Open AccessThe NRF 2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis
Author(s) -
Hammer Anna,
Waschbisch Anne,
Kuhbandner Kristina,
Bayas Antonios,
Lee DeHyung,
Duscha Alexander,
Haghikia Aiden,
Gold Ralf,
Linker Ralf A.
Publication year - 2018
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.553
Subject(s) - dimethyl fumarate , foxp3 , multiple sclerosis , immune system , medicine , biomarker , cd8 , myeloid , immunology , plasmacytoid dendritic cell , cell , cancer research , t cell , dendritic cell , chemistry , biochemistry
Abstract Objective Immunological studies have demonstrated a plethora of beneficial effects of dimethyl fumarate ( DMF ) on various cell types. However, the cellular and molecular targets are incompletely understood and response markers are scarce. Here, we focus on the relation between nuclear factor (erythroid‐derived 2)‐like 2 ( NRF 2) pathway induction under DMF therapy and the composition of the blood immune cell compartment and clinical efficacy in relapsing‐remitting multiple sclerosis ( MS ) patients. Methods We explored effects of DMF on peripheral immune cell subsets by flow cytometric and transcriptional analysis of serial blood samples obtained from 43 MS patients during the first year of therapy. Results Gene expression analysis proved activation of NRF 2 signaling under DMF therapy that was paralleled by a temporal expansion of FoxP3 + regulatory T cells, CD 56 bright natural killer cells, plasmacytoid dendritic cells, and a decrease in CD 8 + T cells, B cells, and type 1 myeloid dendritic cells. In a subgroup of 28 patients with completely available clinical data, individuals with higher levels of the NRF 2 target gene NAD (P)H quinone dehydrogenase 1 ( NQO 1) 4–6 weeks after DMF therapy initiation were more likely to achieve no evidence of disease activity status 1 year later. The degree of NQO 1 induction further correlated with patient age. Interpretation We demonstrate that positive effects of DMF on the clinical outcome are paralleled by induction of the antioxidant NRF 2 transcriptional pathway and a shift toward regulatory immune cell subsets in the periphery. Our data identify a role of the NRF 2 pathway as potential biomarker for DMF treatment in MS .