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.

Background: Inflammation and autoimmune responses contribute to the pathophysiology of Long COVID, and its affective and chronic fatigue syndrome (CFS) symptoms, labeled “the physio-affective phenome.” Objectives: To investigate whether Long COVID and its physio-affective phenome are linked to autoimmunity to the tight junction proteins, zonulin and occludin (ZOOC), and immune reactivity to lipopolysaccharides (LPS), and whether the latter are associated with signs of human herpes virus-6 reactivation (HHV-6), autoimmunity directed against oligodendrocyte and neuronal proteins, including myelin basic protein (MBP). Methods: IgA /IgM/IgG responses to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), HHV-6, ZOOC, and neuronal proteins, C-reactive protein (CRP) and advanced oxidation protein products (AOPP), were measured in 90 Long COVID patients and 90 healthy controls. The physio-affective phenome was conceptualized as a factor extracted from physical and affective symptom domains. Results: Neural network identified IgA directed to LPS (IgA-LPS), IgG-ZOOC, IgG-LPS, and IgA-ZOOC as the most important variables associated with Long COVID diagnosis with an area under the ROC curve of 0.755. Partial Least Squares analysis showed that 40.9% of the variance in the physio-affective phenome was explained by CRP, IgA-MPB and IgG-MBP. A large part of the variances in both autoimmune responses to MBP (36.3-39.7%) was explained by autoimmunity (IgA and IgG) directed to ZOOC. The latter was strongly associated with indicants of HHV-6 reactivation, which in turn was associated with increased IgM-SARS-CoV-2. Conclusions: Autoimmunity against components of the tight junctions and increased bacterial translocation may be involved in the pathophysiology of Long COVID’s physio-affective phenome.