modified CD4+ ( < 0.0001) and CD8+ ( = 0.0002) T cell differentiation toward effector and terminal differentiated T cells in Fontan patients with PLE. Analyses of CD4+ T cell subsets demonstrated significantly increased frequencies of CD4+ CD25+ CD127- regulatory T cells (Treg) in Fontan patients with PLE ( = 0.0011).
PLE in Fontan patients is associated with severe lymphopenia, T cell deficiency, significant alterations of T cell differentiation, and increased Treg frequency reflecting an immune status of chronic inflammation and shortened protection against pathogens and autoimmunity. These cellular alterations seemed to be dysregulated by several miRNA controlled immunological pathways.
蛋白丢失性肠病（PLE）是 Fontan 循环的严重并发症。越来越多的人讨论淋巴调节紊乱是否是 PLE 的发病机制。本研究重点探讨了淋巴细胞改变与免疫途径改变之间的相互作用。
对 49 名患者（ = 10 名 Fontan 合并 PLE 患者， = 30 名 Fontan 无 PLE 患者和 = 9 名右位大动脉转位（dTGA）患者）进行微小核糖核酸（miRNA）表达谱分析。进行 miRNA 通路分析以确定显著富集的通路。采用多参数流式细胞术检测淋巴细胞群和亚群。
PLE 的 Fontan 患者的 miRNA 通路分析显示 20 个显著改变的网络，其中前 10 个中 4 个与免疫过程相关。这一发现得到了支持，PLE 的 Fontan 患者存在显著的 T 细胞缺乏，CD4+计数减少（ = 0.0002），CD4+/CD8+比值改变，以及 CD4+（ < 0.0001）和 CD8+（ = 0.0002）T 细胞向效应和终末分化 T 细胞分化的显著改变。CD4+T 细胞亚群分析显示，PLE 的 Fontan 患者中 CD4+ CD25+ CD127-调节性 T 细胞（Treg）的频率显著增加（ = 0.0011）。
Fontan 合并 PLE 的患者存在严重的淋巴细胞减少、T 细胞缺乏、T 细胞分化的显著改变和 Treg 频率的增加，反映出慢性炎症的免疫状态，对病原体和自身免疫的保护作用缩短。这些细胞改变似乎受几种 miRNA 控制的免疫途径失调的影响。
