Immune System Sex Differences May Bridge the Gap Between Sex and Gender in Fibromyalgia

Abstract

The fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, sleep disturbances, fatigue, and cognitive alterations. A limited efficacy of targeted treatment and a high FMS prevalence (2-5% of the adult population) sums up to high morbidity. Although, altered nociception has been explained with the central sensitization hypothesis, which may occur after neuropathy, its molecular mechanism is not understood. The marked female predominance among FMS patients is often attributed to a psychosocial predisposition of the female gender, but here we will focus on sex differences in neurobiological processes, specifically those of the immune system, as various immunological biomarkers are altered in FMS. The activation of innate immune sensors is compatible with a neuropathy or virus-induced autoimmune diseases. Considering sex differences in the immune system and the clustering of FMS with autoimmune diseases, we hypothesize that the female predominance in FMS is due to a neuropathy-induced autoimmune pathophysiology. We invite the scientific community to verify the autoimmune hypothesis for FMS.

Keywords: autoimmune disease; central nervous system sensitization; fibromyalgia; pathophysiology; sex differences; widespread chronic pain.

FIGURE 1

The autoimmune hypothesis for FMS. FMS complies with all mentioned risk factors of autoimmune disease, as well as with research biomarkers of an altered immune response. The missing pieces (indicated by “?”) are the evidence of autoantibodies or autoreactive lymphocytes against nervous tissue.

FIGURE 2

Neuroanatomy and chemistry of the central modulation of pain. Blue projections, incoming signals from 1st order neurons; red projections, ascending projections from 2nd order neurons toward thalamus (Thal) and cortical areas; yellow projections, projections for 3rd order neurons to cortical areas for awareness; green projections, descending projections that modulate the pain pathway. I-X, Reddit layers within the gray matter of the spinal cord; ↔, Integration of modulatory ascending and descending information in the dorsal horn Reddit laminae I-V (DH LI-V). 5-HT, serotonin; Aα, Aβ, Aδ y C, incoming nerves with decreasing levels of myelination; Amyg, amygdala; CC, cingulate cortex; CCKBR, cholecystokinin B receptor; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglia; Glu, glutamate; Ins, insula; LC, locus ceruleus; Na_v, voltage-gated sodium channels; NE, norepinephrine; NGF, nerve growth factor; PAG, periaqueductal gray; RN, raphe nucleus; RVM, rostroventral medulla; S1, S, somatosensory areas 1 and 2; SP, substance P; TRP, transient receptor potential sensitive to nociceptive stimulus; μR, μ-opioid receptor with high affinity for enkephalins and beta-endorphin. Image based on (Tracey and Mantyh, 2007; Allen Human Brain Atlas, 2010; Ossipov et al., 2010).