■淋巴系统在免疫稳态中具有关键作用。为了更好地理解这一点,我们调查了原发性淋巴异常(PLA)对淋巴细胞数量和表型的影响。
■该研究包括(i)回顾性队列:来自国家原发性淋巴异常注册的177名PLA受试者,具有临床和实验室数据,和(ii)前瞻性队列:28例PLA患者和20例健康对照。使用已建立的表型诊断类别将患者细分,并分为单纯性(仅局部组织受累)和全身性(中央淋巴管受累)。进一步的分组变量包括生殖器受累和共存的肠淋巴管扩张症的可能性。在两个队列中分析血液学实验室参数。在前瞻性队列中,通过流式细胞术分析前瞻性血液样本的增殖标志物,分化,激活,皮肤归巢,和调节性(CD4+Foxp3+)T细胞(Treg)。
■在PLA患者中,淋巴减少是常见的(22%的受试者),主要影响CD4+T细胞亚群,并且在全身性与单纯性疾病类型的受试者中更为严重(36%vs9%的淋巴细胞减少症;70%vs33%的CD4细胞)。B细胞,NK细胞和单核细胞的保守性更好(除了以单核细胞减少为特征的GATA2缺乏症)。生殖器水肿和伴随肠淋巴管扩张的可能性独立预测CD4+T细胞耗竭。通过分化标志物分析CD4+和CD8+T细胞显示幼稚细胞不成比例的消耗,朝着更加差异化的效应器轮廓倾斜。全身性PLA条件与:Ki67表达增加,表明最近的细胞分裂,在幼稚CD4+中,但不是CD8+T细胞;CD4+活化水平增加,但不是CD8+T细胞;和Treg的比例增加。皮肤归巢标记(CCR10,CLA和CCR4)的表达在一些单纯性表型患者中降低。
■患有淋巴管功能失调的PLA患者的循环淋巴细胞选择性减少,从而优先消耗初始CD4+T细胞。全身性疾病的存在,生殖器水肿,和肠淋巴管扩张独立预测CD4淋巴细胞减少症。这种消耗与免疫激活和循环Tregs增加的关联表明淋巴-淋巴细胞相互作用和局部炎症变化在驱动免疫病理学中是关键的。
The lymphatic system has a pivotal role in immune homeostasis. To better understand this, we investigated the impact of Primary Lymphatic Anomalies (PLA) on lymphocyte numbers and phenotype.
The study comprised (i) a retrospective cohort: 177 PLA subjects from the National Primary Lymphatic Anomaly Register with clinical and laboratory data, and (ii) a prospective cohort: 28 patients with PLA and 20 healthy controls. Patients were subdivided using established phenotypic diagnostic categories and grouped into simplex (localised tissue involvement only) and systemic (involvement of central lymphatics). Further grouping variables included genital involvement and the likelihood of co-existent intestinal
lymphangiectasia. Haematology laboratory parameters were analysed in both cohorts. In the prospective cohort, prospective blood samples were analysed by flow cytometry for markers of proliferation, differentiation, activation, skin-homing, and for regulatory (CD4+Foxp3+) T cells (Treg).
In patients with PLA, lymphopaenia was frequent (22% of subjects), affected primarily the CD4+ T cell subset, and was more severe in subjects with systemic versus simplex patterns of disease (36% vs 9% for lymphopaenia; 70% vs 33% for CD4+ cells). B cells, NK cells and monocytes were better conserved (except in GATA2 deficiency characterised by monocytopaenia). Genital oedema and likelihood of concomitant intestinal
lymphangiectasia independently predicted CD4+ T cell depletion. Analysing CD4+ and CD8+ T cells by differentiation markers revealed disproportionate depletion of naïve cells, with a skewing towards a more differentiated effector profile. Systemic PLA conditions were associated with: increased expression of Ki67, indicative of recent cell division, in naïve CD4+, but not CD8+ T cells; increased levels of activation in CD4+, but not CD8+ T cells; and an increased proportion of Treg. Skin-homing marker (CCR10, CLA and CCR4) expression was reduced in some patients with simplex phenotypes.
Patients with PLA who have dysfunctional lymphatics have a selective reduction in circulating lymphocytes which preferentially depletes naïve CD4+ T cells. The presence of systemic disease, genital oedema, and intestinal
lymphangiectasia independently predict CD4 lymphopaenia. The association of this depletion with immune activation and increased circulating Tregs suggests lymphatic-lymphocyte interactions and local inflammatory changes are pivotal in driving immunopathology.