Long Covid and Brain Health
Antibodies from long COVID patients can help predict, prevent and manage neuroautoimmunity or autoimmune brain disorders
It has been recognized that long-haul COVID, or long COVID, is a gateway to possible autoimmunity, especially to neuroautoimmunity. The long-term consequences of COVID-19 remain a major public health concern, particularly the persistent cognitive issues like brain fog and significant brain tissue loss.
This is especially troubling in relation to reactivation of latent herpesviruses, such as Epstein-Barr virus (EBV) and human herpesvirus-6 (HHV-6). These issues make it imperative to explore the mechanisms behind SARS-CoV-2-induced brain damage.
The discovery that spike protein persists in COVID patients’ plasma, brain and immune cells, and cytokines produced by the immune cells suggests that the prolonged symptoms of post-COVID stems from the presence of viral proteins and associated inflammatory response.
Moreover, increased plasma cytokine levels, disruption of the blood-brain barrier, and reactivation of latent herpesviruses have all been linked to the cognitive symptoms observed in long COVID patients. These symptoms, along with the affected organs, tissues, and cells, are not exclusive to long COVID; since 1969 this symptomatology has been observed in patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). By 2002, evidence of immune dysfunction and autoimmunity in chronic fatigue syndrome was introduced, and people with this condition are now recognized as being at heightened risk for long COVID.
Recently, we identified elevated levels of specific tissue antibodies in patients with long COVID, further supporting the involvement of hyperactivation of the immune system and autoimmune phenomena, particularly targeting the brain in long COVID patients. The involvement of latent viruses, hyperactivation of the immune system, the presence of tissue antibodies and associated autoimmune phenomena can lead a practitioner towards a very specific direction in ordering tests to identify patients suffering from autoimmune reactivity or disease brought about by long COVID. Thus, better testing leads to better treatment, because heightened risk for long COVID correlates with heightened levels of associated antibodies in people infected with SARS-CoV-2.
What the Long COVID and Brain Health Panel measures
SARS-CoV-2 contains a unique superantigenlike motif not found in other coronaviruses. Superantigens are highly potent antigens that can send the immune system into overdrive. They have been shown to impact nervous system function and are implicated in the development of neurological conditions and cardiovascular dysfunction. High IgG antibodies against SARS-CoV-2 antigens and superantigens indicate that an individual is exposed to SARS-CoV-2 and possibly to its remnants.
EBV and HHV-6/HHV-7 dUTPases are enzymes found in these viruses during the invasion of the human body and lytic or replication process. These viral enzymes are implicated in the pathophysiology of long COVID or ME/CFS . High levels of IgG antibodies against these viral dUTPases have been detected in some patients who su er from long COVID or ME/CFS syndromes. Antibodies against EBV and HHV-6/HHV-7 dUTPasese are strong predictors of long COVID.
Heat Shock Protein 60 and 90 (HSP60, HSP90) are superantigens found primarily in mitochondria, but are also found in the cytoplasm and membrane of many cells. Cells produce them in response to various triggers, particularly EBV and HHV-6. Over expression of HSPs during EBV and HHV-6 infection help their entry, replication and spread from cell to cell. Production of antibodies against them may result in their malfunction and the induction of in ammatory, cardiovascular and neurodegenerative disorders, as well as cancer.
Activin-A is a cytokine from the TGF-Beta family that is involved in regulating biological processes, including hematopoesis and immune function, and both the innate and adaptive immune system. Activin-A is also produced by Th2 cells and stimulates the production of antibodies by B-cells. High levels of antbodies against Activin-A in patients with long COVID ME/CFS may interfere with the functions of regulatory T-cells (Tregs), resulting in immune dsyregulation, and possible immunode ciency and autoimmunity.
EBNA Mimic Brain Antigen, especially EBNA-1, is a keyprotein encoded by the Epstein-Barr virus (EBV). It cross-reacts with a nervous system antigen called GLialCAM. That is why both EBV and GLialCAM antibodies are detected in patients with multiple sclerosis and long COVID ME/CFS. Interestingly, an injection of EBNA or GLialCAM antibody to an animal model of MS will exacerbate its symptomatologies. EBNA-1 is essential for the virus to maintain a latent state, allowing it to stay in infected B cells for life.
GlialCAM or Glial Cell Protein is a cell adhesion molecule expressed in the central nervous system by astrocytes and oligodendrocytes. It facilitates cell-to-cell and cell-toextracellular matrix interactions, in uencing cell adhesion and movement. It is also found in the liver. This protein is highly expressed in chronic-active plaques of patients with multiple sclerosis. Cross-reactivity between EBV EBNA-1 and GLialCAM may explain the association between EBV and MS. GlialCAM dysfunction can lead to neurological disease.
Myelin Proteolipid Protein (PLP) is the most abundant protein in the central nervous system that insulates nerve fibers. It is a key component of the myelin sheath, which insulates axons and speeds up nerve impulse conduction. It plays a crucial role in maintaining the structural and functional integrity of myelin, which is important in nerve impulse transmission. PLP is the target of pathogenic autoimmunity in long COVID, MS, and chronic inflammatory demyelinating diseases. Mutations in the PLP gene can lead to neurologic disorders.
Removing these disease-causing antibodies and implementing treatments targeting autoimmunity will result in the improvement of the clinical conditions of many patients with long COVID and its overlap with ME/CFS.
In order to be at the forefront of the care and treatment of long COVID and ME/CFS, a practitioner must ask these questions: What are the triggers? Which antigens and antibodies are involved? How can I use these lab results to improve my patient’s condition? These are the questions that lead to useful answers.”
Vojdani A, Vojdani E, Saidara E, Maes M. Persistent SARS-CoV-2 Infection, EBV, HHV-6 and other factors may contribute to inflammation and autoimmunity in long COVID. Viruses, 15(2):400, 2023, doi: 10.3390/v15020400.
Vojdani, A., Almulla A. F., Bo Z., Hussein K. A.-H. and Maes M. Reactivation of herpesvirus type-6 and IgA/IgM-mediated responses to activin-A underpin Long COVID, including affective symptoms and chronic fatigue syndrome. Acta Neuropsychiatrica, 2024, 4:1-13, doi: 10.1017/neu.2024.10.
Almulla, A. F.; Maes, M.; Zhou, B.; A-Hakeim, H.K.; and Vojdani, A. Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms. Journal of Advanced Research, 2024, S2090-1232(24)00530-7. doi: 10.1016/j.jare.2024.11.011. Online ahead of print.
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