Eschenhagen Patience N, Bacher Petra, Grehn Claudia, Mainz Jochen G, Scheffold Alexander, Schwarz Carsten
Cystic Fibrosis Section, Klinikum Westbrandenburg, Campus Potsdam, Potsdam, Germany.
HMU Health and Medical University, Potsdam, Germany.
Front Pharmacol. 2023 Jun 20;14:1180826. doi: 10.3389/fphar.2023.1180826. eCollection 2023.
Together with impaired mucociliary clearance, lung disease in cystic fibrosis (CF) is driven by dysregulation of innate and adaptive immunity caused by dysfunctional CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), leading to airway infection and hyperinflamma-tion. The highly effective CFTR modulator therapy (HEMT) elexacaftor/tezacaftor/ivacaftor (ETI) generates substantial improvements in clinical outcomes of people with CF (pwCF) by restoration of CFTR activity. Aberrant immune responses of lymphocytes due to CFTR dysfunction has been described in the past, but not the effects of CFTR restoration by HEMT on these cells. We aimed to examine the effect of ETI on the proliferative activity of antigen-specific CD154 (+) T cells against bacterial and fungal species relevant in CF and on total IgG and IgE as markers of B cell adaptive immunity. We performed analyses of Ki-67 expression in antigen-specific CD154 (+) T cells against and from 21 pwCF by cytometric assay based on antigen-reactive T cell enrichment (ARTE), and analysis of total serum IgE and IgG before and after initiation of ETI. Mean Ki-67 expression in antigen-specific CD154 (+) T cells against and , but not , mean total serum IgG and mean total serum IgE decreased significantly after initiation of ETI. No correlation was found to change in sputum microbiology of the examined pathogens. Mean BMI and FEV1 increased significantly. HEMT is associated with decreased antigen-specific CD154 (+) T cell proliferation activity in our cohort, independent of findings in sputum microbiology of the examined pathogens. Together with the observed clinical improvement and the decrease in total IgE and IgG, this indicates effects due to CFTR restoration on CD154 (+) T cells by ETI and a reduction of B cell activation with subsequent lower immunoglobulin synthesis under HEMT therapy. These results endorse earlier evidence of CFTR dysfunction in T and B cells leading directly to aberrant immune responses with hyperinflammation.
除了黏液纤毛清除功能受损外，囊性纤维化（CF）患者的肺部疾病还由功能失调的囊性纤维化跨膜传导调节因子（CFTR）导致的先天性和适应性免疫失调所驱动，进而引发气道感染和过度炎症反应。高效的CFTR调节剂疗法（HEMT）依列卡福/替扎卡福/依伐卡托（ETI）通过恢复CFTR活性，显著改善了CF患者（pwCF）的临床结局。过去曾描述过由于CFTR功能障碍导致的淋巴细胞异常免疫反应，但未提及HEMT恢复CFTR对这些细胞的影响。我们旨在研究ETI对抗CF相关细菌和真菌物种的抗原特异性CD154（+）T细胞增殖活性以及作为B细胞适应性免疫标志物的总IgG和IgE的影响。我们通过基于抗原反应性T细胞富集（ARTE）的细胞计数法，对21例pwCF患者针对金黄色葡萄球菌和烟曲霉的抗原特异性CD154（+）T细胞中的Ki-67表达进行了分析，并在ETI治疗开始前后对血清总IgE和IgG进行了分析。ETI治疗开始后，针对金黄色葡萄球菌和烟曲霉的抗原特异性CD154（+）T细胞中的平均Ki-67表达降低，但针对铜绿假单胞菌的未降低，血清总IgG平均值和血清总IgE平均值显著下降。在所检测病原体的痰液微生物学变化中未发现相关性。平均体重指数和第一秒用力呼气容积显著增加。在我们的队列中，HEMT与抗原特异性CD154（+）T细胞增殖活性降低相关，与所检测病原体的痰液微生物学结果无关。连同观察到的临床改善以及总IgE和IgG的降低，这表明ETI恢复CFTR对CD154（+）T细胞有影响，并在HEMT治疗下减少了B细胞活化，随后降低了免疫球蛋白合成。这些结果支持了早期关于CFTR在T细胞和B细胞中功能障碍直接导致伴有过度炎症的异常免疫反应的证据。
