A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein–Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.

Natural killer (NK) cells and cytotoxic T (CD8⁺) cells are two of the most important types of immune cells in our body, protecting it from deadly invaders. While the NK cell is part of the innate immune system, the CD8⁺ cell is one of the major components of adaptive immunity. Still, these two very different types of cells share the most important function of destroying pathogen-infected and tumorous cells by releasing cytotoxic granules that promote proteolytic cleavage of harmful cells, leading to apoptosis. In this review, we look not only at NK and CD8⁺ T cells but also pay particular attention to their different subpopulations, the immune defenders that include the CD56⁺CD16^dim, CD56^dimCD16⁺, CD57⁺, and CD57⁺CD16⁺ NK cells, the NKT, CD57⁺CD8⁺, and KIR⁺CD8⁺ T cells, and ILCs. We examine all these cells in relation to their role in the protection of the body against different microorganisms and cancer, with an emphasis on their mechanisms and their clinical importance. Overall, close collaboration between NK cells and CD8⁺ T cells may play an important role in immune function and disease pathogenesis. The knowledge of how these immune cells interact in defending the body against pathogens and cancers may help us find ways to optimize their defensive and healing capabilities with methods that can be clinically applied.

Background Multiple sclerosis (MS) is a chronic autoimmune disorder affecting the central nervous system (CNS). Reactivation of Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) is observed in MS. Objectives This study investigates immunoglobulins (Ig)G, IgM, and IgA directed against EBV nuclear antigen EBNA-366-406, HHV-6 and EBV deoxyuridine-triphosphatase (dUTPase), and different immune profiles in 58 patients with relapsing remitting MS (RRMS) compared to 60 healthy controls. Methods We employed enzyme-linked immunosorbent assays (ELISA) to measure the immunoglobulins to viral antigens. Multiplex immunoassays were used to measure cytokines, chemokines and growth factor levels that were used to compute immune profiles, including M1 macrophage, T helper (Th)-1, Th-17, and overall immune activation. We assessed disabilities using the Expanded Disability Status Scale (EDSS) and disease progression using the Multiple Sclerosis Severity Score (MSSS). Results IgG/IgA/IgM directed to the three viral antigens were significantly higher in RRMS than in controls. RRMS was significantly discriminated from controls by using IgG and IgM against HHV-6 dUTPase, yielding an accuracy of 91.5% (sensitivity=87.3% and specificity=95.2%). Neural network analysis showed that using IgG to EBV-dUTPase, IgM to EBV-dUTPase, and immune profiles yielded an area under the ROC curve of 1 and a predictive accuracy of 97.1%. There were strong associations between IgG/IgM responses to HHV-6 and EBV-dUTPases and the EDSS/MSSS scores and aberrations in M1, Th-17, profiles, and overall immune activation. Conclusions HHV-6 and EBV reactivation play a key role in RRMS and these effects are mediated by activation of cytokine profiles.

Relapsing-remitting multiple sclerosis (RRMS) is defined by elevated IgG/IgA/IgM responses targeting Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA) and deoxyuridine-triphosphatases (dUTPases) of Human herpsesvirus-6 (HHV-6) and EBV. These responses suggest that the viruses are being replicated and reactivated. An increased prevalence of chronic fatigue syndrome, depression, and anxiety is associated with signs of immune activation in RRMS. Nevertheless, there is a lack of data regarding the association between viral reactivation and neuropsychiatric symptoms of RRMS. This study investigated the IgG/IgA/IgM responses to EBNA, and EBV and HHV-6-dUTPases, in 58 remitted RRMS patients and 63 normal controls. The McDonald criteria were employed to establish the diagnosis of MS. The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score were employed to evaluate disabilities caused by RRMS. We evaluated the scores of the Hamilton Depression (HAMD) and Anxiety (HAMA) Rating Scales, and Fibro-Fatigue (FF) scale. One latent construct was extracted from the EDSS, MSSS, FF, HAMD, and HAMA scores. We discovered that the combined effects of IgG and IgM-HHV-6-dUTPAses accounted for 63.7% of the variance in this construct. Furthermore, the total FF, HAMA, and HAMD scores were substantially associated with the IgG and IgM-HHV-6-dUTPAses, accounting for approximately 38.7% to 51.0% of the variance. The three neuropsychiatric rating scale scores were also significantly correlated with IgA reactivity directed to both dUTPases and IgG/IgA/IgM to EBNA. In conclusion, the reactivation and replication of HHV-6 and EBV significantly contributes to chronic fatigue syndrome, as well as symptoms of depression and anxiety due to RRMS.