Stress describes an adaptive response to noxious endogenous (somatic or psychological) or exogenous stimuli (stressors) which threaten the homeostasis of the organism. Walter B. Cannon employed the greek term homeostasis [from greek homoios (like) and stasis], to describe the capacity of the organism to maintain a dynamic equilibrium via adaptive changes in human physiology which occur in response to nociceptive events, described as “fight or flight response’’ (Cannon, 1929). The latter aims to preserve or reinstitute a new level of homeostasis (called allostasis) in systems of the organism such as the immune system (Nikolaides et al., 2015). In his turn, H. Selye in 1936 defined stress as a general adaptation syndrome which from biological point of view is a “non-specific response of the body to any demand made upon it” (Selye, 1976). In 1992, Chrousos and Gold proposed that above a threshold of intensity, any stressor would elicit the stress adaptive response (Chrousos and Gold, 1992). Stressors can elicit this response either acutely or chronically. Different forms of stressors may have different effects on the release of stress hormones as well as on the immune function (Webster Marketon and Glaser, 2008). This systemic response involves parts of the central nervous system (CNS) and peripheral organs (Nikolaides et al., 2015, Chrousos and Gold, 1992). Thus, the stress system comprises the hypothalamic–pituitary–adrenal (HPA) axis and the locus ceruleus (LC)/norepinephrine (NE) system, which interact at multiple levels and modulate the stress response including that of the immune system. A dysregulated stress adaptive response could interfere with the modulation of the chronic inflammatory/immune (I/I) response including that in autoimmune diseases (e.g. multiple sclerosis, MS) (Nezi et al., 2015).

Multiple sclerosis, the most common autoimmune inflammatory neurological disease, is characterized by multifocal demyelinating lesions which originate from the white matter in the CNS and lead to disturbed nerve conduction (What is MS, 2024). Its pathogenesis remains obscure and involves a multifactorial combination of genetic and environmental mechanisms with a subsequent immune cell-mediated destruction of myelin followed by axonal damage and glial scars in areas of the brain and the spinal cord. It affects over 2.2 million individuals world-wide and it manifests with heterogeneous clinical symptoms. Multiple sclerosis is clinically divided in three forms: relapsing/remitting (RRMS), primary progressive (PPMS) and secondary progressive (SPMS) (GBD 2019 Diseases and Injuries Collaborators, 2020).

In this review we explore critically the role of the stress adaptive response in the generation, manifestation and exacerbation of MS.