Inflammation, Autoimmunity, and Infection in Fibromyalgia: A Narrative Review

Abstract

Fibromyalgia (FM) is a chronic disease characterized by widespread musculoskeletal pain of unknown etiology. The condition is commonly associated with other symptoms, including fatigue, sleep disturbances, cognitive impairment, and depression. For this reason, FM is also referred to as FM syndrome. The nature of the pain is defined as nociplastic according to the latest international classification and is characterized by altered nervous sensitization both centrally and peripherally. Psychosocial conditions have traditionally been considered critical in the genesis of FM. However, recent studies in animal models and humans have provided new evidence in favor of an inflammatory and/or autoimmune pathogenesis. In support of this hypothesis are epidemiological data of an increased female prevalence, similar to that of autoimmune diseases, and the frequent association with immune-mediated inflammatory disorders. In addition, the observation of an increased incidence of this condition during long COVID revived the hypothesis of an infectious pathogenesis. This narrative review will, therefore, discuss the evidence supporting the immune-mediated pathogenesis of FM in light of the most current data available in the literature.

Keywords: autoimmunity; fibromyalgia; immune system; infection; inflammation.

Figure 1

Passive transfer of serum IgG from fibromyalgia patients into mice induces fibromyalgia-like pain. Goebel et al. [122] recently demonstrated in an elegant experimental model that passive transfer of IgG-class immunoglobulin from fibromyalgia patients to mice induced sensory hypersensitivity through sensitization of nociceptive neurons. This experiment represented a breakthrough in understanding the pathogenesis of fibromyalgia, strongly suggesting an autoimmune mechanism mediated by antibodies against satellite glial cells and neurons.

Figure 2

Induction of nociplastic pain by cells of the immune system. Cells of the innate and adaptive immune systems may participate in the genesis of nociplastic pain in FM. Microglia cells, neutrophils, and mast cells produce interleukins and chemokines. B cells produce autoantibodies against nerve cells. T cells produce both inflammatory cytokines, such as IFN-γ and IL-17, and anti-inflammatory cytokines, such as IL-10. NK cells are believed to inhibit pain through their stimulation of Mu-type opioid receptors. Viral and bacterial pathogens can act as stimulators of the immune system. The red circle banned sign above the arrow indicates the inhibitory action by the cell.

Figure 3

Factors participating in the pathogenesis of fibromyalgia. Several factors are involved in the genesis of fibromyalgia (FM). Traditionally, psychosocial stress has been considered the main event in individuals predisposed to the activation of both central and peripheral pain sensitization. However, recent findings have demonstrated the key role played by the immune system. Inflammation mediated by mast cells, neutrophils, microglia cells, and natural killer (NK) cells produces several proinflammatory cytokines and chemokines that contribute to neuroinflammation and the subsequent increase in pain sensitization. On the other hand, recent studies have also involved adaptive immunity, demonstrating the role of T cells, particularly T helper (Th)-1 and Th17 cells capable of producing pro-inflammatory cytokines, and B cells through the production of neuron-specific autoantibodies, as demonstrated through animal models of passive IgG transfer in experimental animals. Finally, infections play an important role. In particular, infection with SARS-CoV-2, the causative agent of COVID-19, is believed to be responsible, through still unknown mechanisms, for the increased incidence of FM reported during the so-called “long COVID”. Once grafted, fibromyalgia has a chronic course and, in addition to widespread musculoskeletal pain, is accompanied by various debilitating symptoms such as depression, fatigue, cognitive impairment, also referred to as fibro fog, and sleep disturbances.