Dynamic Development of Glucocorticoid Resistance during Autoimmune Neuroinflammation

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 postpartum. 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 nonspecific responses of T cells obtained from mice with EAE. GCresistance 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-alpha expression. GCresistance in T cells was also seen in MS patients with radiological evidence for ongoing inflammation. GCresistance was absent in the MS patients during pregnancy, when relapse risk is decreased, but recurred postpartum, 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. (J Clin Endocrinol Metab 97: E1402-E1410, 2012)