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Background: Dimethyl fumarate (DMF) and its active metabolite monomethyl fumarate (MMF) effectively lead to reduction in disease relapses and active magnetic resonance imaging (MRI) lesions. DMF and MMF are known to be effective in modulating T- and B-cell responses; however, their effect on the phenotype and function of human myeloid dendritic cells (mDCs) is not fully understood. Objective: To investigate the role of MMF on human mDCs maturation and function. Methods: mDCs from healthy controls were isolated and cultured in vitro with MMF. The effect of MMF on mDC gene expression was determined by polymerase chain reaction (PCR) array after in vitro MMF treatment. The ability of mDCs to activate T cells was assessed by in vitro co-culture system. mDCs from DMF-treated multiple sclerosis (MS) patients were analyzed by flow cytometry and PCR. Results: MMF treatment induced a less mature phenotype of mDCs with reduced expression of major histocompatibility complex class II (MHC-II), co-stimulatory molecules CD86, CD40, CD83, and expression of nuclear factor κB (NF-κB) subunits RELA and RELB. mDCs from DMF-treated MS patients also showed the same immature phenotype. T cells co-cultured with MMF-treated mDCs showed reduced proliferation with decreased production of interferon gamma (IFN-γ), interleukin-17 (IL-17), and granulocyte-macrophage colony-stimulating factor (GM-CSF) compared to untreated cells. Conclusion: We report that MMF can modulate immune response by affecting human mDC function.

Objective Effect of a probiotic on the gut microbiome and peripheral immune function in healthy controls and relapsing-remitting multiple sclerosis (MS) patients. Methods MS patients (N = 9) and controls (N = 13) were orally administered a probiotic containing Lactobacillus, Bifidobacterium, and Streptococcus twice-daily for two months. Blood and stool specimens were collected at baseline, after completion of the 2-month treatment, and 3 months after discontinuation of therapy. Frozen peripheral blood mononuclear cells (PBMCs) were used for immune cell profiling. Stool samples were used for 16S rRNA profiling and metabolomics. Results Probiotic administration increased the abundance of several taxa known to be depleted in MS such as Lactobacillus. We found that probiotic use decreased the abundance of taxa previously associated with dysbiosis in MS, including Akkermansia and Blautia. Predictive metagenomic analysis revealed a decrease in the abundance of several KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways associated with altered gut microbiota function in MS patients, such as methane metabolism, following probiotic supplementation. At the immune level, probiotic administration induced an anti-inflammatory peripheral immune response characterized by decreased frequency of inflammatory monocytes, decreased mean fluorescence intensity (MFI) of CD80 on classical monocytes, as well as decreased human leukocyte antigen (HLA) D related MFI on dendritic cells. Probiotic administration was also associated with decreased expression of MS risk allele HLA-DQA1 in controls. Probiotic-induced increase in abundance of Lactobacillus and Bifidobacterium was associated with decreased expression of MS risk allele HLA.DPB1 in controls. Interpretation Our results suggest that probiotics could have a synergistic effect with current MS therapies. Ann Neurol 2018.

We have previously reported the molecular signature of murine pathogenic TH17 cells that induce experimental autoimmune encephalomyelitis (EAE) in animals. Here we show that human peripheral blood IFN-γ+IL-17+ (TH1/17) and IFN-γ−IL-17+ (TH17) CD4+ T cells display distinct transcriptional profiles in high-throughput transcription analyses. Compared to TH17 cells, TH1/17 cells have gene signatures with marked similarity to mouse pathogenic TH17 cells. Assessing 15 representative signature genes in patients with multiple sclerosis, we find that TH1/17 cells have elevated expression of CXCR3 and reduced expression of IFNG, CCL3, CLL4, GZMB, and IL10 compared to healthy controls. Moreover, higher expression of IL10 in TH17 cells is found in clinically stable vs. active patients. Our results define the molecular signature of human pro-inflammatory TH17 cells, which can be used to both identify pathogenic TH17 cells and to measure the effect of treatment on TH17 cells in human autoimmune diseases., CD4+ T cells secreting interleukin-17 (TH17) have diverse functions in modulating autoimmune diseases. Here the authors show via transcriptome analyses that a subset of human TH 17 co-expressing interferon-γ (TH1/17) has a molecular signature similar to “pathogenic” mouse TH 17 but distinct from “non-pathogenic” mouse TH 17.

Objective To assess the value of annual serum neurofilament light (NfL) measures in predicting 10‐year clinical and MRI outcomes in multiple sclerosis (MS). Methods We identified patients in our center's Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study enrolled within 5 years of disease onset, and with annual blood samples up to 10 years (n = 122). Serum NfL was measured using a single molecule array (SIMOA) assay. An automated pipeline quantified brain T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) from year 10 high‐resolution 3T MRI scans. Correlations between averaged annual NfL and 10‐year clinical/MRI outcomes were assessed using Spearman's correlation, univariate, and multivariate linear regression models. Results Averaged annual NfL values were negatively associated with year 10 BPF, which included averaged year 1–5 NfL values (unadjusted P < 0.01; adjusted analysis P < 0.01), and averaged values through year 10. Linear regression analyses of averaged annual NfL values showed multiple associations with T2LV, specifically averaged year 1–5 NfL (unadjusted P < 0.01; adjusted analysis P < 0.01). Approximately 15–20% of the BPF variance and T2LV could be predicted from early averaged annual NfL levels. Also, averaged annual NfL levels with fatigue score worsening between years 1 and 10 showed statistically significant associations. However, averaged NfL measurements were not associated with year 10 EDSS, SDMT or T25FW in this cohort. Interpretation Serum NfL measured during the first few years after the clinical onset of MS contributed to the prediction of 10‐year MRI brain lesion load and atrophy.