TY - JOUR
T1 - Brain-homing CD4+ T cells display glucocorticoid-resistant features in MS
AU - Koetzier, Steven C
AU - van Langelaar, Jamie
AU - Blok, Katelijn M
AU - van den Bosch, Thierry P P
AU - Wierenga-Wolf, Annet F
AU - Melief, Marie-José
AU - Pol, Kim
AU - Siepman, Theodora A
AU - Verjans, Georges M G M
AU - Smolders, Joost
AU - Lubberts, Erik
AU - de Vries, Helga E
AU - van Luijn, Marvin M
N1 - Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
PY - 2020
Y1 - 2020
N2 - OBJECTIVE: To study whether glucocorticoid (GC) resistance delineates disease-relevant T helper (Th) subsets that home to the CNS of patients with early MS.METHODS: The expression of key determinants of GC sensitivity, multidrug resistance protein 1 (MDR1/ABCB1) and glucocorticoid receptor (GR/NR3C1), was investigated in proinflammatory Th subsets and compared between natalizumab-treated patients with MS and healthy individuals. Blood, CSF, and brain compartments from patients with MS were assessed for the recruitment of GC-resistant Th subsets using fluorescence-activated cell sorting (FACS), quantitative polymerase chain reaction (qPCR), immunohistochemistry, and immunofluorescence.RESULTS: An MS-associated Th subset termed Th17.1 showed a distinct GC-resistant phenotype as reflected by high MDR1 and low GR expression. This expression ratio was further elevated in Th17.1 cells that accumulated in the blood of patients with MS treated with natalizumab, a drug that prevents their entry into the CNS. Proinflammatory markers C-C chemokine receptor 6, IL-23R, IFN-γ, and GM-CSF were increased in MDR1-expressing Th17.1 cells. This subset predominated the CSF of patients with early MS, which was not seen in the paired blood or in the CSF from patients with other inflammatory and noninflammatory neurologic disorders. The potential of MDR1-expressing Th17.1 cells to infiltrate brain tissue was confirmed by their presence in MS white matter lesions.CONCLUSION: This study reveals that GC resistance coincides with preferential CNS recruitment of pathogenic Th17.1 cells, which may hamper the long-term efficacy of GCs in early MS.
AB - OBJECTIVE: To study whether glucocorticoid (GC) resistance delineates disease-relevant T helper (Th) subsets that home to the CNS of patients with early MS.METHODS: The expression of key determinants of GC sensitivity, multidrug resistance protein 1 (MDR1/ABCB1) and glucocorticoid receptor (GR/NR3C1), was investigated in proinflammatory Th subsets and compared between natalizumab-treated patients with MS and healthy individuals. Blood, CSF, and brain compartments from patients with MS were assessed for the recruitment of GC-resistant Th subsets using fluorescence-activated cell sorting (FACS), quantitative polymerase chain reaction (qPCR), immunohistochemistry, and immunofluorescence.RESULTS: An MS-associated Th subset termed Th17.1 showed a distinct GC-resistant phenotype as reflected by high MDR1 and low GR expression. This expression ratio was further elevated in Th17.1 cells that accumulated in the blood of patients with MS treated with natalizumab, a drug that prevents their entry into the CNS. Proinflammatory markers C-C chemokine receptor 6, IL-23R, IFN-γ, and GM-CSF were increased in MDR1-expressing Th17.1 cells. This subset predominated the CSF of patients with early MS, which was not seen in the paired blood or in the CSF from patients with other inflammatory and noninflammatory neurologic disorders. The potential of MDR1-expressing Th17.1 cells to infiltrate brain tissue was confirmed by their presence in MS white matter lesions.CONCLUSION: This study reveals that GC resistance coincides with preferential CNS recruitment of pathogenic Th17.1 cells, which may hamper the long-term efficacy of GCs in early MS.
U2 - 10.1212/NXI.0000000000000894
DO - 10.1212/NXI.0000000000000894
M3 - Article
C2 - 33037101
SN - 2332-7812
VL - 7
JO - Neurology(R) neuroimmunology & neuroinflammation
JF - Neurology(R) neuroimmunology & neuroinflammation
IS - 6
ER -