Dynamic Development of Glucocorticoid Resistance during Autoimmune Neuroinflammation

• Published in: The journal of clinical endocrinology and metabolism 2012-08, Vol.97 (8), p.E1402-E1410
• Main Authors: Gold, Stefan M, Sasidhar, Manda V, Lagishetty, Venu, Spence, Rory D, Umeda, Elizabeth, Ziehn, Marina O, Krieger, Thorsten, Schulz, Karl-Heinz, Heesen, Christoph, Hewison, Martin, Voskuhl, Rhonda R
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Autoantigens - immunology; Cross-Sectional Studies; Drug Resistance; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Female; Glucocorticoids - therapeutic use; Glycoproteins - immunology; Hot Topics in Translational Endocrinology; Humans; Male; Mice; Mice, Inbred C57BL; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments - immunology; Receptors, Glucocorticoid - genetics; T-Lymphocytes - immunology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2012-1294

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. 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 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.