Multiple sclerosis starts in brain’s outer layers

Researchers at the Mayo Clinic and Cleveland Clinic have reversed the traditional understanding of how multiple sclerosis (MS) begins and travels in the brain.

The common view is that the disease starts in the centre of the brain, in the white matter mostly found there, and then moves toward the outer layers, such as the cortex.

But this study, which is unique because it focused on the brain tissues of patients in the very early stages of MS, shows the opposite: that it moves from the outside in.

It begins in the “subarachnoid space,” which surrounds the brain, cushions it and is filled with cerebrospinal fluid. From there it moves into the white matter. This animation shows how the two hypotheses differ.

The findings are also significant because they support the hypothesis that inflammation, not neurodegeneration, is a main driver of the disease.

The authors conclude that it is “overwhelmingly likely” that MS is fundamentally an inflammatory disease, and not a neurodegenerative disease similar to Alzheimer’s.

Researchers are not entirely sure exactly causes MS, but the prevailing theory is that it is an autoimmune disease in which the body’s own immune system attacks and destroys its own myelin, a fatty substance essential to the nervous system. It protects the crucial nerve fibres enable different sections of the brain to communicate.

When myelin is damaged (as in MS), messages between the brain and the body are delayed or blocked, leading to MS symptoms such as blindness, numbness, paralysis, and thinking and memory difficulties.

“Our study shows the cortex is involved early in MS and may even be the initial target of disease,” co-lead author of the study and Mayo Clinic neurologist Dr. Claudia F. Lucchinetti stated.

“Inflammation in the cortex must be considered when investigating the causes and progression of MS”, she says. She and her co-author, Dr. Richard Ransohoff of the Cleveland Clinic, published the results of their study in the New England Journal of Medicine.

Natural drug Abscisic Acid's infection fighting mechanism revealed

The scientists had reported some of the key molecular events in the immune system of mice that contribute to inflammation-related disease, including the involvement of a specific molecule found on the surface of immune cells involved in the body’s fight against infection (http://www.ncbi.nlm.nih.gov/pubmed/21068720). 

They have now gone one step further and revealed the mechanism by which the natural drug abscisic acid interacts with this protein, known as peroxisome proliferator-activated receptor-gamma, to block inflammation and the subsequent onset of disease.

“In previous work, our research group demonstrated that abscisic acid has beneficial effects on several conditions and diseases including obesity-related inflammation, diabetes, atherosclerosis, and inflammatory bowel disease,” said Josep Bassaganya-Riera, associate professor of immunology at the Virginia Bioinformatics Institute, leader of the Nutritional Immunology and Molecular Medicine Group in the institute’s CyberInfrastructure Division, and principal investigator of the study.

“One idea for how abscisic acid reduces inflammation in these instances is that it binds to a special region of peroxisome proliferator-activated receptor-gamma, a binding site known as the ligand-binding domain where the drug would be expected to latch on to and exert its effect. 

Our results show that this is not the case and, for the first time, we have demonstrated that abscisic acid works independently of this ligand-binding domain of the receptor.”

More information on this article here Science Blog

Key molecular events in the immune system contribute to Inflammatory Bowel Disease (IBD)

Scientists at the Virginia Bioinformatics Institute at Virginia Tech have discovered some of the key molecular events in the immune system that contribute to inflammatory bowel disease.

The results, which help researchers move one step further in their efforts to develop new drugs to treat inflammatory and immune-mediated diseases, are reported in the November 2010 edition (http://www.ncbi.nlm.nih.gov/pubmed/21068720) of the journal Mucosal Immunology from the Nature Publishing Group.

Inflammatory bowel disease starts when the gut initiates an abnormal immune response to some of the one hundred trillion or so bacteria that come into contact with the colon of the human body.

More than 1 million people are affected by inflammatory bowel disease in North America alone and direct healthcare expenses for inflammatory bowel disease in the United States are estimated at more than $15 billion annually.

Earlier mathematical and computational work (http://www.ncbi.nlm.nih.gov/pubmed/20362587) by the scientists pinpointed a special type of immune cell as a possible target for intervention strategies to fight inflammation-related disease in the gut.

The immune cells identified in the earlier work, which are known as M1 or classically activated macrophages, cause inflammation and possess a specific molecule, peroxisome proliferator-activated receptor-gamma, that, when activated, favors a switch to a type of macrophage that reduces the impact of inflammation (alternatively activated macrophage or M2) .

The activation of the receptor protein and the anti-inflammatory M2 macrophage switch plays a beneficial role in reducing the severity of the disease in the gut during experimentally induced inflammatory bowel disease.

“We have been able to validate experimentally some of the key events that take place in the regulation of the mucosal immune system when inflammatory bowel disease is triggered in mice,” said Josep Bassaganya-Riera, associate professor of immunology at the Virginia Bioinformatics Institute, leader of the Nutritional Immunology and Molecular Medicine Group in the institute’s CyberInfrastructure Division, and principal investigator.

“When we produce mice that lack the peroxisome proliferator-activated receptor-gamma specifically found in macrophages, the severity of inflammatory bowel disease increases significantly. In parallel, we are able to observe the impact of the onset of disease on key inflammation-related genes and other molecules involved in inflammation and metabolism.”

More on this article here Science blog website

Vitamin D deficiency confirmed as common across a range of rheumatic conditions

Vitamin D deficiency confirmed as common across a range of rheumatic conditions

Two separate studies have shown that vitamin D deficiency is common in patients with a range of rheumatic diseases, with over half of all patients having below the ‘normal’ healthy levels of vitamin D (48-145 nmol/L) in their bodies.

A further study assessing response to vitamin D supplementation found that taking the recommended daily dose did not normalise vitamin D levels in rheumatic disease patients. The results of these three studies were presented today at EULAR 2010, the Annual Congress of the European League Against Rheumatism in Rome, Italy.

A UK study of 180 patients aimed to assess mean levels of vitamin D in patients with inflammatory joint diseases, osteoarthritis and myalgia (muscle pain that, when experienced long term may be associated with nutritional deficiency).

Data on vitamin D levels were gathered and results showed that 58% of individuals with a rheumatic condition had levels below that clinically considered to be ’sufficient’ in healthy subjects (48-145 nmol/L).

An Italian study of 1,191 RA patients aimed to determine a correlation between vitamin D deficiency and several different clinical measures of disease activity.

Researchers found that, regardless of supplementation, levels of 25-hydroxyvitamin D (25(OH)D), (a standard clinical measure of vitamin D in the blood), were lower than healthy levels (<50 nmol/L) in 85% of the patients not taking a vitamin D supplement and in 60% of those taking 800 IU or more vitamin D daily as a supplement.

In non-supplemented patients levels of 25(OH)D significantly correlated with three measures of disease activity – the Health Assessment Questionnaire Disability Index, (p=0.000) the Mobility Activities of Daily Living Score (p=0.000) and the Number of Swollen Joints count (p=0.000).

“We have seen in studies that vitamin D deficiency is common in patients with a range of rheumatic diseases, and our results have confirmed this using several clinically accepted measures of disease activity,” said Dr. L. Idolazzi, of the Rheumatology Unit, University of Verona, Italy.

“What we need to see now is a range of long term studies, which examine the clinical response of patients to vitamin D supplementation.”

Furthermore, a third study undertaken in Italy aimed to evaluate the affect of vitamin D supplementation in patients with inflammatory autoimmune disease (IAD) and non-inflammatory autoimmune disease (NIAD).

Following supplementation, only 29% patients reached vitamin D levels greater than the level clinically considered to be ’sufficient’ in healthy subjects, with no significant differences in vitamin D levels observed between the IAD and NIAD groups.

“Whilst it is well known that hypovitaminosis D is often seen in patients with inflammatory autoimmune diseases, the effects of supplementation have not been fully investigated in this setting,” said Dr. Pier Paolo Sainaghi of the Immuno-Rheumatology Clinic, A. Avogadro University of Eastern Piedmont, Novara, Italy and author of the third study.

“The results of our study show that daily 800-1,000 IU supplementation is not sufficient to normalise vitamin D levels in patients with rheumatologic or bone conditions. What is unclear is whether a higher dose would be more effective.”

Study details machinery of immune protection against colitis and inflammatory diseases

Study details machinery of immune protection against colitis and inflammatory diseases ScienceBlog.com

Scientists report a protein made by a gene already associated with a handful of human inflammatory immune diseases plays a pivotal role in protecting the intestinal tract from colitis.

St. Jude Children's Research Hospital investigators led the research, which points to possible new strategies for combating colitis. Colitis is a chronic inflammatory disease associated with colon damage, resulting in abdominal pain, bleeding and other symptoms.

The work also expands the link between the Nlrp3 protein and Crohn's disease, said Thirumala-Devi Kanneganti, Ph.D., assistant member of the St. Jude Department of Immunology and the paper's senior author.

Md. Hasan Zaki, Ph.D., a St. Jude postdoctoral fellow, is first author of the study, which appears in the March 18 online edition of the journal Immunity.

Researchers demonstrated that in a mouse model of colitis, Nlrp3 plays a pivotal role in keeping the intestinal tract intact, thus preventing further damage that occurs if intestinal bacteria leak into the body.

Nlrp3 works by anchoring a large, multi-protein complex known as the Nlrp3 inflammasome where the messenger protein interleukin 18 (IL-18) is made. IL-18 belongs to a family of molecules known as cytokines, which shape the body's immune response.

In this study, researchers showed IL-18 produced by the Nlrp3 inflammasome helped mice maintain healthy colon by triggering production of more epithelial cells to compensate for those damaged or destroyed by colitis.

"This paper provides the basis for more effective, potentially disease-modifying approaches to treatment," Kanneganti said. She added that in this study, scientists showed the specific pathway activated in the epithelial cells lining the colon for IL-18 production.

Previous studies linked changes in the NLRP3 gene to several auto-inflammatory problems in which a person's immune system mistakenly attacks healthy tissue. The gene is part of the body's innate immune response. That is the branch of the immune system programmed to act immediately against infectious diseases and other threats.

"I believe if we target molecules that are part of the innate immune response we can find cures for many diseases, including cancer," Kanneganti said. She and her colleagues focused on Nlrp3 in colitis after reports that patients with Crohn's disease, another disorder characterised by chronic intestinal inflammation, had low levels of the protein.

In a series of experiments, scientists demonstrated that the Nlrp3 inflammasome not only helps protect against chemically induced colitis in mice, but also showed how and where in the body the protection occurred.

The researchers demonstrated that in response to colitis, the Nlrp3 inflammasome is activated in the epithelial cells lining the colon, where IL-18 can be produced.

Investigators also established that IL-18 is crucial for protecting the colon from colitis. In fact, researchers reported that injecting IL-18 into mice that lacked the molecule eased colitis symptoms.

The other authors of this study are Kelli Boyd, Peter Vogel and Michael Kastan (all St. Jude) and Mohamed Lamkanfi (Ghent University, Ghent, Belgium).

This research was supported in part by the National Institutes of Health, the National Cancer Institute and ALSAC.

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