Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms

Abstract

BackgroundAutoimmune responses contribute to the pathophysiology of Long COVID, affective symptoms and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).ObjectivesTo examine whether Long COVID, and its accompanying affective symptoms and CFS are associated with immunoglobulin (Ig)A/IgM/IgG directed at neuronal proteins including myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin, α+β-tubulin, neurofilament protein (NFP), cerebellar protein-2 (CP2), and the blood-brain-barrier-brain-damage (BBD) proteins claudin-5 and S100B.MethodsIgA/IgM/IgG to the above neuronal proteins, human herpes virus-6 (HHV-6) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were measured in 90 Long COVID patients and 90 healthy controls, while C-reactive protein (CRP), and advanced oxidation protein products (AOPP) in association with affective and CFS ratings were additionally assessed in a subgroup thereof.ResultsLong COVID is associated with significant increases in IgG directed at tubulin (IgG-tubulin), MBP, MOG and synapsin; IgM-MBP, MOG, CP2, synapsin and BBD; and IgA-CP2 and synapsin. IgM-SARS-CoV-2 and IgM-HHV-6 antibody titers were significantly correlated with IgA/IgG/IgM-tubulin and -CP2, IgG/IgM-BBD, IgM-MOG, IgA/IgM-NFP, and IgG/IgM-synapsin. Binary logistic regression analysis shows that IgM-MBP and IgG-MBP are the best predictors of Long COVID. Multiple regression analysis shows that IgG-MOG, CRP and AOPP explain together 41.7% of the variance in the severity of CFS. Neural network analysis shows that IgM-synapsin, IgA-MBP, IgG-MOG, IgA-synapsin, IgA-CP2, IgG-MBP and CRP are the most important predictors of affective symptoms due to Long COVID with a predictive accuracy of r=0.801.ConclusionBrain-targeted autoimmunity contributes significantly to the pathogenesis of Long COVID and the severity of its physio-affective phenome.

From HHV-6 reactivation to autoimmune reactivity against tight junctions and neuronal antigens, to inflammation, depression, and chronic fatigue syndrome due to Long COVID

“…Similarly, antibodies against SARS-CoV-2 superantigen, HHV-6 U24, and HHV-6 dUTPase, MBP, MOG, NFP, synapsin, cerebellar protein-2, and tubulin were measured using enzymelinked immunosorbent assay (ELISA) as explained previously [15,18].…”

“…In their study, Almulla et al [18] found that heightened autoimmune responses, specifically those mediated by IgG and IgM to neuronal antigens, play a significant role in the development of Long COVID and the emergence of new affective and CFS symptoms. Some of the proteins mentioned in the study are myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), neurofilament light (NFL), synapsin, tubulin, cerebellar protein-2, and the blood-brain barrier (BBB) proteins claudin-5 and S100B [18]. Thus, it can be inferred that infection with the SARS-CoV-2 virus has the potential to reactivate dormant viruses.…”

“…Therefore, these authors concluded that reactivation of dormant viruses could potentially contribute to the development of Long-COVID. In their study, Almulla et al [18] found that heightened autoimmune responses, specifically those mediated by IgG and IgM to neuronal antigens, play a significant role in the development of Long COVID and the emergence of new affective and CFS symptoms. Some of the proteins mentioned in the study are myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), neurofilament light (NFL), synapsin, tubulin, cerebellar protein-2, and the blood-brain barrier (BBB) proteins claudin-5 and S100B [18].…”

“…This, in turn, may lead to heightened oxidative and nitrosative stress, weakened antioxidant defenses, activation of the immune response system, and an elevated risk of microglial activation and neuroinflammation. These processes can result in damage to neuronal cells and an increased production of antibodies targeting neuronal antigens [15, 16, 18].…”

Editorial: Neuropsychiatric and neurodegenerative aspects of acute and long COVID

“…Recent studies, however, have identified key factors contributing to these conditions. Notably, evidence points to increased neuroimmune-inflammation, oxidative and nitrosative stress (Al-Hakeim et al, 2022 ), persistent SARS-CoV-2 infection (Vojdani et al, 2023 ), and autoimmune reactions (Almulla et al, 2023b ). These findings have spurred the construction of the current Research Topic encompassing articles, reviews, and case reports, aimed at deepening our understanding of the biological mechanisms driving psychiatric and neurodegenerative comorbidities in acute and Long COVID.…”