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.

Keywords: autoimmunity; chronic fatigue syndrome; irritable bowel syndrome; myalgic encephalomyelitis; postexertional malaise.

Figure 1

Approximate course of events during which ME/CFS develops, and overview of the explanatory model. The postulated immunometabolic energy block is shown as an antibody and a mitochondrion. Italicized text refers to the explanatory model presented under “Trying to place it all under one umbrella.” Abbreviations are explained in the text.

Figure 2

Mutational fate of a hypothetic germ line immunoglobulin heavy chain sequence (Vhy) in successive B cell clones, which gradually expand their paratope diversity in interplay with gut microbiota, T cells, and dendritic cells. If there is a chronic antigen stimulation, sequences more or less close to germ line sequence may be selected. Resulting B cells are stored as memory cells in germinal centers of gut-associated lymph nodes. Some of the developmental branches end due to clonal anergy or deletion (tolerization). Others are postulated to descend along a path to autospecificity due to an abnormality in gut commensal spectrum. An exogenous, triggering, antigenic stimulation (e.g., infection), eventually leads to overt pathogenic autospecificity (“evil” B cell clones, magenta) and ME/CFS. Similar fates of other B cell clones, which eventually turn autopathic and give comorbidities, are indicated under “F.” Characters A–F in bold refer to the stages mentioned under “Trying to place it under one umbrella.” This figure was inspired by work on the autoreactive clone VH4-34 (23, 24).

Figure 3

Metabolites and enzymes that are reportedly changed in ME/CFS. Molecules localized in energy metabolic organelles (peroxisome and mitochondrion), and the whole cell, are shown in pink if increased in abundance and green if decreased in abundance. Changes may sometimes be visible only after exercise. The blue “X” indicates a metabolic block implicated in ME/CFS (275). Normally functioning mitochondria convert oxygen to water through the respiratory chain. If the aerobic energy production is impaired, some oxygen can be converted to hydrogen peroxide and reactive oxygen species (ROS). PPP is the pentose phosphate pathway, an alternative pathway for energy production from carbohydrates. It produces the antioxidant NADPH. Together with glutathione, a product of one-carbon metabolism, NADPH controls ROS accumulation (“Redox ctrl”). A panel including some of the marked molecules may be useful as biomarker for ME/CFS.