In our experience, many patients complain that the effects of stress on MS symptoms can occur within hours. We are not aware of any good empirical work in humans that confirm or disconfirm these reports. Laboratory stressors such as the Trier Social Stress Test (TSST) have been shown to produce significant elevations in proinflammatory cytokines in some studies (Ackerman et al., 1996,1998), although not in others (Heesen et al., 2002, 2005). (We note that Ackerman reported in a personal communication that the cognitive tasks are not as effective as public speaking in eliciting a neuroendocrine stress response among MS patients, possibly because MS patients do not expect themselves to perform as well on cognitive tasks; the two studies that did not elicit a stress response only used cognitive tasks.) However, even when the TSST produced increases in proinflammatory cytokines, these elevations were similar to those seen in healthy controls. Similarly, acute stressors such as injury have not been associated with exacerbation (Goodin et al., 1999). However, it is possible that there are subtle permissive effects and increased risk under specific circumstances. For example, low levels of glucocorticoids, consistent with endogenous cortisol response to moderate stress, may have numerous effects that can promote inflammation, including increased T-cell proliferation (Wiegers et al., 1993, 1995). Indeed, these permissive effects may be particularly enhanced within the central nervous system (Dinkel et al., 2003). However, the mechanism associated with stress onset that has been most thoroughly investigated with respect to potential MS pathways involves the acute activation of mast cells (Theoharides, 2002; Zappulla et al., 2002).
Mast cells have been referred to as an immune gate to the brain (Theoharides, 2002). Increasing evidence suggests that this gate may be opened by environmental stressors (for reviews, see Theoharides, 2002; Zappulla et al., 2002). Mast cells are multifunctional effector cells of the innate immune system and are distributed broadly throughout human tissue, including vascular endothelium in the brain (Zappulla et al., 2002). For more than a century, it has been known that mast cells are found in MS demyelinated plaques, particularly around the venules and capillaries (Kruger et al., 1990; Kruger, 2001). Mast cells may participate in MS exacerbation by facilitating vascular permeability. Mast cells are known to be critical in the initial retardation of leukocytes rolling along the endothelium and the subsequent firm adhesion and extravasation through the cell wall (Kubes and Granger, 1996; Kubes and Ward, 2000). Extravasation is facilitated by mast cell-produced tryptase, as well as adhesion molecules (Kanbe et al., 1999;Theoharides, 2002; Zappulla et al., 2002). All of these vasodilators have been implicated in BBB permeability in MS (Tuomisto et al., 1983; Spuler et al., 1996; Waubant et al., 1999; Piccio et al., 2002).
Mast cell activity is also triggered by stress. Restraint stress has been shown to increase BBB permeability in rats through mast cell activation (Esposito et al., 2001), and subordination stress has been shown to increase numbers of mast cells across a number of brain regions (Cirulli et al., 1998). A principal mediator of stress-related mast cell activation is CRH (Theoharides et al., 1998). Hypothalamic CRH is a primary hormonal response to stressful life events. However, CRH is also present at sites of inflammation. Stress-related BBB breakdown via mast cell activation has repeatedly been shown to be facilitated by immune CRH (Theoharides et al., 1998; Singh et al., 1999; Esposito et al., 2001). Recent studies further indicate that increases in hypothalamic CRH consistent with stress responses can increase immune CRH and induce mast cell degranulation, thereby increasing BBB permeability (Esposito et al., 2002).This would suggest that stress onset might have a permissive effect on MS exacerbation by facilitating BBB permeability.
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