Inflammation, lesions & 'black holes'
New research into the causes of the excessive inflammation that drives multiple sclerosis has identified a faulty "brake" within immune cells, a brake that should be controlling the inflammation. This points to a potential target for developing new therapies to treat MS and could have important implications for other autoimmune diseases, such as the colon disease colitis and the chronic skin condition atopic dermatitis, say researchers.
Further, the work has produced new research models of MS symptoms such as movement disorders and balance control problems that have, until now, resisted efforts to mimic them effectively in the lab. These models represent important new tools in the efforts to better understand - and eventually cure - MS and other autoimmune conditions.
The researchers determined that a mutation in the gene Nlrp12 was causing immune cells known as T cells to go haywire. Normally, the researchers determined, the protein the gene produces acts as a brake within T cells to control the inflammatory response. But a mutation in that gene disrupts the natural process and provokes severe inflammation - with effects the researchers found most intriguing.
To the researchers' surprise, the resulting inflammation did not produce the paralysis often associated with MS. It did, however, produce other MS symptoms - such as movement disorders and problems with balance control - which scientists have struggled to replicate in experimental lab settings.
"It's important to note that MS is a spectrum disorder - some patients present with paralysing conditions and some patients don't," said researcher John Lukens, PhD, of the University of Virginia School of Medicine Department of Neuroscience and its Center for Brain Immunology and Glia. "Not everybody's symptoms are the same, so this might give us a glimpse into the etiology or pathogenesis of that family of MS."
By blocking the inflammatory response, doctors may one day be able to control the symptoms it causes, both in MS and in other diseases driven by hyperinflammation.
The findings have been published by the scientific journal Immunity. Source: Science Newsline (20/05/15)
When the seasons change, your immune system response may also change, researchers report.
These findings might explain why conditions such as rheumatoid arthritis and heart disease are worse in the winter than in the summer, the new study finds.
The researchers from the University of Cambridge analysed genes from more than 16,000 people worldwide, including those from both the Northern and Southern hemispheres. They found that the activity of nearly one-quarter of the genes differed according to the time of the year. Some are more active in winter and some are more active in summer, the research revealed.
Seasons also affect our immune cells, and the composition of our blood and fat, according to the study.
Findings were published May 12 in the journal Nature Communications.
It's been known that there are seasonal variations in a number of conditions, including heart disease, autoimmune disorders such as type 1 diabetes, multiple sclerosis and mental illness, as well as in vitamin D metabolism. However, the researchers said this is the first study to show that seasonal changes may affect immune system function.
"In some ways, it's obvious -- it helps explain why so many diseases, from heart disease to mental illness, are much worse in the winter months -- but no one had appreciated the extent to which this actually occurred," said John Todd, professor and director of the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory at the University of Cambridge.
"The implications for how we treat disease like type 1 diabetes, and even how we plan our research studies, could be profound," he said in a university news release.
One gene that was more active in the summer and less active in the winter has been shown to suppress inflammation in mice. If the same is true in people, those in the Northern Hemisphere would have higher levels of inflammation in the winter.
Inflammation is a risk factor for a number of diseases, which means that those at high risk might be more likely to have more health problems during the winter. Drugs that target inflammation may offer a way of treating these diseases more effectively in the colder months, the researchers suggested.
They also found that certain genes associated with people's responses to vaccines were more active in winter. This means that some vaccination programs might be more effective during that season.
"Given that our immune systems appear to put us at greater risk of disease related to excessive inflammation in colder, darker months, and given the benefits we already understand from vitamin D, it is perhaps understandable that people want to head off for some 'winter sun' to improve their health and well-being," Todd said.
Exposure to sun triggers vitamin D production in the body.
Source: HealthDay Copyright © 2015 HealthDay (13/05/15)
Promising prevention method found(17/03/15)
Scientists at the Walter and Eliza Hall Institute in Australia have developed a new drug-like molecule which can halt inflammation and has shown promise in preventing the progression of MS, reports Business Insider Australia.
Dr Ueli Nachbur, Associate Professor John Silke, Associate Professor Guillaume Lessene, Professor Andrew Lew and colleagues say the molecule inhibits a key signal which triggers inflammation.
“Inflammation results when our immune cells release hormones called cytokines, which is a normal response to disease,” Dr Nachbur said. “However when too many cytokines are produced, inflammation can get out-of-control and damage our own body, all of which are hallmarks of immune or inflammatory diseases.”
To apply the brakes on this runaway immune response, institute researchers developed a small drug-like molecule called WEHI-345 that binds to and inhibits a key immune signalling protein called RIPK2. This prevents the release of inflammatory cytokines.
The molecule is seen as a great starting point for a drug discovery program which may one day lead to new treatments for MS and other inflammatory diseases.
The research is published in the journal Nature Communications.
Source: Business Insider Australia © 2007-2015 Allure Media (17/03/15)
Scientists have developed a new inhibitor for the treatment of inflammatory diseases. They have come up with a potent, selective, small-molecule inhibitor called MCC950. MCC950 is the inhibitor of NLRP3, a NOD-like receptor (NLR) family, pyrin domain–containing protein 3 inflammasome. NLRP3 inflammasome s a component of the inflammatory process, and its activation is pathogenic in conditions like multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis.
The results have been published in Nature Medicine and could prove to be a therapy for various conditions in the future. MCC950 specifically inhibits only NLRP3 and not other inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis.
Dr. Rebecca Coll, from UQ’s Institute for Molecular Bioscience, said “Inflammatory diseases result when our immune system is unable to switch off and so causes chronic inflammation in the body. Current therapies for inflammatory diseases, such as asprin, ibuprofen and steroids, don’t work well in severe cases and are not targeted, which can limit their effectiveness and cause side-effects. We now know that MCC950 can block an important component of the immune response — an inflammasome called NLRP3 that ‘switches on’ inflammation in our immune cells.”
Researchers hope this development would help in treating patients diagnosed with Cryopyrin-Associated Periodic Syndromes (CAPS), a family of rare and severe autoinflammatory diseases caused by a genetic mutation to NLRP3. Professor Luke O’Neill, Co-author and from Trinity College Dublin said, “We are excited about MCC950, which we believe has real potential to benefit patients suffering from several highly debilitating diseases, where there is a dire need for new medicines.”
Source: biotechin.asia (16/03/15)
Six Case Western Reserve scientists are part of an international team that has discovered two compounds that show promise in decreasing inflammation associated with diseases such as ulcerative colitis, arthritis and multiple sclerosis. The compounds, dubbed OD36 and OD38, specifically appear to curtail inflammation-triggering signals from RIPK2 (serine/threonine/tyrosine kinase 2). RIPK2 is an enzyme that activates high-energy molecules to prompt the immune system to respond with inflammation. The findings of this research appear in the Journal of Biological Chemistry.
"This is the first published indication that blocking RIPK2 might be efficacious in inflammatory disease," said senior author Derek Abbott, MD, PhD, associate professor of pathology, Case Western Reserve University School of Medicine. "Our data provides a strong rationale for further development and optimization of RIPK2-targeted pharmaceuticals and diagnostics."
In addition to Abbott and his medical school colleagues, the research team included representatives of Oncodesign, a therapeutic molecule biotechnology company in Dijon, France; Janssen Research & Development, a New Jersey-based pharmaceutical company; and Asclepia Outsourcing Solutions, a Belgium-based medicinal chemistry company.
The normal function of RIPK2 is to send warning signals to cells that bacterial infection has occurred, which in turn spurs the body to mobilize white blood cells. The white blood cells identify and encircle pathogens, which cause blood to accumulate in the region. It is this blood build-up that leads to the red and swollen areas characteristic of inflammation. When this process goes awry, the inflammation increases dramatically and tissue destruction ensues. RIPK2 works in conjunction with NOD1 and NOD2 (nucleotide-binding oligomerization domain) proteins in controlling responses by the immune system that lead to this inflammation process.
In this research project, investigators applied state-of-the-art genetic sequencing to learn the unique set of genes driven specifically by NOD2 proteins. They ultimately zeroed in on three specific NOD2-driven inflammation genes (SLC26a, MARCKSL1, and RASGRP1) that guided investigators in finding the most effective compounds.
Oncodesign searched its library of 4,000 compounds that targeted kinases, and after exhaustive study, narrowed the selection down to 13. Then investigators tested the 13 compounds in mouse and human cells and found that two compounds, OD36 and OD38, were most effective in blocking RIPK2.
"Based on the design of OD36 and OD38, we have developed with Oncodesign fifth-generation compounds that are even more effective than the first-generation OD36 and OD38," Abbott said. "Our next step is to seek a larger pharmaceutical company that can move these compounds forward into Phase 1 clinical trials in humans."
Source: News-Medical.Net Copyright 2000-2014 AZoM.com Limited (27/10/14)
Progressive multiple sclerosis CSF induces inflammatory demyelination, axonal loss, and astrogliosis in mice(15/08/14)
Cristofanilli M, Rosenthal H, Cymring B, Gratch D, Pagano B, Xie B, Sadiq SA.
Multiple sclerosis (MS) is an autoimmune disease characterised by inflammatory demyelination and neurodegeneration throughout the CNS, which lead over time to a condition of irreversible functional decline known as progressive MS.
Currently, there are no satisfactory treatments for this condition because the mechanisms that underlie disease progression are not well understood. This is partly due to the lack of a specific animal model that represents progressive MS.
We investigated the effects of intracerebroventricular injections of cerebrospinal fluid (CSF) derived from untreated primary progressive (PPMS), secondary progressive (SPMS), and relapsing/remitting (RRMS) MS patients into mice.
We found discrete inflammatory demyelinating lesions containing macrophages, B cell and T cell infiltrates in the brains of animals injected with CSF from patients with progressive MS. These lesions were rarely found in animals injected with RRMS-CSF and never in those treated with control-CSF.
Animals that developed brain lesions also presented extensive inflammation in their spinal cord. However, discrete spinal cord lesions were rare and only seen in animals injected with PPMS-CSF. Axonal loss and astrogliosis were seen within the lesions following the initial demyelination. In addition, Th17 cell activity was enhanced in the CNS and in lymph nodes of progressive MS-CSF injected animals compared to controls. Furthermore, CSF derived from MS patients who were clinically stable following therapy had greatly diminished capacity to induce CNS lesions in mice. Finally, we provided evidence suggesting that differential expression of pro-inflammatory cytokines present in the progressive MS CSF might be involved in the observed mouse pathology. Our data suggests that the agent(s) responsible for the demyelination and neurodegeneration characteristic of progressive MS is present in patient CSF and is amenable to further characterization in experimental models of the disease.
Source: Exp Neurol. 2014 Aug 8. pii: S0014-4886(14)00248-9. doi: 10.1016/j.expneurol.2014.07.020. [Epub ahead of print] & Pubmed PMID: 25111532 (15/08/14)