This figure describes the putative role of immune brain communication in the pathogenesis of severe intractable fatigue. Toll-like receptors (TLRs) on antigen presentation cells (APCs) may be activated by pathogen- or damage-associated molecular patterns (PAMPs/DAMPs) leading to the activation of nuclear factor-κB (NF-κB) and the subsequent upregulation of pro-inflammatory cytokines (PICs), including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and reactive oxygen and nitrogen species (ROS/RNS). These radical species may further damage macromolecules, increasing levels of redox-derived DAMPs which further engage TLRs in a self-sustaining cycle. PIC signals reach the brain via the afferent arm of the vagus nerve, engagement with transporters in the blood brain barrier (BBB) and passive diffusion. Inflammatory signaling from the periphery activates microglia which produce a range of neurotoxic molecules activating astrocytes causing a loss of brain homoeostasis and disruption of the BBB. The latter allows abnormally high numbers of activated T and B cells and macrophages to circulate between the periphery and the brain. This figure is original.