Epub: Gold et al. Dynamic Development of Glucocorticoid Resistance during Autoimmune Neuroinflammation. J Clin Endocrinol Metab. 2012 Jun 1.
Context: Glucocorticoids (GC) are powerful endogenous and therapeutic modulators of inflammation and play a critical role for controlling autoimmunity. GC resistance can be seen in patients with cell-mediated autoimmune disorders, but it is unknown whether this represents a stable trait or a state.
Objective: The objective of the study was to determine whether GC resistance of T cell responses is dynamically regulated in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS).
Design: This was a translational observational study.
Patients and animals: EAE was induced in C57BL/6 mice. A cross-sectional sample of 25 patients with relapsing-remitting MS was included as well as four MS patients during pregnancy and post-partum (after delivery of the baby).
Main outcome measures: Outcome measures included GC sensitivity of T cell proliferation and GC-mediated apoptosis.
Results: GC resistance was seen in both autoantigen-specific and non-specific responses of T cells obtained from mice with EAE. GC resistance preceded clinical symptoms and central nervous system infiltration of immune cells. T cells obtained during EAE were resistant to GC-induced apoptosis, and this was linked to down-regulation of GC receptor-α expression. GC resistance in T cells was also seen in MS patients with radiological evidence for ongoing inflammation. GC resistance was absent in the MS patients during pregnancy, when relapse risk is decreased, but recurred post-partum, a time of increased relapse risk.
Conclusions: These data demonstrate that GC resistance during autoimmune neuroinflammation is dynamically regulated. This has implications for the timing of steroid treatments and provides a putative pathway to explain the observed association between psychological stress and exacerbation of autoimmune diseases.
Glucocorticoids (GC) are a class of steroid hormones that bind to the glucocorticoid receptor (GR). The name glucocorticoid (glucose + cortex + steroid) derives from their role in the regulation of the metabolism of glucose, their synthesis in the adrenal cortex, and their steroidal structure.
GCs are part of the feedback mechanism in the immune system that turns immune activity (inflammation) down.
- When you take steroids (such as methyl prednisolone) the body stops producing the steroid hormones from the adrenal glands. So this is why you have to be careful when using them and why you taper-down the dosing rather stopping abruptly.
- However, cells may be insensitive to the actions of the corticosteriods and this is steroid resistance. This could be lack of inhibition to immune cell growth or steroid- induced killing of the cells (apoptosis = cell suicide) that can quell the response.
- This study shows that there is a dynamic change in steroid resistance in animal models of MS.
- In MS this insensitivity was absent after having the baby when there is a risk of MS relapse. This could imply that one could be resistant to steroids at a time, when they would be used therapeutically, such as during relapse.
- However, there is reason to believe that during relapse there is some positive response to glucocoritcosteroids, because this is how they are used.
- Whilst this has impact on physiological stress, how this really ties in with physchological stress, is far from clear.