MS lesions

Podocalyxin, a protein found in cells lining the interior of blood vessels, is key for maintaining the integrity of the blood-brain barrier (BBB) in mice with systemic infection, suggesting its potential as a therapeutic target for neurodegenerative diseases such as multiple sclerosis (MS), a study shows. Disruption of the…

Two newly identified variants of the known pharmaceutical agent chloroindazole showed significant anti-inflammatory and neuroprotective benefits in a mouse model of multiple sclerosis, a new study shows. Multiple sclerosis is an autoimmune, demyelinating disease of the central nervous system with no known cause or cure. Patients with MS characteristically show loss of the myelin sheath, a protective coat in nerve cells that helps increase cell-to-cell signaling. Several studies have suggested that estrogens — a type of hormone — are beneficial to the functioning of the central nervous system, and help regulate the immune system. Thus, they are attractive candidates for the treatment of MS. However, despite their potential to treat MS, estrogen-based therapies can have several undesirable side effects, such as feminizing male recipients and increasing the risk of developing breast and endometrial cancers in females. Interestingly, estrogens work by binding and activating two different types of receptors: the estrogen receptor (ER)α and ERβ. The cancer-inducing effects of estrogens are mediated mainly through estrogen receptor ERα. Hence, therapies that specifically target ERβ can bypass these deleterious effects. Chloroindazole (IndCl), a pharmaceutical agent, has up to 100-fold relative binding affinity for ERβ over ERα. IndCl has been shown previously to have beneficial effects on modulating the immune system and the central nervous system, and inducing myelination of nerve cells in mouse models of MS. Furthermore, IndCl and other ERβ-activating agents directly support the growth, differentiation (maturation), and overall myelination activity of oligodendrocytes, which are the nerve cells that produce the myelin sheath. Therefore, in order to optimize the benefits of IndCl, researchers developed and screened seven novel IndCl analogues for their ability to promote oligodendrocyte survival, growth, and differentiation. These analogues have a molecular structure closely similar to that of IndCl, but interact with estrogen receptors in subtly different ways. Among these seven compounds, researchers found two analogues — IndCl-o-chloro and IndCl-o-methyl — that stimulated growth and differentiation similar to the original IndCl. Next, researchers evaluated the benefits of these compounds in a mouse model of MS — the experimental autoimmune encephalomyelitis (EAE) mouse model — to determine whether they could alter the disease course, white matter pathology (level of demyelination), and inflammation. Results indicated that both compounds “ameliorated disease severity, increased mature OLs [oligodendrocytes], and improved overall myelination in the corpus callosum and white matter tracts of the spinal cord,” researchers wrote. Corpus callosum is a thick band of nerves that connect the left and right side of the brain. White matter tracts connect the cortex (the largest part of the brain) with other areas in the central nervous system. These beneficial effects were accompanied by a reduced production of the toxic, inflammatory molecules interferon-γ and CXCL10. Additionally, IndCl-o-methyl also reduced the levels of peripheral interleukin (IL)-17, a molecule that strongly induces inflammation. Furthermore, IndCl and both analogues upregulated the expression of a compound called CXCL1, which is associated with increased production of oligodendrocytes. Not only were these two newly identified compounds equivalent to IndCl, but the two analogues performed better in reducing disability and encouraging remyelination than the original compound, and without any obvious side effects. “The o-Methyl and o-Chloro IndCl analogues represent a class of ERβ ligands that offer significant remyelination and neuroprotection, as well as modulation of the immune system; hence, they appear appropriate to consider further for therapeutic development in multiple sclerosis and other demyelinating diseases,” the researchers concluded. “We believe we created a drug that does two things really well, modulating inflammation and allowing axon remyelination. No other drug on the market can do these two things simultaneously,” Seema K. Tiwari-Woodruff, said in a press release written by Stacy Kish. Tiwari-Woodruff is the study's lead author. “The most amazing part of the study is that these new analogues of a known estrogen modulator, chloroindazole, are superior in treating mouse model of multiple sclerosis,” she added. The team has patented the analogues, and hopes to begin further pharmacological and toxicity studies soon.

A protein called Satb1 appears to be the "on switch" that turns a type of T-cell called Th17 from its typical protective role into one that is disease-causing, and key in the development of multiple sclerosis (MS) and other inflammatory autoimmune disorders, a study reports. These findings suggest that Satb1 may be a therapeutic target for autoimmune diseases like MS. The research article, “Satb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation,” was published in the journal Nature Communications. Immune cells called T-helper 17 (Th17) cells play a range of roles in immunity, including protecting against infecting pathogens — bacteria, viruses, and other microorganisms that can cause disease. But Th17 cells are also players in the development of such autoimmune diseases as MS, psoriasis, inflammatory bowel disease, and rheumatoid arthritis. This is because Th17 cells can be stimulated to become T-cells that engage in pathogenic, or disease-causing, immune programs. How Th17 cells switch from their typical and helpful immunity role to that of a pathogenic actor has not been resolved, although it is thought critical to treating inflammatory autoimmune diseases. An international team led by researchers at Osaka University and Kyoto University, in Japan, tried to identify the mechanism behind the disease-causing program of Th17 cells. To do so, they built upon previous findings showing that a protein regulator called Satb1 is important in the development of Th17 cell subsets. "We have known for some time that Satb1 is indispensable for the development of T-cells in the thymus. However, how it is involved in the regulation of pathogenic processes of Th17 cells in inflamed tissues had not been examined," Keiko Yasuda, MD, the study's lead author, said in a press release. Researchers used a standard mouse model of MS, called experimental autoimmune encephalomyelitis (EAE) mice. These animals had genetically-modified Th17 cells that lacked Satb1. Researchers tested how Th17 cells lacking Satb1 acted when subject to inflammatory conditions, and how they were stimulated to activate a "pathogenic effector program." Interestingly, these modified mice were resistant to the development of EAE, or MS-like, disease. Researchers saw fewer Th17 cells infiltrating the animals' spinal cord. Also, Th17 cells lacking Satb1 showed poorer production of key pathogenic signaling molecules in autoimmunity, notably one called granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is known to cause localized tissue inflammation in MS and other inflammatory autoimmune diseases. Researchers went on to show that Satb1 can act as a switch between benign and pathogenic Th17 cells, depending on their exposure to healthy or inflammatory conditions. They found molecules that boost the pathogenicity of Th17 cells, such as Bhlhe40, and molecules that promote normal immune function, such as PD-1.  Of note, PD-1 is shut down when Th17 cells engage in their pathogenic effector program. These results showed Satb1 to be a key regulator of Th17 cell pathogenicity in these MS mice. Halting Th17 cells from making Satb1 may offer a way of treatting various autoimmune diseases. “Together, our findings, in addition to providing novel insights into the molecular mechanisms underlying the pathogenic program of tissue Th17 cells in mice, may help design novel immunotherapeutic approaches such as small molecule modifiers of Satb1 for the treatment of autoimmune diseases,” the researchers wrote. Future studies are needed to confirm these results in people. A previous study in people also suggested a link between Satb1 and the pathogenic function of Th17 cells in the central nervous system of MS patients. Overall, "our results suggest that manipulating Satb1 gene expression in Th17 cells could form the basis of novel treatments for various autoimmune diseases caused by Th17 cells. If we can prevent the pathogenic processes of Th17 cells, we may be able to alleviate or even eliminate disease symptoms," concluded Shimon Sakaguchi, PhD, one of the study's senior authors.

Almost one in five patients diagnosed with multiple sclerosis (MS) and referred to one of two MS-specialized centers in the U.S. were found to not have the disease, a study at those two centers reported. Migraine was the most common correct diagnosis eventually given these people. The retrospective study…

Genetic variants that enhance the activity of the NLRP3 inflammasome or the interleukin-1 beta cytokine are linked to higher severity and progression of multiple sclerosis, a study suggests. Previous studies with mouse models of MS have shown that a complex of innate immune system receptors and sensors, known as the inflammasome, is likely a player promoting the immune system’s attack on the central nervous system in MS and, consequently, the loss of myelin. Follow-up studies showed that people carrying mutations that enhance the function of the NLRP3 inflammasome — one of the three components of the inflammasome complex — had a worse prognosis, once again supporting the role of the inflammasome in MS. Once activated, the inflammasome triggers an enzyme called caspase-1 that promotes the production of two very powerful proinflammatory cytokines called interleukin (IL)-1 beta and IL-18. To further evaluate the role of the inflammasome in MS, a team led by researchers at the Universidade de Sao Paulo in Brazil analyzed the genetic sequence of five inflammasome genes — NLRP1, NLRP3, NLRC4, IL-1 beta, and IL-18 — in blood samples retrieved from 264 patients diagnosed with MS or other demyelinating diseases. They also analyzed 233 healthy individuals used as controls. The team specifically looked at eight variations in certain nucleotides (the building blocks of DNA), called single nucleotide polymorphisms (SNPs). Previous studies reported a link between SNPs in inflammasome-related genes and certain forms of MS. Results showed that SNPs associated with low serum levels of IL-18 were significantly less frequent in MS patients than in controls. In contrast, variants that enhance the function of NLRP3 and IL-1 beta were associated with severity and progression of MS, as measured by the Expanded Disability Status Scale. These results suggest that the "activation of NLRP3 inflammasome could represent a risk factor for MS clinical presentation,” the researchers wrote. A particular variant in the NLRC4 gene was less frequent in patients whose disease progressed rapidly compared with those who had a slower disease, an intriguing observation, according to researchers, suggestive of a “protection effect of this variant against a bad prognosis.” Carriers of this variant also responded better to treatment with interferon-beta. Regarding MS type, the genetic variant that promotes the function of the IL-1 beta gene was significantly more frequent in progressive forms of MS than in relapsing-remitting MS, strengthening once again the negative effects of IL-1 beta in the disease. An analysis of inflammasome activity in blood monocytes, a group of immune cells, showed that the inflammasome is permanently activated in MS compared with healthy controls. "This study emphasizes that a constitutive activation of NLRP3 inflammasome, principally through IL-1 beta production, represents a risk factor for both the development of MS and the progression to severe forms of the disease. On the other hand, low IL-18 production and/or NLRC4 activation were beneficial for MS patients,” the team concluded.

The progressive decline in brain volume in multiple sclerosis (MS) patients, despite treatment with the disease-modifying therapy Tysabri (natalizumab), is driven by atrophy — shrinkage due to the degeneration of cells — in gray matter and not white matter structures, a new study reports. This finding points to new markers…

Tiny ruptures in the cell membrane of nerve fibers enable the entry of calcium and ultimately lead to their degeneration, a study in a mouse model of multiple sclerosis (MS) suggests. The study, “Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple…

A protein marker for activated immune cells called Chi3I3 is key for the production of myelin-forming cells, and may become a target to boost myelin repair in multiple sclerosis (MS), according to a new study. The research, “Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune…

Editor’s note: “Need to Know” is a series inspired by common forum questions and comments from readers. Have a comment or question about multiple sclerosis? Visit our forum. This week’s question is inspired by the forum topic “Can there be a connection between Epstein-Barr virus…

The herbicide linuron, commonly used with other herbicides, insecticides and fungicides to control the growth of grass and weeds, may be an important environmental risk factor in the development of neurological diseases that include multiple sclerosis, researchers suggest. Used in the U.S. and other countries — but recently…

Unusually high levels of a transcription factor called paired related homeobox protein 1 (PRRX1) in human oligodendrocyte progenitor cells hinders their ability to respond to the loss of myelin and to transform into mature, myelin-producing oligodendrocytes, a new study shows. These findings suggest a new potential way of treating …

A product called acrolein, which is naturally excreted by the body and possible to measure in urine and blood, may be a potential biomarker to help diagnose and evaluate disease activity in people with multiple sclerosis (MS), according to preliminary research in animal models and humans. Researchers are investigating whether acrolein…

A genetic variant associated with an increased risk of multiple sclerosis (MS) due to its impact on certain immune system cells can also affect brain cells called astrocytes, a study shows. Reported in the study, “Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple…

Inactivation of S1PR2, a cell surface protein, helps improve clinical disability and reduce demyelination in a mouse model of experimental autoimmune encephalitis (EAE), a condition similar to multiple sclerosis (MS) in humans, a study shows. This finding suggests that therapies blocking S1PR2 could have the potential to treat MS. The…

Microglia, the resident immune cells of the brain, were seen to change throughout the lifespan of mice in a study — and to be diverse, with distinct cell subtypes. Those with pro-inflammatory behavior may be disease-causing, as they were found to accumulate in the brains of a mouse model of…

Homotaurine, a compound proven safe for humans in long-term clinical trials, has eased autoimmune responses, brain inflammation, and multiple sclerosis-like symptoms in a mouse model of the disease, a study has found. The findings represent proof-of-principle evidence that homotaurine may represent a new potential class…

The cells that produce myelin in the brain and spinal cord, called oligodendrocytes, may play an active role in the onset or progression of multiple sclerosis (MS), according to a study combining data from MS mouse models and the human brain. This discovery supports the…

The pro-inflammatory Th17 cells that characterize multiple sclerosis (MS) may also underlie symptoms of obsessive-compulsive disorder (OCD), results of a mouse study show. The study, “Auto-Reactive Th17-Cells Trigger Obsessive-Compulsive-Disorder Like Behavior in Mice With Experimental Autoimmune Encephalomyelitis,” was published in the journal Frontiers in Immunology. “For the first time,…

Appropriate control of immune B-cell numbers and activation in the nervous system is key to preventing inflammation in multiple sclerosis (MS), according to a study. These findings also showed that patients with higher levels of a specific B-cell-regulating cell type had less disease activity. The study, “…

Blocking SARM1, a protein identified as a central mediator of nerve cell degeneration, works to prevent damage to axons — nerve cell fibers essential in cell-to-cell communication — and may be a way of treating neurodegenerative diseases like multiple sclerosis (MS), data from Disarm Therapeutics shows. Specially, genetically deleting…

Myelin loss might be prevented by astrocytes, a brain cell that regulates myelin’s thickness in coating nerve fibers to support the proper transmission of nerve signals, after astrocytes were seen to block an enzyme called thrombin in a study from the National Institutes of Health (NIH). Its…

Infection with the most common member of the herpes virus family, called HHV-6, may pass unnoticed and without symptoms, but the very act of being infected significantly accelerated the development and progression of a multiple sclerosis-like disease in nonhuman primates, a study reports. Its findings support the role of viral infection in…

Stress granules forming inside the nerve cells of people with multiple sclerosis (MS) may be the underlying cause of nerve cell degeneration and permanent disability in these patients, researchers report. The reason for this stress response seems to a protein that behaves aberrantly in the neurons of an…

An antibody that blocks a blood-clotting factor from leaking into the brain was seen to lessen neuroinflammation and nerve cell damage in mouse models of multiple sclerosis (MS) and Alzheimer’s disease. Scientists developed an antibody that selectively inhibits the inflammation-triggering capacity of fibrin in…

An enzyme produced by bacteria in the gut was seen to activate immune cells linked to the development and progression of multiple sclerosis, a finding that may pave the way for a vaccine that might alter autoimmune mechanisms involved in MS. The study, “…

Despite its lack of specificity to multiple sclerosis (MS) in particular, monitoring patients with a blood biomarker — serum neurofilament light (sNfL) — may hold promise as a relatively easy way to assess treatment response and brain damage, according to MS experts. But there’s considerable work still to be…

Measuring the blood level of neurofilament light chain (NfL) may predict brain shrinkage in primary progressive (PPMS) and secondary progressive multiple sclerosis (SPMS), according to a new study. The findings also show that NfL levels are associated with brain lesion load in these patients. The research, “…

Merck KGaA announced that evobrutinib, its oral candidate for relapsing multiple sclerosis (MS), was able to safely and significantly reduce active brain lesions over 24 weeks of treatment, according to results of a Phase 2 study sponsored by the company.

Advances in multiple sclerosis research and the development of new treatments over the last several decades give sustained reasons for hope as continue moving toward our future, according to Jerry S. Wolinsky, a neurologist and MS specialist whose career spans more than 40 years. In a wide-ranging interview with Multiple…

Treatment of relapsing-remitting multiple sclerosis (RRMS) patients with Tecfidera (dimethyl fumarate) is associated with fewer new brain lesions at two years, lower relapse rates, increased time to first relapse, and reduced treatment discontinuation than with Aubagio (teriflunomide), according to a nationwide study from France and a real-world, population-based…