Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model

Abstract

Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Autoimmunity in the condition is an area which remains little researched, and has been most recently summarized and presented as a hypothetical model for ME/CFS, with some ties to gut dysbiosis and aberrant metabolism [105]. Other autoimmune models for ME/CFS have been previously based on rituximab's role in B cell depletion as a possible therapeutic based on the promising outcomes of earlier studies [106,107].…”

Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset

“…Autoantibodies against various antigens, including neurotransmitter receptors, were reported by several groups (3). Comorbidity with Hashimoto's thyroiditis, fibromyalgia, postural orthostatic tachycardia syndrome and a higher rate of autoimmune disease were reported for ME/CFS patients and their families (2,3).…”

“…Patients suffer from persistent exhaustion, cognitive dysfunctions, pain and flu-like symptoms, leading to a substantial reduction of life quality (1). The underlying pathomechanism is not well-understood, but there is convincing evidence that, at least in a subset of ME/CFS patients, autoimmunity contributes to disease etiology (2,3). Autoantibodies against various antigens, including neurotransmitter receptors, were reported by several groups (3).…”

Searching for Serum Antibodies to Neuronal Proteins in Patients With Myalgic Encephalopathy/Chronic Fatigue Syndrome

“…Despite the lack of strong evidence for an increase of these mediators in these patients, 27 cytokine levels might correlate with symptoms severity, 28 and infections and depression 29 can also trigger stress and inflammation, 30,31 which have also been implicated in ME/CSF. 25,32 Several other mechanisms have been implicated in the pathogenesis of ME/CFS, including dysfunction of the neuroendocrine system. Fatigue has been suggested to be the consequence of abnormalities in energy metabolic processes.…”