Zubchenko Svitlana, Havrylyuk Anna, Kril Iryna, Nadishko Olena, Kolinkovskyi Oleksandr, Chopyak Valentyna
Department of Clinical Immunology and Allergology, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
Department of hygiene and prophylactic toxicology FPDO of Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
Rheumatol Int. 2024 Dec;44(12):2873-2883. doi: 10.1007/s00296-024-05677-3. Epub 2024 Sep 30.
Long-COVID are often accompanied by the development of autoimmun disorders. Such dysregulation of the immune system can be caused by reactivation of "sluggish" herpesvirus infection in patients after COVID-19. The one of the possible causes of autoimmunization is a change in the cytotoxic functions of NK cells under the influence of HHV6. The aim of research was to study the expression of receptor-ligand Fas-FasL, regulating marker CD38 and inhibitory receptor TIM-3 on NK cells in patients with long-COVID after mild, moderate, and severe stage of COVID-19 in the anamnesis with or without reactivation of HHV-6 and to identify risk factors for the formation of autoimmune disorders in these patients. This study investigated 124 adults (73 female and 51 male) aged 18 to 65 years with long-COVID. The groups of patients with long-COVID were divided depending on mild, moderate, and severe forms of COVID-19 in the anamnesis and with/without reactivation of HHV-6. The control group included 20 healthy participants. Molecular genetic studies (PCR) were performed for all patients to detect the existence of DNA HHV6. Multiparametric flow cytometry was performed on 124 EDTA peripheral blood samples collected from long-COVID patients and 20 healthy controls. There was defined an imbalance between acute antiviral mechanisms, the response contributing to tissue damage and immunopathology, probably autoimmunity in patients with long-COVID after different forms of COVID-19 with reactivation of HHV-6. The presence of HHV-6 in groups with long-COVID was accompanied by higher expression of FasL and CD38, especially in patients, who had a severe form of COVID-19 in the anamnesis. The decrease in TIM-3 in patients with reactivation of HHV-6 compared to patients without HHV-6 puts the preservation of immunological tolerance at risk of Th1-dependent immune responses. The reactivation of HHV-6 is accompanied by higher expression of FasL and CD38, which indicates increased hyperactivation of NK cells, their cytotoxic activity, and subsequent exhaustion. NK cells of these patients lose their immunoregulatory ability, this creates prerequisites for the development of immunopathology, probably autoimmune processes.
长期新冠通常伴有自身免疫性疾病的发展。这种免疫系统失调可能由新冠后患者体内“潜伏”的疱疹病毒感染重新激活引起。自身免疫化的可能原因之一是在HHV6影响下自然杀伤细胞（NK细胞）的细胞毒性功能发生变化。本研究的目的是研究在有或无HHV - 6重新激活的既往史中，经历过轻度、中度和重度新冠阶段的长期新冠患者NK细胞上调节标志物CD38、抑制性受体TIM - 3以及受体 - 配体Fas - FasL的表达，并确定这些患者自身免疫性疾病形成的危险因素。本研究调查了124名年龄在18至65岁之间患有长期新冠的成年人（73名女性和51名男性）。长期新冠患者组根据既往史中新冠的轻度、中度和重度形式以及有无HHV - 6重新激活进行划分。对照组包括20名健康参与者。对所有患者进行分子遗传学研究（PCR）以检测HHV6 DNA的存在。对从长期新冠患者采集的124份EDTA外周血样本和20名健康对照进行多参数流式细胞术检测。结果发现，在不同形式新冠且伴有HHV - 6重新激活的长期新冠患者中，急性抗病毒机制、导致组织损伤和免疫病理学（可能是自身免疫）的反应之间存在失衡。长期新冠组中HHV - 6的存在伴随着FasL和CD38的更高表达，尤其是在既往史中有重度新冠形式的患者中。与无HHV - 6的患者相比，HHV - 6重新激活患者中TIM - 3的降低使Th1依赖性免疫反应的免疫耐受维持面临风险。HHV - 6的重新激活伴随着FasL和CD38的更高表达，这表明NK细胞的过度激活增加、其细胞毒性活性增强以及随后的耗竭。这些患者的NK细胞失去免疫调节能力，这为免疫病理学（可能是自身免疫过程）的发展创造了前提条件。
