Dynamic development of glucocorticoid resistance during autoimmune neuroinflammation.
BACKGROUND
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).


METHODS
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.


METHODS
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.
Center for Molecular Neurobiology, University Hospital Hamburg-Eppendorf, Falkenried 94, D-20251 Hamburg, Germany. stefan.gold@zmnh.uni-hamburg.de
Stefan M
SM
Gold
Manda V
MV
Sasidhar
Venu
V
Lagishetty
Rory D
RD
Spence
Elizabeth
E
Umeda
Marina O
MO
Ziehn
Thorsten
T
Krieger
Karl-Heinz
KH
Schulz
Christoph
C
Heesen
Martin
M
Hewison
Rhonda R
RR
Voskuhl
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001324:Autoantigens / Q000276:immunology; D003430:Cross-Sectional Studies; D004351:Drug Resistance; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
D001324:Autoantigens; D005938:Glucocorticoids; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C445081:myelin oligodendrocyte glycoprotein (35-55)