Guerrera Gisella, Sambucci Manolo, Timperi Eleonora, Picozza Mario, Misiti Andrea, Placido Roberta, Corbisiero Silvia, D'Orso Silvia, Termine Andrea, Fabrizio Carlo, Gargano Francesca, Eleuteri Sharon, Marchioni Luisa, Bordoni Veronica, Coppola Luigi, Iannetta Marco, Agrati Chiara, Borsellino Giovanna, Battistini Luca
Neuroimmunology Unit, Santa Lucia Foundation IRCCS, Rome, Italy.
Data Science Unit, Santa Lucia Foundation IRCCS, Rome, Italy.
Front Immunol. 2025 Jan 8;15:1502937. doi: 10.3389/fimmu.2024.1502937. eCollection 2024.
Acute COVID-19 infection causes significant alterations in the innate and adaptive immune systems. While most individuals recover naturally, some develop long COVID (LC) syndrome, marked by persistent or new symptoms weeks to months after SARS-CoV-2 infection. Despite its prevalence, there are no clinical tests to distinguish LC patients from those fully recovered. Understanding the immunological basis of LC is essential for improving diagnostic and treatment approaches.
We performed deep immunophenotyping and functional assays to examine the immunological profiles of LC patients, individuals with active COVID-19, recovered patients, and healthy donors. This analysis assessed both innate and adaptive immune features, identifying potential biomarkers for LC syndrome. A Binomial Generalized Linear Model (BGLM) was used to pinpoint immune features characterizing LC.
COVID-19 patients exhibited depletion of innate immune cell subsets, including plasmacytoid and conventional dendritic cells, classical, non-classical, and intermediate monocytes, and monocyte-derived inflammatory dendritic cells. Elevated basal inflammation was observed in COVID-19 patients compared to LC patients, whose immune profiles were closer to those of healthy donors and recovered individuals. However, LC patients displayed persistent immune alterations, including reduced T cell subsets (CD4, CD8, Tregs) and switched memory B cells, similar to COVID-19 patients. Through BGLM, a unique adaptive immune signature for LC was identified, featuring memory CD8 and gd T cells with low proliferative capacity and diminished expression of activation and homing receptors.
The findings highlight a unique immunological signature associated with LC syndrome, characterized by persistent adaptive immune dysregulation. While LC patients displayed recovery in innate immune profiles comparable to healthy and Recovered individuals, deficits in T cell and memory B cell populations were evident, differentiating LC from full recovery. These findings provide insights into LC pathogenesis and may support the development of diagnostic tools and targeted therapies.
急性新冠病毒感染会导致先天性和适应性免疫系统发生显著改变。虽然大多数人能自然康复，但有些人会发展为新冠后综合征（LC），其特征是在感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）数周或数月后出现持续或新出现的症状。尽管其很常见，但目前尚无临床检测方法可区分LC患者和完全康复的患者。了解LC的免疫学基础对于改进诊断和治疗方法至关重要。
我们进行了深度免疫表型分析和功能测定，以检查LC患者、新冠病毒感染活跃期患者、康复患者和健康供体的免疫谱。该分析评估了先天性和适应性免疫特征，确定了LC综合征的潜在生物标志物。使用二项广义线性模型（BGLM）来确定表征LC的免疫特征。
新冠病毒感染患者表现出先天性免疫细胞亚群的耗竭，包括浆细胞样和常规树突状细胞、经典、非经典和中间单核细胞以及单核细胞衍生的炎性树突状细胞。与LC患者相比，新冠病毒感染患者的基础炎症水平升高，LC患者的免疫谱更接近健康供体和康复个体。然而，LC患者表现出持续的免疫改变，包括T细胞亚群（CD4、CD8、调节性T细胞）减少和转换记忆B细胞，这与新冠病毒感染患者相似。通过BGLM，确定了一种独特的LC适应性免疫特征，其特点是记忆性CD8和γδ T细胞增殖能力低，激活和归巢受体表达减少。
研究结果突出了与LC综合征相关的独特免疫特征，其特点是适应性免疫持续失调。虽然LC患者的先天性免疫谱恢复到与健康和康复个体相当的水平，但T细胞和记忆B细胞群体的缺陷很明显，这使LC与完全康复区分开来。这些发现为LC的发病机制提供了见解，并可能支持诊断工具和靶向治疗的开发。
