LCSB discovers endogenous antibiotic in the brain
Scientists from the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have discovered that immune cells in the brain can produce a substance that prevents bacterial growth: namely itaconic acid.
Until now, biologists had assumed that only certain fungi produced itaconic acid. A team working with Dr. Karsten Hiller, head of the Metabolomics Group at LCSB and funded by the ATTRACT program of Luxembourg’s National Research Fund, and Dr. Alessandro Michelucci has now shown that even so-called microglial cells in mammals are also capable of producing this acid. “This is a ground breaking result,” says Prof. Dr. Rudi Balling, director of LCSB: “It is the first proof of an endogenous antibiotic in the brain.” The researchers have now published their results in the prestigious scientific journal PNAS.
Alessandro Michelucci is a cellular biologist, with focus on neurosciences. This is an ideal combination for LCSB with its focus on neurodegenerative diseases, and Parkinson’s disease especially – i.e. changes in the cells of the human nervous system. “Little is still known about the immune responses of the brain,” says Michelucci. “However, because we suspect there are connections between the immune system and Parkinson’s disease, we want to find out what happens in the brain when we trigger an immune response there.” For this purpose, Michelucci brought cell cultures of microglial cells, the immune cells in the brain, into contact with specific constituents of bacterial membranes. The microglial cells exhibited a response and produced a cocktail of metabolic products.
This cocktail was subsequently analysed by Karsten Hiller´s metabolomics group. Upon closer examination, the scientists discovered that production of one substance in particular - itaconic acid - was upregulated. “Itaconic acid plays a central role in the plastics production. Industrial bioreactors use fungi to mass-produce it,” says Hiller: ” The realisation that mammalian cells synthesise itaconic acid came as a major surprise.”
However, it was not known how mammalian cells can synthesise this compound. Through sequence comparisons of the fungi’s enzyme sequence to human protein sequences, Karsten Hiller then identified a human gene, which encodes a protein similar to the one in fungi: immunoresponsive gene 1, orIRG1for short – a most exciting discovery as the function of this gene was not known. Says Hiller: “When it comes toIRG1, there is a lot of uncharted territory. What we did know is that it seems to play some role in the big picture of the immune response, but what exactly that role was, we were not sure.”
To change this situation, the team turned offIRG1in cell cultures and instead added the gene to cells that normally do not express it. The experiments confirmed that in mammals,IRG1codes for an itaconic acid-producing enzyme. But why? When immune cells like macrophages and microglial cells take up bacteria in order to inactivate them, the intruders are actually able to survive by using a special metabolic pathway called the glyoxylate shunt. According to Hiller, “macrophages produce itaconic acid in an effort to foil this bacterial survival strategy.The acid blocks the first enzyme in the glyoxylate pathway. Which is how macrophages partially inhibit growth in order to support the innate immune response and digest the bacteria they have taken up.”
LCSB director Prof. Dr. Rudi Balling describes the possibilities that these insights offer: “Parkinson’s disease is highly complex and has many causes. We now intend to study the importance of infections of the nervous system in this respect – and whether itaconic acid can play a role in diagnosing and treating Parkinson’s disease.”
Suppressing Protein May Stem Alzheimer’s Disease Process
Scientists funded by the National Institutes of Health have discovered a potential strategy for developing treatments to stem the disease process in Alzheimer’s disease. It’s based on unclogging removal of toxic debris that accumulates in patients’ brains, by blocking activity of a little-known regulator protein called CD33.
“Too much CD33 activity appears to promote late-onset Alzheimer’s by preventing support cells from clearing out toxic plaques, key risk factors for the disease,” explained Rudolph Tanzi, Ph.D., of Massachusetts General Hospital and Harvard University, a grantee of the NIH’s National Institute of Mental Health (NIMH) and National Institute on Aging (NIA). “Future medications that impede CD33 activity in the brain might help prevent or treat the disorder.”
Tanzi and colleagues report on their findings April 25, 2013 in the journal Neuron.
“These results reveal a previously unknown, potentially powerful mechanism for protecting neurons from damaging toxicity and inflammation,” said NIMH Director Thomas R. Insel, M.D. “Given increasing evidence of overlap between brain disorders at the molecular level, understanding such workings in Alzheimer’s disease may also provide insights into other mental disorders.”
Variation in the CD33 gene turned up as one of four prime suspects in the largest genome-wide dragnet of Alzheimer’s-affected families, reported by Tanzi and colleagues in 2008. The gene was known to make a protein that regulates the immune system, but its function in the brain remained elusive. To discover how it might contribute to Alzheimer’s, the researchers brought to bear human genetics, biochemistry and human brain tissue, mouse and cell-based experiments.
They found over-expression of CD33 in support cells, called microglia, in postmortem brains from patients who had late-onset Alzheimer’s disease, the most common form of the illness. The more CD33 protein on the cell surface of microglia, the more beta-amyloid protein and plaques – damaging debris – had accumulated in their brains. Moreover, the researchers discovered that brains of people who inherited a version of the CD33 gene that protected them from Alzheimer’s conspicuously showed reduced amounts of CD33 on the surface of microglia and less beta-amyloid.
Brain levels of beta-amyloid and plaques were also markedly reduced in mice engineered to under-express or lack CD33. Microglia cells in these animals were more efficient at clearing out the debris, which the researchers traced to levels of CD33 on the cell surface.
Evidence also suggested that CD33 works in league with another Alzheimer’s risk gene in microglia to regulate inflammation in the brain.
The study results – and those of a recent rat study that replicated many features of the human illness – add support to the prevailing theory that accumulation of beta-amyloid plaques are hallmarks of Alzheimer’s pathology. They come at a time of ferment in the field, spurred by other recent contradictory evidence suggesting that these presumed culprits might instead play a protective role.
Since increased CD33 activity in microglia impaired beta-amyloid clearance in late onset Alzheimer’s, Tanzi and colleagues are now searching for agents that can cross the blood-brain barrier and block it.
Got allergies? You're 50% less likely to get cancer
Have allergies or high histamine? Lucky you! Your immune system is primed to take down brain tumour cells. Researchers have yet to explore which other kinds of cancer (if any) having high histamine levels protects against. Seems that those pesky cancerous cells are annihilated by brain histamine, at least 50% of the time.
It could be that the immune system of a person with allergies is working harder, and as it defends the body against allergens, it also works against tumors. Another idea has to do with the blood-brain barrier, a barrier between the immune function cells and the brain.
“It’s hard for immune cells to get into the brain because you wouldn’t want to have inflammation in your brain. It’s kind of protective, but it’s possible that a consequence of allergies is that this blood-brain barrier is more accessible to immune cells, and the immune system [in those people with allergies] can get rid of very small early tumors.”
Judith Schwartzbaum, PhD, associate professor of epidemiology at Ohio State University in Columbus, Ohio,
This fits in with what Dirk Budka (my histamine hero) told me about my immune system being in overdrive. Because not only do I have the honour of having histaminosis/histamine intolerance, tyramine sensitivity, I am also the proud owner of a hypersensitivity disorder. Sheesh, and you thought your diagnosis was grim!
Dirk (I’m paraphrasing here):
“Imagine a person with a normal immune system eats a food that it takes a dislike to. The immune system swats it away like a little fly. You eat anything and your immune system gets out the bazooka and starts blasting away.”
Having experienced significant war zone action (as a journalist), I can indeed confirm that is exactly what it feels like - a freaking war inside my body.
New Drug Stimulates Immune System to Kill Infected Cells in Animal Model of Hepatitis B Infection
A novel drug developed by Gilead Sciences and tested in an animal model at the Texas Biomedical Research Institute in San Antonio suppresses hepatitis B virus infection by stimulating the immune system and inducing loss of infected cells.
In a study conducted at Texas Biomed’s Southwest National Primate Research Center, researchers found that the immune modulator GS-9620, which targets a receptor on immune cells, reduced both the virus levels and the number of infected liver cells in chimpanzees chronically infected with hepatitis B virus (HBV). Chimpanzees are the only species other than humans that can be infected by HBV. Therefore, the results from this study were critical in moving the drug forward to human clinical trials which are now in progress.
The new report, co-authored by scientists from Texas Biomed and Gilead Sciences, appears in the May issue of Gastroenterology. Gilead researchers had previously demonstrated that the same therapy could induce a cure of hepatitis infection in woodchucks that were chronically infected with a virus similar to human HBV.
“This is an important proof-of-concept study demonstrating that the therapy stimulates the immune system to suppress the virus and eliminate infected liver cells,” said co-author Robert E. Lanford, Ph.D., of Texas Biomed. “One of the key observations was that the therapy continued to suppress virus levels for months after therapy was stopped.
The current therapy for HBV infection targets the virus and works very well at suppressing viral replication and delaying progression of liver disease, but it is a lifelong therapy that does not provide a cure.
“This GS-9620 therapy represents the first conceptually new treatment for HBV in more than a decade, and combining it with the existing antiviral therapy could be transformative in dealing with this disease,” stated Lanford.
The Gilead drug binds a receptor called Toll-Like Receptor 7 that is present in immune cells. The receptor normally recognizes invading viruses and triggers the immune system to suppress viral replication by the innate immune response and kill infected cells by the adaptive immune response, thus orchestrating both arms of the immune system.
HBV damages the liver, leading to cirrhosis and liver cancer. Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer death. According to the United States Centers for Disease Control and Prevention (CDC), up to 1.4 million Americans are chronically infected with HBV.
The World Health Organization estimates that two billion people have been infected with the hepatitis B virus, resulting in more than 240 million people with chronic infections and 620,000 deaths every year.
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