Major epidemics drive the evolution of the human immune system. While immune system "plasticity" provides a survival advantage, it comes at a cost. Research on the skeletal remains of individuals who survived versus succumbed to the Black Death in the mid-14th century revealed that the survivors had a propensity for autoimmune conditions. It is possible that the increasing prevalence of autoimmune diseases has been occurring in tandem with modernity's denser populations and rapid travel. An increased temporal incidence of autoimmune conditions has correspondingly been observed in patients with post-SARS-19 infection.
"Certain viruses can act as 'provocateurs' of immune system derangements that persist long after the offending virus is cleared from the system," explains Dr. Mary E. Herman, author of the Research Highlight on Neuroprotection , "How pandemics reshape our brain: Common links and targets between long-haul COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), oxidative stress, and neurodegeneration," published on 29 May 2025.
The enigmatic derangements seen in both long-haul COVID-19 and ME/CFS include, in some individuals, a release of the "brakes"—the inherent constraints—on the activity level of immune function. The array of consequences includes chronic inflammation, such as the characteristic "cytokine storm," as well as the generation of multiple autoantibodies over time. This is in contrast to the production of a single autoantibody in more "classic" autoimmune disorders, such as rheumatoid arthritis or multiple sclerosis. Rather, autoantibodies may be generated against steroid hormones, neurotransmitters, and nuclear factors, among others.
The onset of ME/CFS following viral outbreaks has been recorded as early as 1934. 75 known pandemics caused by a variety of virus provocateurs of ME/CFS have been documented. The prevalence of ME/CFS has nearly tripled since the beginning of the COVID pandemic; approximately half of the cases of long-haul COVID-19 meet the diagnostic criteria for ME/CFS.
"Few patients suffering from long-haul COVID-19 (and the millions of patients with undiagnosed ME/CFS) realize the long road ahead of them. We currently have no curative treatment, and no means to rachet back down the immune system that is jammed in overdrive," says Dr. Herman. "The neurologic outcomes of ME/CFS warrant a call-to-action for contemplative research design in neurodegeneration."
Of equal import is a pressing need to set straight some misconceptions about these diseases. In the rush-to-publish environment of long-haul COVID-19 research, conclusions have been drawn without building on existing research on ME/CFS. New pillars are being laid within neurobiology on erroneous foundations. A number of neuroscientists have recently posited that ME/CFS / long-haul COVID-19 are not neurodegenerative disorders, based on an inability to "retrofit" outcomes of long-haul COVID-19 with those of established neurologic conditions. The errors resulting from this kind of bias have already made for a painful lesson in the field of neurology with the well-known, specious exclusion of a role for insulin in brain energy metabolism. Researchers were simply looking in the wrong place and with the wrong tools.
Meanwhile, other workers found, using EEG, that patterns observed in long-haul COVID-19 patients are reminiscent of patterns characteristic of early neurodegenerative disease. The well-studied disease course of ME/CFS is associated with a wide range of adverse long-term neurologic outcomes. For example, poor and unrefreshing sleep is a prevalent and unrelenting symptom of ME/CFS as well as a strong risk factor for dementia.
The underlying pathophysiologies of ME/CFS include interference with mitochondrial energy conversion. This contributes to profound, often debilitating, fatigue. Malfunctions of metabolic-immune-inflammatory processes are noted across multiple organ systems. Within the neurons, these dysfunctions tax daily operations of the cells, as well as incur long-term detriment to neuron integrity and viability. Oxidative stress is known to be an executioner of apoptosis (cell death) in all neurodegenerative disorders. Multiple perturbed oxidative pathways have been well characterized in the ME/CFS state.
"The immediacy of the pandemic has perhaps led some researchers to a hasty judgement of what long-haul COVID-19 IS and what it is NOT," says Dr. Herman. "The wholesale rejection of these conditions as neurodegenerative not only goes against the wealth of evidence-based research on ME/CFS, but also puts blinders on our perspective. We lose sight of evaluating these patient populations as invaluable research models, clinical correlates, and/or proxies for the study of neurological processes and degeneration, including the effects of sustained oxidative stress."
"This should urge us to expand our definitions of neurodegeneration and neuroprotection to encompass the derivations and variations that exist in ME/CFS," stresses Dr. Herman. Subjects are widely available for clinical studies, from newly diagnosed patients to those whose cells have been functioning under conditions of excessive oxidative stress for decades. Repositories for tissue samples for basic research exist from live patients, and potentially from past ME/CFS donors to the University of Maryland Baltimore Brain & Tissue Bank and other sources.
