Service de Médecine Interne et Immunologie Clinique, Centre de compétence maladie de Rendu-Osler, Centre Hospitalo-Universitaire Dijon Bourgogne, Dijon, France.
Université de Bourgogne, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Dijon, France.
Front Immunol. 2023 Dec 8;14:1321182. doi: 10.3389/fimmu.2023.1321182. eCollection 2023.
Hereditary hemorrhagic telangiectasia (HHT) is a rare inherited disease due to heterozygous loss-of-function mutations on the BMP9/10 pathway ( or mainly). HHT endothelial cells are prone to lose their quiescence, leading to progressive appearance of numerous telangiectases on skin and mucosa (complicated by epistaxis and anemia), and to larger arteriovenous malformations in lungs, liver and brain. HHT is also associated with T lymphocyte abnormalities, which are currently poorly understood. We quantified by flow-cytometry the main T lymphocyte circulating subsets in 40 HHT patients and 20 matched healthy controls. Immunostaining was done on 2 HHT skin telangiectases. Disruptions in T lymphocyte homeostasis was observed, characterized by increases in subsets known to promote angiogenesis: Th2 (1.38% vs 1.15%, p=0.021), Th17 (0.32% vs 0.22%, p=0.019 2) and Treg (4.94% vs 3.51%, p= 0.027). T angiogenic lymphocytes (Tang), defined as CD3+CD31+CXCR4+ T cells, were at similar levels in both groups, but the proportion of VEGF-A+ Tang after stimulation was higher in the HHT group compared to controls (68.2% vs 44.9%, p=0.012). The global HHT T lymphopenia predominantly affected the effector memory T-helper cells (200 vs 270 cells/mm, p=0.017), and the lymphocytic infiltrate around HHT telangiectases consisted of memory T-helper cells. The Th17 circulating subset was positively correlated with the monthly epistaxis duration (r coefficient: +0,431, p=0.042), prospectively assessed. HHT T-helper lymphocytes are affected by several pro-angiogenic changes, potentially resulting from their recruitment by abnormal endothelial cells. They could constitute a biologically relevant source of VEGF-A and a valuable therapeutic target in HHT.
遗传性出血性毛细血管扩张症（HHT）是一种罕见的遗传性疾病，由于 BMP9/10 通路（或主要）的杂合功能丧失突变。HHT 内皮细胞容易失去静止状态，导致皮肤和粘膜上出现无数毛细血管扩张（伴有鼻出血和贫血），并在肺部、肝脏和大脑中出现更大的动静脉畸形。HHT 还与 T 淋巴细胞异常有关，目前对此了解甚少。我们通过流式细胞术定量检测了 40 例 HHT 患者和 20 例匹配的健康对照者的主要循环 T 淋巴细胞亚群。对 2 例 HHT 皮肤毛细血管扩张症进行免疫染色。观察到 T 淋巴细胞稳态失调，表现为已知促进血管生成的亚群增加：Th2（1.38%对 1.15%，p=0.021）、Th17（0.32%对 0.22%，p=0.0192）和 Treg（4.94%对 3.51%，p=0.027）。定义为 CD3+CD31+CXCR4+T 细胞的 T 血管生成淋巴细胞（Tang）在两组中的水平相似，但 HHT 组刺激后 VEGF-A+Tang 的比例高于对照组（68.2%对 44.9%，p=0.012）。HHT 整体 T 淋巴细胞减少主要影响效应记忆 T 辅助细胞（200 对 270 个细胞/mm，p=0.017），HHT 毛细血管扩张周围的淋巴细胞浸润由记忆 T 辅助细胞组成。Th17 循环亚群与每月鼻出血持续时间呈正相关（r 系数：+0.431，p=0.042），前瞻性评估。HHT T 辅助淋巴细胞受到多种促血管生成变化的影响，这些变化可能是由异常内皮细胞募集引起的。它们可能构成 VEGF-A 的生物学相关来源，也是 HHT 的有价值的治疗靶点。
