Posts tagged immune cells
Articles and news from the latest research reports.
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.”
(Source: wwwen.uni.lu)
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.
(Source: nimh.nih.gov)
Comparing mouse and human immune systems
It is a familiar note struck when authors conclude their reports on experiments conducted in mouse models: They suggest caution when translating their findings from mouse to human. A variation of this refrain can be heard when a small molecule that works in mice fails in human clinical trials.
There may be myriad reasons why results differ, and some challenges to the relevance of mouse models to human disease and therapy may be more anecdotal than evidence-driven, scientists say. But the need for better understanding the differences and similarities between human and mouse is clear. Genomic tools and analysis have opened the door to making comprehensive comparisons at a basic level that can inform future research in both mice and humans.
Scientists studying cell differentiation and function in the immune system set out to chart how the mouse and human compare in this area. Tal Shay, a postdoctoral associate in Aviv Regev’s lab at the Broad Institute of Harvard and MIT, led a team from Harvard Medical School, the Broad and Stanford University who compared two large compendia containing transcriptional profiles—how genes are expressed—in human and mouse immune cell types.
The researchers found remarkable consistency between gene expression profiles in the mouse and human immune systems but also some instances of divergence. The majority of gene expression patterns—conservatively estimated at 80 percent—were the same in mouse and human. In addition, they suggest a role for transcriptional regulators that may guide some of the similarities.
Shay and her colleagues reported their findings in PNAS and also deposited their data and analysis in a web portal, which they hope will serve as a reference map for other investigators. Their work is part of the ImmGen Consortium, a collaboration of immunologists and computational biologists generating a complete compendium of gene expression and its regulation in the mouse immune system.
“We wanted to pinpoint where immune system genes and gene expression are different and where you should be very suspicious if something is found in mouse and likely to be translated to human,” said Shay, who is a lead author of the paper. “We thought we might be able to map those places where the comparison is less robust, but we had a very hard time pinpointing convincing differences.”
The researchers had to take extraordinary pains to make sure they were comparing only what was comparable—apples to apples. Not all mouse genes had a corresponding gene in the human data set, or they had more than one: There might be one gene in humans versus five in mice for smell receptors, for example. Sometimes differences were a matter of timing: Genes were activated earlier or later, depending on the species, said David Puyraimond-Zemmour, an HMS graduate student in immunology in the lab of Christophe Benoist and Diane Mathis and a co-author of the PNAS paper.
In all, they found several dozen genes in seven immune cell types that have different expression in 80 human and 137 mouse samples. Their conclusions are based on comparing data from the Differentiation Map—which measures gene expression in about 40 human cell types—and data from ImmGen, which does the same for about 200 mouse cell types. They did further analyses of gene expression when cells were activated in different states, such as responding to infection, based on a data set produced by Ei Wakamatsu and Ting Feng, postdoctoral fellows in the Benoist-Mathis lab. Shay also worked with the Differentiation Map data from the lab of Benjamin Ebert, HMS associate professor of medicine at Brigham and Women’s Hospital and Dana-Farber Cancer Institute and an associate member of the Broad Institute, as well as from the ImmGen Project.
“What we assume most people will be interested in knowing is, if they are working on gene X, whether gene X has the same expression pattern in human and mouse immune systems,” Shay said. “Most lineages have the same expression signature but some genes behave differently and we think it’s important for why some things work in mice but not humans and the other way around.”
Benoist, Morton Grove-Rasmussen Professor of Immunohematology at Harvard Medical School, said the continuing debate about the usefulness of mouse models in understanding humans “is often at the level of the emotional and not necessarily very informed.” Wildly different experimental conditions—hugely varying doses or duration in clinical trials—make comparisons suspect, he said.
Having clear data that scientists can freely access will be useful, said Benoist, who is also a co-author of the PNAS paper.
“The value here is putting up signposts, signaling when the function of a gene in mice may not be relevant to humans,” he said, referring to data and analysis from the work published in PNAS. “Because the differentiation and function of human and mouse lineages are highly related, there is the expectation of conservation, so it is important to know when inter-species inferences may be an issue. Mouse models are far too valuable to be jettisoned for pre-clinical exploration, but it is important to know when caution is needed.”
Obesity makes fat cells act like they’re infected
The inflammation of fat tissue is part of a spiraling series of events that leads to the development of type 2 diabetes in some obese people. But researchers have not understood what triggers the inflammation, or why.
In Cell Metabolism this month (cover), scientists from The Methodist Hospital report fat cells themselves are at least partly to blame — high calorie diets cause the cells to make major histocompatibility complex II, a group of proteins usually expressed to help the immune system fight off viruses and bacteria. In overweight mice and humans the fat cells, or adipocytes, are issuing false distress signals — they are not under attack by pathogens. But this still sends local immune cells into a tizzy, and that causes inflammation.
"We did not know fat cells could instigate the inflammatory response," said principal investigator and Methodist Diabetes & Metabolism Institute Director Willa Hsueh, M.D. "That’s because for a very long time we thought these cells did little else besides store and release energy. But what we have learned is that adipocytes don’t just rely on local resident immune cells for protection — they play a very active role in their own defense. And that’s not always a good thing."
In pinpointing major histocompatibility complex II (MHCII) as a cause of inflammation, the researchers may have also identified a new drug target for the treatment of obesity. Blocking the MHCII response of adipocytes wouldn’t cure obesity, Hsueh said, “but it could make it possible for doctors to alleviate some of obesity’s worst consequences while the condition itself is treated.”
Could the inflammation caused by a high fat diet serve any purpose, or is it a senseless response to an unnaturally caloric diet?
"The expression of MHCII in adipocytes does not seem to be helpful to the body," said co-lead author Christopher Lyon, Ph.D. "It is not at all clear what the advantage would be, given all the negative long-term consequences of fat tissue inflammation in people who are obese, including insulin resistance and, eventually, full diabetes. This just appears to be a runaway immune response to a modern high calorie diet."
Hsueh added, “The bottom line is, you’re feeding and feeding these fat cells and they’re turning around and biting you back. They’re doing the thing they’re supposed to do — storing energy — but reacting negatively to too much of it.”
The scientists studied fat cells from obese, female humans (via biopsy) and overfed male mice. The researchers said that while they expect similar MHCII expression to occur in overweight male humans and female mice, further studies are needed to establish this.
The immunology of adipocyte inflammation is complex. It begins with the import of excess nutrients from the bloodstream, which are converted and stored as fat and stimulate the production of the hormone leptin. Excess leptin, spurred by a high calorie diet, excites CD4 T cells to produce a second signaling molecule, interferon gamma, which causes adipocytes to produce MHCII. This dialogue between adipocytes and T cells appears to initiate the inflammatory response to high fat diet — Hsueh and her group found that overfed mice lacking MHCII experienced less inflammation.
Interferon gamma from T cells exacerbates the inflamed adipocytes’ behavior and causes another type of immune cell, M2 macrophages, to be converted to their pro-inflammatory (M1) version.
"It was known that macrophages and T cells are major players," said lead author Tuo Deng, Ph.D. "But no one knew what the start signals were to ignite inflammation.
RNA was extracted from adipocytes purified from fat tissue biopsies and subjected to microarray analysis, which allowed the researchers to see what genes were increased in overweight subjects. The researchers found high expression of most MHCII complex and MHCII antigen processing genes. Similar gene expression patterns were observed in mice within two weeks of starting a high-fat diet, and this mirrored pro-inflammatory changes in fat tissue CD4 T cells. Hsueh says her group plans to investigate whether the inflammatory response in overfed mice can be blocked when MHCII expression is specifically reduced in adipocytes.
Hsueh says that if she and her group can identify the antigen(s) that MHCII is presenting to T cells in fat tissue, medical researchers would have a new approach to target adipose inflammation in obese patients. The hypothesis is that if a treatment can interfere with the production or MHCII presentation of these antigens, this would reduce the activation of fat tissue immune cells and thus reduce inflammation. Determining the MHCII antigen(s) involved in the inflammatory response of fat tissue to weight gain is one of her group’s next goals, she says.
Vitamin D, omega-3 may help clear amyloid plaques found in Alzheimer’s
A team of academic researchers has pinpointed how vitamin D3 and omega-3 fatty acids may enhance the immune system’s ability to clear the brain of amyloid plaques, one of the hallmarks of Alzheimer’s disease.
In a small pilot study published in the Feb. 5 issue of the Journal of Alzheimer’s Disease, the scientists identified key genes and signaling networks regulated by vitamin D3 and the omega-3 fatty acid DHA (docosahexaenoic acid) that may help control inflammation and improve plaque clearance.
Previous laboratory work by the team helped clarify key mechanisms involved in helping vitamin D3 clear amyloid-beta, the abnormal protein found in the plaque. The new study extends the previous findings with vitamin D3 and highlights the role of omega-3 DHA.
"Our new study sheds further light on a possible role for nutritional substances such as vitamin D3 and omega-3 in boosting immunity to help fight Alzheimer’s," said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA.
A new promising approach in the therapy of pain
The treatment of inflammatory pain can be improved by endogenous opioid peptides acting directly in injured tissue. Scientists at the Charité – Universitätsmedizin Berlin and the Université Paris Descartes showed that pain can be successfully treated by targeting immune and nerve cells outside the brain or spinal cord. The study is published in the current issue of The FASEB Journal.
Inflammatory pain is the most common form of painful diseases. Examples are acute pain after surgery, and chronic pain as in the case of rheumatoid arthritis. However, the treatment of inflammatory pain is often difficult because it rarely responds to conventional therapies. Furthermore, opiates, such as morphine, produce serious side effects including addiction mediated in the brain, while drugs, such as ibuprofen, may cause stomach ulcers, internal bleeding, and cardiovascular complications. The activation of opiate receptors in nerve cells outside the brain or spinal cord can alleviate pain without serious side effects. This can be achieved by synthetic opiates or endogenous opioid peptides, e.g. enkephalins and endorphins. However, these peptides are rapidly inactivated by two major enzymes, aminopeptidase N (APN) and neutral endopeptidase (NEP), which limit their analgesic effects.
The aim of the research group of Prof. Halina Machelska-Stein from the Klinik für Anästhesiologie at Campus Benjamin Franklin was to prevent the breakdown of endogenous opioid peptides directly in the inflamed tissue. In an animal model, the group has shown that inflammatory pain can be alleviated if the two enzymes (APN and NEP), responsible for the inactivation of the opioid peptides, were blocked by the selective inhibitors. In preparations from immune or nerve cells, which express these enzymes, the opioid peptides were quickly broken down. This was prevented by the enzyme inhibitors, bestatin, thiorpan and P8B. As a result, the sensation of pain was either markedly reduced or completely disappeared. “Targeting of endogenous opioid peptides directly in injured tissues might be a promising strategy to treat inflammatory pain without serious side effects,” states Prof. Machelska-Stein, explaining the results of the investigation. Furthermore, blocking pain at the site of its origin may prevent excitatory mechanisms in the nervous system, which lead to the development of chronic pain.
(Source: charite.de)