Decreased hydrocortisone sensitivity of T cell function in multiple sclerosis-associated major depression

Abstract

Summary Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS with a high prevalence of depression. Both MS and depression have been linked to elevated cortisol levels and inflammation, indicating disturbed endocrine-immune regulation. An imbalance in mineralocorticoid versus glucocorticoid signaling in the CNS has been proposed as a pathogenetic mechanism of depression. Intriguingly, both receptors are also expressed in lymphocytes, but their role for 'escape' of the immune system from endocrine control is unknown. Using steroid sensitivity of T cell function as a read-out system, we here investigate a potential role of mineralocorticoid receptor (MR) versus glucocorticoid receptor (GR) regulation in the immune system as a biological mechanism underlying MS-associated major depression. Twelve female MS patients meeting diagnostic criteria for current major depressive disorder (MDD) were compared to twelve carefully matched MS patients without depression. We performed lymphocyte phenotyping by flow cytometry. In addition, steroid sensitivity of T cell proliferation was tested using hydrocortisone as well as MR (aldosterone) and GR (dexamethasone) agonists. Sensitivity to hydrocortisone was decreased in T cells from depressed MS patients. Experiments with agonists suggested disturbed MR regulation, but intact GR function. Importantly, there were no differences in lymphocyte composition and frequency of T cell subsets, indicating that the differences in steroid sensitivity are unlikely to be secondary to shifts in the immune compartment. To our knowledge, this study provides first evidence for altered steroid sensitivity of T cells from MS patients with comorbid MDD possibly due to MR dysregulation.

Glucocorticoid mediated regulation of inflammation in human monocytes is associated with depressive mood and obesity

“…For example, impaired suppression of T-cell proliferation by dexamethasone was prospectively associated with greater depressive symptoms in deployed military personnel (van Zuiden et al, 2012) and multiple sclerosis patients (Fischer et al, 2012). However, the findings of TNF production in relation to GC sensitivity are limited; to our knowledge, no other reports are currently available in which intracellular monocytic TNF was measured under cortisol treatment to directly investigate cellular responses in a well-defined monocytic population.…”

The inflammasome: Pathways linking psychological stress, depression, and systemic illnesses

“…The prevalence of depression in populations with these different diseases is much higher (up to 30% or even higher) than that of the general population, which is 10.3%. (Bachen et al, 2009; Besnard et al, 2011; Cafarella et al, 2012; Duewell et al, 2010; Eisner et al, 2005; Evans et al, 2005; Fischer et al, 2012; Gasse et al, 2009; Gris et al, 2010; Halle et al, 2008; Kastbom et al, 2008; Kessler et al, 1994; Mason et al, 2012; Mitroulis et al, 2010; Nery et al, 2007; Pontillo et al, 2012; Sheehy et al, 2006; Shin et al, 2012; Vandanmagsar et al, 2011; Wen et al, 2011; Zhou et al, 2010). …”

Steroid Regulation of T Cell Function Appears Unaltered in Borderline Personality Disorder

“…The inhibitory concentration 50 (IC-50) values representing concentrations inhibiting 50% of the PHA-induced proliferation for each subject and agonist were determined by nonlinear sigmoidal curve fitting utilizing Prism® Software as described by Fischer et al (2012). All variables were tested for normality and equality of variance.…”

“…Our data suggest that GC sensitivity of T cell function is unaltered in BDP, which may indicate a tissue-specific dysregulation of steroid signaling. In vitro inhibition of cell proliferation has previously been used to reveal differences in GC sensitivity of T cells as a biological substrate of depressive symptoms in patients with multiple sclerosis, a neuroinflammtory disease of presumably T cell-driven origin (Fischer et al, 2012). Similarly, studies have shown altered GC sensitivity of T cell proliferation in patients with PTSD (de Kloet et al, 2007) and major depression (Lowy, Reder, Gormley, & Meltzer, 1988;Wodarz et al, 1991).…”

“…Samples from BPD patients and HC were run in parallel using the same batch of reagents. Functional steroid sensitivity of T cell function was assessed as previously described (Fischer et al, 2012). Cells were seeded at 2 × 10 6 viable cells/mL in RPMI-1640 (PAA Laboratories, Pasching, Austria) supplemented with 2 mM L-glutamine and penicillin/streptomycin and stimulated with phytohemagglutinin (PHA) at a concentration of 1 µg/mL alone or in combination with one of seven concentrations of the agonists dexamethasone (10 -12 M to 10 -6 M), aldosterone, or hydrocortisone (each 10 -11 M to 10 -5 M).…”