Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease, mediated by pathogenic T helper 17 (Th17) cells. However, the therapeutic effect is accompanied by the fluctuation of the proportion and function of Th17 cells, which prompted us to find the key regulator of Th17 differentiation in MS. Here, we demonstrated that the triggering receptor expressed on myeloid cells 2 (TREM-2), a modulator of pattern recognition receptors on innate immune cells, was highly expressed on pathogenic CD4-positive T lymphocyte (CD4⁺ T) cells in both patients with MS and experimental autoimmune encephalomyelitis (EAE) mouse models. Conditional knockout of Trem-2 in CD4⁺ T cells significantly alleviated the disease activity and reduced Th17 cell infiltration, activation, differentiation, and inflammatory cytokine production and secretion in EAE mice. Furthermore, with Trem-2 knockout in vivo experiments and in vitro inhibitor assays, the TREM-2/zeta-chain associated protein kinase 70 (ZAP70)/signal transducer and activator of transcription 3 (STAT3) signal axis was essential for Th17 activation and differentiation in EAE progression. In conclusion, TREM-2 is a key regulator of pathogenic Th17 in EAE mice, and this sheds new light on the potential of this therapeutic target for MS.
Animals ; Humans ; Mice ; CD4-Positive T-Lymphocytes/pathology* ; Cell Differentiation ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Mice, Inbred C57BL ; Multiple Sclerosis ; Th1 Cells/pathology*

Humans ; PPAR gamma/metabolism* ; Multiple Sclerosis ; Transcription Factors/metabolism* ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

The primary chemical components of Astragalus membranaceus include polysaccharides, saponins, flavonoids, and amino acids. Recent studies have shown that Astragalus membranaceus has multiple functions, including improving immune function and exerting antioxidative, anti-radiation, anti-tumor, antibacterial, antiviral, and hormone-like effects. Astragalus membranaceus and its extracts are widely used in clinical practice because they have obvious therapeutic effects against various autoimmune diseases and relatively less adverse reaction. Multiple sclerosis (MS) is an autoimmune disease of central nervous system (CNS), which mainly caused by immune disorder that leads to inflammatory demyelination, inflammatory cell infiltration, and axonal degeneration in the CNS. In this review, the authors analyzed the clinical manifestations of MS and experimental autoimmune encephalomyelitis (EAE) and focused on the efficacy of Astragalus membranaceus and its chemical components in the treatment of MS/EAE.
Animals ; Humans ; Astragalus propinquus/chemistry* ; Multiple Sclerosis/drug therapy* ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Drugs, Chinese Herbal/chemistry* ; Polysaccharides

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), a pathologically similar disease used to model MS in rodents, are typical CD4+ T cell-dominated autoimmune diseases. CD4+ interleukin (IL)17+ T cells (Th17 cells) have been well studied and have shown that they play a critical role in the pathogenesis of MS/EAE. However, studies have suggested that CD8+IL17+ T cells (Tc17 cells) have a similar phenotype and cytokine and transcription factor profiles to those of Th17 cells and have been found to be crucial in the pathogenesis of autoimmune diseases, including MS/EAE, psoriasis, type I diabetes, rheumatoid arthritis, and systemic lupus erythematosus. However, the evidence for this is indirect and insufficient. Therefore, we searched for related publications and attempted to summarize the current knowledge on the role of Tc17 cells in the pathogenesis of MS/EAE, as well as in the pathogenesis of other autoimmune diseases, and to find out whether Tc17 cells or Th17 cells play a more critical role in autoimmune disease, especially in MS and EAE pathogenesis, or whether the interaction between these two cell types plays a critical role in the development of the disease.
Animals ; Mice ; Encephalomyelitis, Autoimmune, Experimental ; Th17 Cells ; CD8-Positive T-Lymphocytes/metabolism* ; CD4-Positive T-Lymphocytes/metabolism* ; Multiple Sclerosis/metabolism* ; Mice, Inbred C57BL

Background: Disease-modifying therapy is the standard treatment for patients with multiple sclerosis (MS) in remission. The primary objective of the current analysis was to assess the efficacy and safety of two teriflunomide doses (7 mg and 14 mg) in the subgroup of Chinese patients with relapsing MS included in the TOWER study. Methods: TOWER was a multicenter, multinational, randomized, double-blind, parallel-group (three groups), placebo-controlled study. This subgroup analysis includes 148 Chinese patients randomized to receive either teriflunomide 7 mg (n = 51), teriflunomide 14 mg (n = 43), or placebo (n = 54). Results: Of the 148 patients in the intent-to-treat population, adjusted annualized relapse rates were 0.63 (95% confidence interval [CI]: 0.44, 0.92) in the placebo group, 0.48 (95% CI: 0.33, 0.70) in the teriflunomide 7 mg group, and 0.18 (95% CI: 0.09, 0.36) in the teriflunomide 14 mg group; this corresponded to a significant relative risk reduction in the teriflunomide 14 mg group versus placebo (-71.2%, P = 0.0012). Teriflunomide 14 mg also tended to reduce 12-week confirmed disability worsening by 68.1% compared with placebo (hazard ratio: 0.319, P = 0.1194). There were no differences across all treatment groups in the proportion of patients with treatment-emergent adverse events (TEAEs; 72.2% in the placebo group, 74.5% in the teriflunomide 7 mg group, and 69.8% in the teriflunomide 14 mg group); corresponding proportions for serious adverse events were 11.1%, 3.9%, and 11.6%, respectively. The most frequently reported TEAEs with teriflunomide versus placebo were neutropenia, increased alanine aminotransferase, and hair thinning. Conclusions: Teriflunomide was as effective and safe in the Chinese subpopulation as it was in the overall population of patients in the TOWER trial. Teriflunomide has the potential to meet unmet medical needs for MS patients in China. Trial Registration ClinicalTrials.gov, NCT00751881; https://clinicaltrials.gov/ct2/show/NCT00751881?term=NCT00751881&rank=1.
China ; Crotonates ; administration & dosage ; adverse effects ; therapeutic use ; Double-Blind Method ; Drug Administration Schedule ; Humans ; Immunosuppressive Agents ; administration & dosage ; adverse effects ; therapeutic use ; Multicenter Studies as Topic ; Multiple Sclerosis ; drug therapy ; metabolism ; Proportional Hazards Models ; Toluidines ; administration & dosage ; adverse effects ; therapeutic use

Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. It has a physiologic role in DNA metabolism via methylation, a process governed by the presentation of folate, and vitamins B6 and B12. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy (eHcy) can be caused by deficiency of either vitamin B12 or folate, or a combination thereof. Certain genetic factors also cause eHcy, such as C667T substitution of the gene encoding methylenetetrahydrofolate reductase. eHcy has been observed in several medical conditions, such as cardiovascular disorders, atherosclerosis, myocardial infarction, stroke, minimal cognitive impairment, dementia, Parkinson's disease, multiple sclerosis, epilepsy, and eclampsia. There is evidence from laboratory and clinical studies that Hcy, and especially eHcy, exerts direct toxic effects on both the vascular and nervous systems. This article provides a review of the current literature on the possible roles of eHcy relevant to various neurologic disorders.
Atherosclerosis ; Dementia ; DNA ; Eclampsia ; Epilepsy ; Female ; Folic Acid ; Homocysteine ; Hyperhomocysteinemia* ; Metabolism ; Methionine ; Methylation ; Methylenetetrahydrofolate Reductase (NADPH2) ; Multiple Sclerosis ; Myocardial Infarction ; Nervous System ; Nervous System Diseases* ; Parkinson Disease ; Plasma ; Pregnancy ; Stroke ; Vitamin B 12 ; Vitamins

BACKGROUNDBilirubin is the end product of heme catabolism and has strong antioxidant properties. Serum bilirubin levels are reported to be reduced in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). The pathophysiology of optic neuritis (ON) resembles that of MS; however, the role of endogenous bilirubin in ON is unclear. The aim of this study is to measure serum bilirubin levels in patients with ON, and to investigate the correlation between ON and serum antioxidant status of bilirubin.

METHODSSerum levels of bilirubin were measured in 42 patients with ON, 50 patients with multiple sclerosis (MS), 48 patients with neuromyelitis optica (NMO) and 48 healthy control subjects.

RESULTSSerum total bilirubin (Tbil), direct bilirubin (Dbil) and indirect bilirubin (Ibil) levels in patients with ON were significantly lower than those in the healthy controls. However, no statistical significance was found between levels in the ON and MS, ON and NMO, and MS and NMO groups. In patients with ON, serum Tbil, Dbil, and Ibil levels were lower in those with recurrence or those with ON for a longer duration (≥ 1 year). Moreover, Tbil, Dbil, and Ibil concentrations were lower in patients with papillitis than in those with retrobulbar type ON, but the differences were not statistically significant.

CONCLUSIONSLow antioxidant status may exist in patients with ON. But serum levels of Tbil, Dbil, and Ibil did not correlate with clinical presentations, such as recurrence, duration of disease and subtypes of ON. Low antioxidant status already existed in MS or NMO patients before systemic symptoms appeared.

Adolescent ; Adult ; Aged ; Antioxidants ; metabolism ; Bilirubin ; blood ; Child ; Child, Preschool ; Female ; Humans ; Male ; Middle Aged ; Multiple Sclerosis ; blood ; Neuromyelitis Optica ; blood ; Optic Neuritis ; blood ; Young Adult

Treatment with interferon beta (IFN-beta) induces the production of binding antibodies (BAbs) and neutralizing antibodies (NAbs) in patients with multiple sclerosis (MS). NAbs against IFN-beta are associated with a loss of IFN-beta bioactivity and decreased clinical efficacy of the drug. The objective of this study was to evaluate the incidence and the prevalence of binding antibodies (BAbs) and neutralizing antibodies (NAbs) to IFN-beta in MS patients receiving CinnoVex, Rebif, or Betaferon. The presence of BAbs was studied in serum samples from 124 MS patients using one of these IFN-beta medications by ELISA. The NAbs against IFN-beta were measured in BAb-positive MS patients receiving IFN-beta using an MxA gene expression assay (real-time RT-PCR). Of the 124 patients, 36 (29.03%) had BAbs after at least 12 months of IFN-beta treatment. The proportion of BAb+ was 38.1% for Betaferon, 21.9% for Rebif, and 26.8% for CinnoVex. Five BAb-positive MS patients were lost to follow-up; thus 31 BAb-positive MS patients were studied for NAbs. NAbs were present in 25 (80.6%) of BAb-positive MS patients receiving IFN-beta. In conclusion, the three IFN-beta preparations have different degrees of immunogenicity.
Adolescent ; Adult ; Antibodies/*blood/immunology ; Antibodies, Neutralizing/*blood/immunology ; Cross Reactions ; DNA, Complementary/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Interferon-beta/*immunology/therapeutic use ; Male ; Middle Aged ; Multiple Sclerosis/drug therapy/*immunology ; Myxovirus Resistance Proteins/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Young Adult

Antigens, CD ; metabolism ; Antigens, CD34 ; metabolism ; Antigens, Differentiation, Myelomonocytic ; metabolism ; Arteriovenous Malformations ; complications ; metabolism ; pathology ; Diagnosis, Differential ; Female ; Glial Fibrillary Acidic Protein ; metabolism ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Multiple Sclerosis ; Spinal Cord Diseases ; complications ; metabolism ; pathology

Sphingosine-1-phosphate (S1P) is a lysophospholipid signaling molecule that regulates important biological functions in both intracellular and extracellular compartments. It interacts with five G protein-coupled receptors subtypes (S1PR(1-5)) to generate multiple downstream signaling. Activation of S1PR1 has been validated to be involved in the process of immune modulation. Fingolimod (FTY720), the novel S1PR1 agonist, has been approved for the treatment of multiple sclerosis in clinical trials. The study towards discovery of selective S1PR1 agonists has become hot spot for immunological diseases. This article summarized the research progress of S1PR1 agonists, emphasizing their structure types, structure-activity relationship and direction of development.
Animals ; Fingolimod Hydrochloride ; Humans ; Immunosuppressive Agents ; pharmacology ; therapeutic use ; Lysophospholipids ; physiology ; Multiple Sclerosis ; drug therapy ; Propylene Glycols ; pharmacology ; therapeutic use ; Receptors, Lysosphingolipid ; agonists ; classification ; metabolism ; physiology ; Sphingosine ; analogs & derivatives ; pharmacology ; physiology ; therapeutic use ; Structure-Activity Relationship