Treg and Oxidative Stress Biomarker Profiles in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
9 affiliations
- 1Center of Competence Immunopathogen, National Center of Infectious and Parasitic Diseases (NCIPD), 1504 Sofia, Bulgaria
- 2Research and Innovation Program for the Development of MU-PLOVDIV (SRIPD-MUP), Creation of a Network of Research Higher Schools, National Plan for Recovery and Sustainability, EuropeanUnion–NextGenerationEU, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
- 3Department of Medical Microbiology and Immunology “Elissay Yanev”, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
- 4Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
- 5Department of Microbiology and Virology, Medical University of Pleven, 5800 Pleven, Bulgaria
- 6Institute of Innovation and Smart Technology, University of Telecommunication and Posts, 1700 Sofia, Bulgaria
- 7Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
- 8Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu 610072, China
- 9Department of Psychiatry, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
Abstract
Chronic immune dysregulation is the possible pathophysiological mechanism in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long coronavirus infectious disease (long COVID, LC). However, a detailed characterization of regulatory and effector T-cell subsets in these conditions remains limited. To assess and compare T-cell subsets in relation to serum biomarkers of chronic activation and oxidative/nitrosative stress in an attempt to differentiate between LC and ME/CFS patients. Peripheral blood mononuclear cells (PMNC) from LC patients (n = 89), ME/CFS patients (n = 125), and healthy controls (HC, n = 80) were analyzed using multiparameter flow cytometry. The frequencies of naïve (CD45RA+), effector (CD45RA-), CD31+, CD39+, CD73+, GARP+, PI16+, CD15s/CD161+, and CD147+ Treg subsets were determined in relation to CD4+ and CD8+ T-cell differentiation, activation, and effector subsets. Catalase (CAT), superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPX1), malondialdehyde (MDA), nitric oxide synthase 1 and 3 (NOS1, NOS3), zonulin, lipopolysaccharide (LPS), immunoglobulin G (IgG) against lipopolysaccharide (IgG-LPS), Toll-like receptor 4 (TLR4), indoleamine 2,3-dioxygenase (IDO), and Dickkopf-related protein 1 (DKK1) were measured in serum by ELISA. Clinical symptom scores (HAMA, HAMD, FF, dePol) were additionally assessed. The immune-serum biomarkers distinguishing LC, ME/CFS, and HC comprised Th17, CD15s+CD161−eTreg, and CD161+ Treg. The five-marker signature retained significance after adjustment for age, BMI, and sex. Altered T-cell subsets were strongly associated with markers of oxidative (GPX1) and nitrosative (NOS3) stress but not directly with symptom severity. ME/CFS showed a strong separation from HC across Random Forest (AUC = 0.907) and logistic regression (AUC = 0.924). The modest distinction of LC from HC (AUC = 0.727 and 0.577 respectively) possibly reflected important endotypic diversity, though differences in disease duration, vaccination history, biomarker selection, and other cohort characteristics might add to it. MDA was an independent predictor for three-class classification, ME/CFS vs. HC, and LC vs. HC pairwise comparisons, while GPX1 discriminated between ME/CFS and LC. In spite of shared biomarkers of oxidative stress and T-cell response dysregulation, our results support the hypothesis that LC and ME/CFS differ in the extent of cellular damage and the exhaustion of compensatory mechanisms.
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BibTeX
@article{todorova2026treg,
title = {{Treg and Oxidative Stress Biomarker Profiles in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome}},
author = {Yana Todorova and Radostina Dimitrova and Teodora Kalfova and Steliyan Petrov and Martina Bozhkova and Mariya Ivanovska and Dobrina Dudova and Mariana Murdjeva and Hristo Taskov and Michael Maes and Maria Nikolova},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219422},
url = {https://www.mdpi.com/1422-0067/27/21/9422},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Treg and Oxidative Stress Biomarker Profiles in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
AU - Yana Todorova
AU - Radostina Dimitrova
AU - Teodora Kalfova
AU - Steliyan Petrov
AU - Martina Bozhkova
AU - Mariya Ivanovska
AU - Dobrina Dudova
AU - Mariana Murdjeva
AU - Hristo Taskov
AU - Michael Maes
AU - Maria Nikolova
PY - 2026
DA - 2026/10/22
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219422
UR - https://www.mdpi.com/1422-0067/27/21/9422
AB - Chronic immune dysregulation is the possible pathophysiological mechanism in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long coronavirus infectious disease (long COVID, LC). However, a detailed characterization of regulatory and effector T-cell subsets in these conditions remains limited. To assess and compare T-cell subsets in relation to serum biomarkers of chronic activation and oxidative/nitrosative stress in an attempt to differentiate between LC and ME/CFS patients. Peripheral blood mononuclear cells (PMNC) from LC patients (n = 89), ME/CFS patients (n = 125), and healthy controls (HC, n = 80) were analyzed using multiparameter flow cytometry. The frequencies of naïve (CD45RA+), effector (CD45RA-), CD31+, CD39+, CD73+, GARP+, PI16+, CD15s/CD161+, and CD147+ Treg subsets were determined in relation to CD4+ and CD8+ T-cell differentiation, activation, and effector subsets. Catalase (CAT), superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPX1), malondialdehyde (MDA), nitric oxide synthase 1 and 3 (NOS1, NOS3), zonulin, lipopolysaccharide (LPS), immunoglobulin G (IgG) against lipopolysaccharide (IgG-LPS), Toll-like receptor 4 (TLR4), indoleamine 2,3-dioxygenase (IDO), and Dickkopf-related protein 1 (DKK1) were measured in serum by ELISA. Clinical symptom scores (HAMA, HAMD, FF, dePol) were additionally assessed. The immune-serum biomarkers distinguishing LC, ME/CFS, and HC comprised Th17, CD15s+CD161−eTreg, and CD161+ Treg. The five-marker signature retained significance after adjustment for age, BMI, and sex. Altered T-cell subsets were strongly associated with markers of oxidative (GPX1) and nitrosative (NOS3) stress but not directly with symptom severity. ME/CFS showed a strong separation from HC across Random Forest (AUC = 0.907) and logistic regression (AUC = 0.924). The modest distinction of LC from HC (AUC = 0.727 and 0.577 respectively) possibly reflected important endotypic diversity, though differences in disease duration, vaccination history, biomarker selection, and other cohort characteristics might add to it. MDA was an independent predictor for three-class classification, ME/CFS vs. HC, and LC vs. HC pairwise comparisons, while GPX1 discriminated between ME/CFS and LC. In spite of shared biomarkers of oxidative stress and T-cell response dysregulation, our results support the hypothesis that LC and ME/CFS differ in the extent of cellular damage and the exhaustion of compensatory mechanisms.
SN - 1422-0067
ER -