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- Published: 17 August 2021
Clinical Rheumatology volume 40, pages3865–3866 (2021)Cite this article
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“Everything is autoimmune until proven otherwise” (Yehuda Shoenfeld)
Fibromyalgia scientific knowledge has come a long way from the days when influential physicians viewed fibromyalgia as a “virtual disease” [1] and when fibromyalgia patients were considered “normal people whose individual personality traits and vulnerability predispose them to learning to lead a life of somatizing” [2]. Significant strides in fibromyalgia understanding have been gained in the last decade. The clear link between small fiber neuropathy and fibromyalgia [3] supports the long-standing, but neglected, proposal of fibromyalgia as a neuropathic pain syndrome [4, 5]. Nowadays, skin biopsy and corneal confocal microscopy can objectively define the presence of small nerve fiber pathology in fibromyalgia individuals [3].
A recent meticulous investigation proposes autoimmunity at the epicenter of fibromyalgia pathogenesis. Goebel et al. describe mice injected with immunoglobulin G (IgG) from fibromyalgia patients developing hyperalgesia and peripheral small fiber denervation. Fibromyalgia patients IgG was exclusively accumulated in mice dorsal root ganglia (DRG). Among DRG components, satellite glial cells were the main IgG antigenic target [6]. With this new ground-breaking information, a key investigational issue emerges; is fibromyalgia a primarily autoimmune illness?
Autoimmune disease can be defined as “a pathologic state in which an aberrant immune response directed at a normal bodily constituent leads to inflammation, cell injury, or a functional disturbance with clinical manifestations.” The molecular element (i.e., protein, carbohydrate, nucleic acid) that is targeted in autoimmunity is called an autoantigen. An autoimmune disease usually involves both a T and B cell response and can be generalized or tissue- or organ-specific [7].
Fibromyalgia is clearly a stress-related disorder. Different psychological, physical, metabolic, infectious, and/or autoimmune stressors are frequent fibromyalgia drivers [8] Nevertheless, only a minority of fibromyalgia patients displays clinically recognizable autoimmunity and/or auto-antibodies. The stress-evoked neuropathic pain animal model is informative. In rodents, diverse physical [9] or environmental stressors [10] can lead to DRG phenotypic changes and to hyperalgesia.
Goebel et al.’s autoimmune findings can be reconciled with the proposal of fibromyalgia as a stress-related disorder. Stress-related biomolecules exert control over various cells in the innate and adaptive arms of the immune system. Stress has been linked to the onset and/or exacerbation of diverse autoimmune diseases [11].
DRG have a unique physio-anatomy. They contain the small nerve fiber nucleus tightly enveloped by immunologically active satellite glial cells and surrounded by different immune competent/pronociceptive mediators including macrophages and lymphocytes [12]. DRG can sequester antigen-specific antibodies [13]. Different stressors induce profound DRG phenotypic changes [9].
It can be postulated that in fibromyalgia, stress-evoked DRG molecular changes become antigenic. These neo-antigens would induce localized antibody response leading to sensory nerve fiber inflammation, hyper-excitability, and peripheral denervation. DRG phenotypic changes can also explain fibromyalgia dysautonomia-related symptoms including chronic fatigue and irritable bowel. There is direct anatomical communication between DRG and the paravertebral sympathetic chain [14]. DRG mechanosensitive neurons projecting to distal blood vessels seem to play a major role in cardiovascular autonomic regulation [15]. Satellite glial cells not only encase DRG neuron cell bodies but also neurons lying in sympathetic and parasympathetic ganglia [16].
Goebel et al.’s provocative study supports our reiterated proposal of DRG as the key neural hub where different fibromyalgia-inducing stressors, including autoimmune illnesses, are converted into neuropathic pain [14, 17, 18].
More research is needed to define if fibromyalgia is a localized autoimmune illness. Auspiciously, we have now a novel coherent physio-pathological model to explain fibromyalgia elusive mechanisms. Accumulating evidence proposes DRG at the epicenter of fibromyalgia pain, and this is a clearly testable hypothesis. DRG culture has become a standard research tool. Cultured DRG would be able to identify the purported fibromyalgia antigen. This in vitro assay can be applied in studies using neural electrophysiology, signal transduction, neurotransmitter release, or imaging [19]. Theoretically, DRG culture may also help to design specific fibromyalgia therapeutic molecules directed to well-defined pronociceptive targets or antigenic epitopes.
We are transiting from an era of misogynistic disbelief of fibromyalgia structural underpinning to a time of innovative research based on well-structured scientific evidence.