Background: The Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) are frequently linked to neuropsychiatric illnesses such as multiple sclerosis, depression, and chronic fatigue syndrome/myalgic encephalomyelitis. These viruses may induce autoimmune reactions by molecular mimicry, leading to damage to self-epitopes in the central nervous system (CNS). Objective: This study seeks to explore the common pentapeptides present in EBV and HHV-6 viral antigens alongside various CNS-related proteins via molecular mimicry. Additionally, it will assess the immunogenicity of these shared pentapeptides in T and B cells. Method: Sequence alignment was conducted to assess molecular mimicry between 32 EBV and HHV-6 antigens and 10 CNS autoantigens. Protein sequences were obtained from UniProt, structural homology was analyzed using AlphaFold and PyMol, and shared pentapeptides were identified with Alignmentaj. Immunogenicity was assessed via the Immune Epitope Database (IEDB) for potential T- and B-cell activation. Results: A total of 91 mimicry pentapeptides were identified between viral antigens (EBV and human HHV-6), and CNS proteins. Notably, synapsin (SYN)1 exhibited the highest mimicry, sharing multiple pentapeptides with EBV nuclear antigen (EBNA)1, EBNA6, latent membrane protein (LMP)1, and early antigen diffused (EA-D) and 6 different HHV-6 antigens. Myelin proteins including myelin basic protein, myelin-associated glycoprotein, and myelin-oligodendrocyte glycoprotein also displayed shared pentapeptides with EBV/HHV-6 antigens, indicating potential immune cross-reactivity. EBNA1, EBNA2, EBNA6, LMP1, LMP2, EA-D, and BLLF1 structurally resemble CNS autoantigens and act as immunoreactive epitopes for human T and B cells. Except for EBNA2 and protein U94, all share immunogenic pentapeptide sequences with SYN1. Conclusion: EBV and HHV-6 antigens mimic CNS proteins, potentially triggering autoimmune responses via T and B cell activation. Shared pentapeptides suggest a link between viral infections and CNS autoimmunity. Further research is needed to clarify molecular mechanisms and explore targeted therapies to mitigate virus-induced neuroinflammation.

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.

Schizophrenia comprises various symptom domains the two most important being positive and negative symptoms. Nevertheless, using (un)supervised machine learning techniques it was shown that a) negative symptoms are significantly interrelated with PHEM (psychosis, hostility, excitation, and mannerism) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR); and b) stable phase schizophrenia comprises two distinct classes, namely Major Neuro-Cognitive Psychosis (MNP, largely overlapping with deficit schizophrenia) and Simple NP (SNP). In this study, we recruited 120 MNP patients and 54 healthy subjects and measured the above-mentioned symptom domains. In MNP, there were significant associations between negative and PHEM symptoms, FTD and PMR. A single latent trait, which is essentially unidimensional, underlies these key domains of schizophrenia and additionally shows excellent internal consistency reliability, convergent validity, and predictive relevance. Confirmatory Tedrad Analysis indicates that this latent vector fits a reflective model. Soft Independent Modeling of Class Analogy (SIMCA) shows that MNP (diagnosis based on negative symptoms) is better modeled with PHEM symptoms, FTD and PMR than with negative symptoms. In conclusion, in MNP, a restricted sample of the schizophrenia population, negative and PHEM symptoms, FTD and PMR belong to one underlying latent vector reflecting general psychopathology and, therefore, may be used as an overall severity of schizophrenia (OSOS) index. The bi-dimensional concept of positive and negative symptoms and type I and II schizophrenia is revised.