Activated immune cells undergo a metabolic switch to aerobic glycolysis akin to the Warburg effect, presenting a potential therapeutic target in autoimmune disease. Dimethyl fumarate, a derivative of the Krebs cycle intermediate fumarate, is an immunomodulatory drug used to treat multiple sclerosis and psoriasis. Although its therapeutic mechanism remains uncertain, it covalently modifies cysteine residues in a process termed “succination.” Here, we show that dimethyl fumarate succinates and inactivates the catalytic cysteine of the glycolytic enzyme GAPDH both in vitro and in vivo. It thereby downregulates aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its anti-inflammatory effects. Our findings provide mechanistic insight into immune modulation by dimethyl fumarate and represent a proof of concept that aerobic glycolysis is a therapeutic target in autoimmunity.

Objective The aim of this work was to determine whether atrophy of specific retinal layers and brain substructures are associated over time, in order to further validate the utility of optical coherence tomography (OCT) as an indicator of neuronal tissue damage in patients with multiple sclerosis (MS). Methods Cirrus high-definition OCT (including automated macular segmentation) was performed in 107 MS patients biannually (median follow-up: 46 months). Three-Tesla magnetic resonance imaging brain scans (including brain-substructure volumetrics) were performed annually. Individual-specific rates of change in retinal and brain measures (estimated with linear regression) were correlated, adjusting for age, sex, disease duration, and optic neuritis (ON) history. Results Rates of ganglion cell + inner plexiform layer (GCIP) and whole-brain (r = 0.45; p<0.001), gray matter (GM; r = 0.37; p<0.001), white matter (WM; r = 0.28; p = 0.007), and thalamic (r = 0.38; p < 0.001) atrophy were associated. GCIP and whole-brain (as well as GM and WM) atrophy rates were more strongly associated in progressive MS (r = 0.67; p<0.001) than relapsing-remitting MS (RRMS; r = 0.33; p = 0.007). However, correlation between rates of GCIP and whole-brain (and additionally GM and WM) atrophy in RRMS increased incrementally with step-wise refinement to exclude ON effects; excluding eyes and then patients (to account for a phenotype effect), the correlation increased to 0.45 and 0.60, respectively, consistent with effect modification. In RRMS, lesion accumulation rate was associated with GCIP (r = −0.30; p = 0.02) and inner nuclear layer (r = −0.25; p = 0.04) atrophy rates. Interpretation Over time GCIP atrophy appears to mirror whole-brain, and particularly GM, atrophy, especially in progressive MS, thereby reflecting underlying disease progression. Our findings support OCT for clinical monitoring and as an outcome in investigative trials.

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Neutron reflectometry analysis methods for under-determined, multi-layered structures are developed and used to determine the composition depth profile in cases where the structure is not known a priori. These methods, including statistical methods, sophisticated fitting routines, and coupling multiple data sets, are applied to hydrated and dehydrated Nafion nano-scaled films with thicknesses comparable to those found coating electrode particles in fuel cell catalyst layers. These results confirm the lamellar structure previously observed on hydrophilic substrates, and demonstrate that for hydrated films they can accurately be described as layers rich in both water and sulfonate groups alternating with water-poor layers containing an excess of fluorocarbon groups. The thickness of these layers increases slightly and the amplitude of the water volume fraction oscillation exponentially decreases away from the hydrophilic interface. For dehydrated films, the composition oscillations die out more rapidly. The Nafion-SiO2 substrate interface contains a partial monolayer of sulfonate groups bonded to the substrate and a large excess of water compared to that expected by the water-to-sulfonate ratio, λ, observed throughout the rest of the film. Films that were made thin enough to truncate this lamellar region showed a depth profile nearly identical to thicker films, indicating that there are no confinement or surface effects altering the structure. Comparing the SLD profile measured for films dried at 60 °C to modeled composition profiles derived by removing water from the hydrated lamellae suggests incomplete re-mixing of the polymer groups upon dehydration, indicated limited polymer mobility in these Nafion thin films.