Posts tagged immune cells
Articles and news from the latest research reports.
Why HIV patients develop dementia
Immune cells in the brain under suspicion
“HIV-associated neurocognitive disorders” (HAND) include disorders of the cognitive functions, motor capacities as well as behavioural changes. How exactly HAND occur has not, as yet, been fully understood. “Scientists assume that HIV is harmful to cells directly and that it also triggers indirect mechanisms that lead to nerve cell damage,” explains Dr Simon Faissner (RUB clinic for neurology, St. Josef-Hospital). The researchers strongly suspect that, once activated in the brain and the spinal cord, immune cells keep up a chronic inflammation level which then results in the destruction of nerve cells. An immune activation in peripheral tissue as well as therapeutic consequences may likewise contribute to nerve cell damage in the brain.
First steps of HIV infection are sufficient
The HI virus overcomes the blood-brain barrier hitchhiking on infected immune cells, the monocytes and probably the T cells. The researchers from Bochum tested the hypothesis that HIV-infected monocytes activate specific immune cells in the brain, the so-called microglial cells. These cells, in turn, respond by releasing harmful substances, such as reactive oxygen metabolites and inflammatory signalling molecules, i.e. cytokines. To test this hypothesis, the researchers developed a cell culture system in which they initially examined the effect of HIV-infected monocytes on microglial cells. The researchers simulated the individual steps of HIV infection and measured the concentration of the cytokines released at each stage. Thus, they were able to demonstrate that releasing the viral RNA in the monocytes was a sufficient trigger for maximal microglial activation. Subsequent infection phases – reverse transcription into DNA and the resulting formation of HIV proteins – did not augment activation any further.
Released substances result in neuronal cell death
In the second step, they analysed nerve cells from rat brains to determine if the substances released by the microglial cells could lead to cell death. Compared with the control group, the amount of cell death was indeed twice as high. Studies of liquor cerebrospinalis received from HIV-infected patients have shown a positive correlation with marker of neuronal degeneration in patients who did not as yet present any neurocognitive disorders.
Detailed understanding necessary for therapeutic strategies
“Thanks to our research, we have gained a better understanding of the mechanisms of HIV-associated neurodegeneration,” concludes Prof Dr Andrew Chan. “These results are likely to contribute to HAND biomarkers becoming established. In the long term, these data may be used to develop therapeutic strategies aiming at retarding HAND progression in HIV-infected patients.” Starting points may include activation of microglial cells – a method that is applied in other autoimmune diseases of the central nervous system, for example in multiple sclerosis.
Start-up through FoRUM funds
The research, which was initiated following a collaboration between clinics for neurology and dermatology, St. Josef Hospital, as well as the Department for Molecular and Medical Virology, has been made possible through start-up funding provided by the Faculty of Medicine at Ruhr-Universität (FoRUM). The collaboration has evolved into an international consortium of clinics and basic research organisations in Bochum, Langen, Strasbourg and Mailand. One objective of the follow-up study, for which an application for EU funds is pending, is going to be an in-depth analysis of inflammatory processes in the central nervous system. The researchers will attempt to inhibit inflammatory processes with different drugs. They are, moreover, planning to study direct cell-cell interaction by means of state-of-the-art microscopy, in collaboration with the University of Strasbourg.
(Image credit: Mehau Kulyk/Science Photo Library)
(Image caption: Aggressor cells, which have the potential to cause autoimmunity, are targeted by treatment, causing conversion of these cells to protector cells. Gene expression changes gradually at each stage of treatment, as illustrated by the color changes in this series of heat maps. Credit: University of Bristol/Dr. Bronwen Burton)
Scientists discover how to ‘switch off’ autoimmune diseases
Scientists have made an important breakthrough in the fight against debilitating autoimmune diseases such as multiple sclerosis by revealing how to stop cells attacking healthy body tissue.
Rather than the body’s immune system destroying its own tissue by mistake, researchers at the University of Bristol have discovered how cells convert from being aggressive to actually protecting against disease.
The study, funded by the Wellcome Trust, is published in Nature Communications.
It’s hoped this latest insight will lead to the widespread use of antigen-specific immunotherapy as a treatment for many autoimmune disorders, including multiple sclerosis (MS), type 1 diabetes, Graves’ disease and systemic lupus erythematosus (SLE).
MS alone affects around 100,000 people in the UK and 2.5 million people worldwide.
Scientists were able to selectively target the cells that cause autoimmune disease by dampening down their aggression against the body’s own tissues while converting them into cells capable of protecting against disease.
This type of conversion has been previously applied to allergies, known as ‘allergic desensitisation’, but its application to autoimmune diseases has only been appreciated recently.
The Bristol group has now revealed how the administration of fragments of the proteins that are normally the target for attack leads to correction of the autoimmune response.
Most importantly, their work reveals that effective treatment is achieved by gradually increasing the dose of antigenic fragment injected.
In order to figure out how this type of immunotherapy works, the scientists delved inside the immune cells themselves to see which genes and proteins were turned on or off by the treatment.
They found changes in gene expression that help explain how effective treatment leads to conversion of aggressor into protector cells. The outcome is to reinstate self-tolerance whereby an individual’s immune system ignores its own tissues while remaining fully armed to protect against infection.
By specifically targeting the cells at fault, this immunotherapeutic approach avoids the need for the immune suppressive drugs associated with unacceptable side effects such as infections, development of tumours and disruption of natural regulatory mechanisms.
Professor David Wraith, who led the research, said: “Insight into the molecular basis of antigen-specific immunotherapy opens up exciting new opportunities to enhance the selectivity of the approach while providing valuable markers with which to measure effective treatment. These findings have important implications for the many patients suffering from autoimmune conditions that are currently difficult to treat.”
This treatment approach, which could improve the lives of millions of people worldwide, is currently undergoing clinical development through biotechnology company Apitope, a spin-out from the University of Bristol.
Sublime Microglia: Expanding Roles for the Guardians of the CNS
Recent findings challenge the concept that microglia solely function in disease states in the central nervous system (CNS). Rather than simply reacting to CNS injury, infection, or pathology, emerging lines of evidence indicate that microglia sculpt the structure of the CNS, refine neuronal circuitry and network connectivity, and contribute to plasticity. These physiological functions of microglia in the normal CNS begin during development and persist into maturity. Here, we develop a conceptual framework for functions of microglia beyond neuroinflammation and discuss the rich repertoire of signaling and communication motifs in microglia that are critical both in pathology and for the normal physiology of the CNS.
Study helps explain why MS is more common in women
A newly identified difference between the brains of women and men with multiple sclerosis (MS) may help explain why so many more women than men get the disease, researchers at Washington University School of Medicine in St. Louis report.
In recent years, the diagnosis of MS has increased more rapidly among women, who get the disorder nearly four times more than men. The reasons are unclear, but the new study is the first to associate a sex difference in the brain with MS.
(Image caption: An image of tissue from a female brain (left) affected by multiple sclerosis (MS) shows that the brain has much higher levels of a blood vessel receptor (shown in red) than a male brain affected by MS (right). The difference could help explain why so many more women get MS. Credit: Robyn Klein)
The findings appear May 8 in The Journal of Clinical Investigation.
Studying mice and people, the researchers found that females susceptible to MS produce higher levels of a blood vessel receptor protein, S1PR2, than males and that the protein is present at even higher levels in the brain areas that MS typically damages.
“It was a ‘Bingo!’ moment – our genetic studies led us right to this receptor,” said senior author Robyn Klein, MD, PhD. “When we looked at its function in mice, we found that it can determine whether immune cells cross blood vessels into the brain. These cells cause the inflammation that leads to MS.”
An investigational MS drug currently in clinical trials blocks other receptors in the same protein family but does not affect S1PR2. Klein recommended that researchers work to develop a drug that disables S1PR2.
MS is highly unpredictable, flaring and fading at irregular intervals and producing a hodgepodge of symptoms that includes problems with mobility, vision, strength and balance. More than 2 million people worldwide have the condition.
In MS, inflammation caused by misdirected immune cells damages a protective coating that surrounds the branches of nerve cells in the brain and spinal column. This leads the branches to malfunction and sometimes causes them to wither away, disrupting nerve cell communication necessary for normal brain functions such as movement and coordination.
For the new research, Klein studied a mouse model of MS in which the females get the disease more often than the males. The scientists compared levels of gene activity in male and female brains. They also looked at gene activity in the regions of the female brain that MS damages and in other regions the disorder typically does not harm.
They identified 20 genes that were active at different levels in vulnerable female brain regions. Scientists don’t know what 16 of these genes do. Among the remaining genes, the increased activity of S1PR2 stood out because researchers knew from previous studies that the protein regulates how easy it is for cells and molecules to pass through the walls of blood vessels.
Additional experiments showed that S1PR2 opens up the blood-brain barrier, a structure in the brain’s blood vessels that tightly regulates the materials that cross into the brain and spinal fluid. This barrier normally blocks potentially harmful substances from entering the brain. Opening it up likely allows the inflammatory cells that cause MS to get into the central nervous system.
When the researchers tested brain tissue samples obtained from 20 patients after death, they found more S1PR2 in MS patients’ brains than in people without the disorder. Brain tissue from females also had higher levels of S1PR2 than male brain tissue. The highest levels of S1PR2 were found in the brains of two female patients whose symptoms flared and faded irregularly, a pattern scientists call relapsing and remitting MS.
Klein is collaborating with chemists to design a tracer that will allow scientists to monitor S1PR2 levels in the brains of people while they are living. She hopes this will lead to a fuller understanding of how S1PR2 contributes to MS.
“This is an exciting first step in resolving the mystery of why MS rates are dramatically higher in women and in finding better ways to reduce the incidence of this disorder and control symptoms,” said Klein, associate professor of medicine. Klein also is an associate professor of pathology and immunology and of neurobiology and anatomy.
(Source: news.wustl.edu)
Lack of coronin 1 protein causes learning deficits and aggressive behavior
Learning and memory relies on the proper processing of signals that stimulate neuronal cells within the brain. Researchers at the Biozentrum of the University of Basel, together with an international team of scientists, has uncovered an important role for the protein coronin 1 in cognition and behavior. They found that a lack of coronin 1 in mouse and in man is associated with poor memory, defective learning and aggressive behavior. The results, recently published in PLOS Biology, identify a novel risk factor for neurobehavioral dysfunction and reveal a molecular pathway involved in transferring information within neurons.
Organisms must be able to sense signals from the outside and translate these into biochemical cues in order to adequately respond to their environment. This capability is also required to process information that reaches the brain. Within the brain, stimulation of neurons activates genes that are required, for example for learning and memory. In collaboration with an international and interdisciplinary team the research group led by Prof. Jean Pieters from the Biozentrum, University of Basel, has now uncovered the role of an evolutionarily conserved protein, called coronin 1, in providing a link between the extracellular stimulus and neuronal activation that ultimately results in efficient learning and memory in both mice and men.
From the immune system to the brain
In earlier work, Pieters’ team discovered the protein coronin 1 as being essential for the proper transduction of signals in immune cells. In mice lacking coronin 1 the researchers further investigated the molecular mechanism. Surprisingly, these mice showed aberrant behavior. In particular, mice lacking coronin 1 appeared to be far more aggressive and display extreme grooming activity, an indication of reduced sociability. An in-depth analysis in collaboration with scientists from the Friedrich Miescher Institute in Basel and the University of Bordeaux unveiled profound learning and behavioral problems and severe defects in the ability to activate neurons in the absence of coronin 1.
Activation of a signaling cascade
But how does coronin 1 ensure proper neurobehavioral functioning? Normally, stimulation of the cell surface results in an activation of an intracellular cascade of reactions and ultimately stimulates the production of the signaling molecule cAMP which then activates a number of processes, including the transcription of gene involved in neurobehavior. “We found that in the absence of coronin 1, cell surface stimulation leads to a defective cAMP production”, explains Pieters. “This in turn affects the signal transduction which is finally responsible for the deficits in learning and memory formation.”
Of mice and men
Furthermore, the researchers analyzed the clinical history of a patient lacking coronin 1 due to a mutation: it turned out that this patient showed learning defects and aggressive behavior. With this study, Pieters and his project collaborators not only define a crucial role for coronin 1 in cognition and behavior, but also unravel a coronin 1-dependent signaling pathway that may be explored both for potential risk factors as well as future interventions to modulate neurobehavioral dysfunction.
Halting Immune Response Could Save Brain Cells After Stroke
A new study in animals shows that using a compound to block the body’s immune response greatly reduces disability after a stroke.
The study by scientists from the University of Wisconsin School of Medicine and Public Health also showed that particular immune cells – CD4+ T-cells produce a mediator, called interleukin (IL)-21 that can cause further damage in stroke tissue.
Moreover, normal mice, ordinarily killed or disabled by an ischemic stroke, were given a shot of a compound that blocks the action of IL-21. Brain scans and brain sections showed that the treated mice suffered little or no stroke damage.
“This is very exciting because we haven’t had a new drug for stroke in decades, and this suggests a target for such a drug,” says lead author Dr. Zsuzsanna Fabry, professor of pathology and laboratory medicine
Stroke is the fourth-leading killer in the world and an important cause of permanent disability. In an ischemic stroke, a clot blocks the flow of oxygen-rich blood to the brain. But Fabry explains that much of the damage to brain cells occurs after the clot is removed or dissolved by medicine. Blood rushes back into the brain tissue, bringing with it immune cells called T-cells, which flock to the source of an injury.
The study shows that after a stroke, the injured brain cells provoke the CD4+ T-cells to produce a substance, IL-21, that kills the neurons in the blood-deprived tissue of the brain. The study gave new insight how stroke induces neural injury.
Similar Findings in Humans
Fabry’s co-author Dr. Matyas Sandor, professor of pathology and laboratory medicine, says that the final part of the study looked at brain tissue from people who had died following ischemic strokes. It found that CD4+ T-cells and their protein, IL-21 are in high concentration in areas of the brain damaged by the stroke.
Sandor says the similarity suggests that the protein that blocks IL-21 could become a treatment for stroke, and would likely be administered at the same time as the current blood-clot dissolving drugs.
“We don’t have proof that it will work in humans,” he says, “but similar accumulation of IL-21 producing cells suggests that it might.”
The paper was published this week in the Journal of Experimental Medicine.
(Source: med.wisc.edu)
Study identifies new culprit that may make aging brains susceptible to neurodegenerative diseases
The steady accumulation of a protein in healthy, aging brains may explain seniors’ vulnerability to neurodegenerative disorders, a new study by researchers at the Stanford University School of Medicine reports.
The study’s unexpected findings could fundamentally change the way scientists think about neurodegenerative disease.
The pharmaceutical industry has spent billions of dollars on futile clinical trials directed at treating Alzheimer’s disease by ridding brains of a substance called amyloid plaque. But the new findings have identified another mechanism, involving an entirely different substance, that may lie at the root not only of Alzheimer’s but of many other neurodegenerative disorders — and, perhaps, even the more subtle decline that accompanies normal aging.
The study, published Aug. 14 in the Journal of Neuroscience, reveals that with advancing age, a protein called C1q, well-known as a key initiator of immune response, increasingly lodges at contact points connecting nerve cells in the brain to one another. Elevated C1q concentrations at these contact points, or synapses, may render them prone to catastrophic destruction by brain-dwelling immune cells, triggered when a catalytic event such as brain injury, systemic infection or a series of small strokes unleashes a second set of substances on the synapses.
“No other protein has ever been shown to increase nearly so profoundly with normal brain aging,” said Ben Barres, MD, PhD, professor and chair of neurobiology and senior author of the study. Examinations of mouse and human brain tissue showed as much as a 300-fold age-related buildup of C1q.
The finding was made possible by the diligence and ingenuity of the study’s lead author, Alexander Stephan, PhD, a postdoctoral scholar in Barres’ lab. Stephan screened about 1,000 antibodies before finding one that binds to C1q and nothing else. (Antibodies are proteins, generated by the immune system, that adhere to specific “biochemical shapes,” such as surface features of invading pathogens.)
Comparing brain tissue from mice of varying ages, as well as postmortem samples from a 2-month-old infant and an older person, the researchers showed that these C1q deposits weren’t randomly distributed along nerve cells but, rather, were heavily concentrated at synapses. Analyses of brain slices from mice across a range of ages showed that as the animals age, the deposits spread throughout the brain.
“The first regions of the brain to show a dramatic increase in C1q are places like the hippocampus and substantia nigra, the precise brain regions most vulnerable to neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, respectively,” said Barres. Another region affected early on, the piriform cortex, is associated with the sense of smell, whose loss often heralds the onset of neurodegenerative disease.
Other scientists have observed moderate, age-associated increases (on the order of three- or four-fold) in brain levels of the messenger-RNA molecule responsible for transmitting the genetic instructions for manufacturing C1q to the protein-making machinery in cells. Testing for messenger-RNA levels — typically considered reasonable proxies for how much of a particular protein is being produced — is fast, easy and cheap compared with analyzing proteins.
But in this study, Barres and his colleagues used biochemical measures of the protein itself. “The 300-fold rise in C1q levels we saw in 2-year-old mice — equivalent to 70- or 80-year-old humans — knocked my socks off,” Barres said. “I was not expecting that at all.”
C1q is the first batter on a 20-member team of immune-response-triggering proteins, collectively called the complement system. C1q is capable of clinging to the surface of foreign bodies such as bacteria or to bits of our own dead or dying cells. This initiates a molecular chain reaction known as the complement cascade. One by one, the system’s other proteins glom on, coating the offending cell or piece of debris. This in turn draws the attention of omnivorous immune cells that gobble up the target.
The brain has its own set of immune cells, called microglia, which can secrete C1q. Still other brain cells, called astrocytes, secrete all of C1q’s complement-system “teammates.” The two cell types work analogously to the two tubes of an Epoxy kit, in which one tube contains the resin, the other a catalyst.
Previous work in Barres’ lab has shown that the complement cascade plays a critical role in the developing brain. A young brain generates an excess of synapses, creating a huge range of options for the potential formation of new neural circuits. These synapses strengthen or weaken over time, in response to their heavy use or neglect. The presence of feckless connections contributes noise to the system, so the efficiency of the maturing brain’s architecture is improved if these underused synapses are pruned away.
In a 2007 paper in Cell, Barres’ group reported that the complement system is essential to synaptic pruning in normal, developing brains. Then in 2012, in Neuron, in a collaboration with the lab of Harvard neuroscientist Beth Stevens, PhD, they showed that it is specifically microglia — the brain’s in-house immune cells — that attack and ingest complement-coated synapses.
Barres now believes something similar is happening in the normal, aging brain. C1q, but not the other protein components of the complement system, gradually becomes highly prevalent at synapses. By itself, this C1q buildup doesn’t trigger wholesale synapse loss, the researchers found — although it does seem to impair their performance. Old mice whose capacity to produce C1q had been eliminated performed subtly better on memory and learning tests than normal older mice did.
Still, this leaves the aging brain’s synapses precariously perched on the brink of catastrophe. A subsequent event such as brain trauma, a bad case of pneumonia or perhaps a series of tiny strokes that some older people experience could incite astrocytes — the second tube in the Epoxy kit — to start secreting the other complement-system proteins required for synapse destruction.
Most cells in the body have their own complement-inhibiting agents. This prevents the wholesale loss of healthy tissue during an immune attack on invading pathogens or debris from dead tissue during wound healing. But nerve cells lack their own supply of complement inhibitors. So, when astrocytes get activated, their ensuing release of C1q’s teammates may set off a synapse-destroying rampage that spreads “like a fire burning through the brain,” Barres said.
“Our findings may well explain the long-mysterious vulnerability specifically of the aging brain to neurodegenerative disease,” he said. “Kids don’t get Alzheimer’s or Parkinson’s. Profound activation of the complement cascade, associated with massive synapse loss, is the cardinal feature of Alzheimer’s disease and many other neurodegenerative disorders. People have thought this was because synapse loss triggers inflammation. But our findings here suggest that activation of the complement cascade is driving synapse loss, not the other way around.”
(Source: med.stanford.edu)
Computer Simulations Shed New Light On How The Immune System Works
Researchers at McGill University in Montreal have developed computer simulations that better explain how a person’s immune cells can detect foreign antigens and fight infections.
In an effort to determine exactly how the body’s natural defenses are able to sort through large amounts of similar-looking proteins in order to locate and eliminate harmful invaders, physics professor Paul François and graduate student Jean-Benoît Lalanne used computational tools to study how the process works.
They discovered that the antigen-fighting process is related to the phenomenon of biochemical adaptation – a mechanism that enables organisms to cope with a variety of different environmental conditions. According to the authors of the study, their work could prove essential insight into AIDS and other immune diseases.
“For immune cells, singling out foreign proteins is like looking for a needle in a haystack – where the needle may look very much like a straw, and where some straws may also look very much like a needle,” François said. “Our approach provides a simpler theoretical framework and understanding of what happens” as the immune cells sort through that “haystack” in search of foreign antigens and to trigger the body’s immune response.
The researchers’ computer simulation used an algorithm that was inspired by Darwinian evolution, the university explained. The algorithm randomly creates mathematical models of biochemical networks, and then scores them by comparing their properties to those of an actual immune system. The highest-rated networks are duplicated in the next generation and mutated, a process that is repeated until the networks achieve a perfect score.
“Our model shares many similarities with real immune networks,” explained François. “Strikingly, the simplest evolved solution we found has both similar characteristics and some of the blind spots of real immune cells we studied in a previous collaborative study with the groups of Grégoire Altan-Bonnet (Memorial Sloane Kettering, New York), Eric Siggia (Rockefeller University, New York) and Massimo Vergassola (Pasteur Institute, Paris).”
The Natural Sciences and Engineering Research Council of Canada and the Human Frontier Science Program provided funding for the research, which was published in a recent edition of the journal Physical Review Letters.
Enhanced White Blood Cells Heal Mice With MS-like Disease
Genetically engineered immune cells seem to promote healing in mice infected with a neurological disease similar to multiple sclerosis (MS), cleaning up lesions and allowing the mice to regain use of their legs and tails.
The new finding, by a team of University of Wisconsin School of Medicine and Public Health researchers, suggests that immune cells could be engineered to create a new type of treatment for people with MS. Currently, there are few good medications for MS, an autoimmune inflammatory disease that affects some 400,000 people in the United States, and none that reverse progress of the disease.
Dr. Michael Carrithers, assistant professor of neurology, led a team that created a specially designed macrophage – an immune cell whose name means “big eater.” Macrophages rush to the site of an injury or infection, to destroy bacteria and viruses and clear away damaged tissue. The research team added a human gene to the mouse immune cell, creating a macrophage that expressed a sodium channel called NaVI.5, which seems to enhance the cell’s immune response.
But because macrophages can also be part of the autoimmune response that damages the protective covering (myelin) of the nerves in people with MS, scientists weren’t sure whether the NaV1.5 macrophages would help or make the disease worse.
When the mice developed experimental autoimmune encephalomyelitis – the mouse version of MS — they found that the NaV1.5 macrophages sought out the lesions caused by the disease and promoted recovery.
“This finding was unexpected because we weren’t sure how much damage they would do, versus how much cleaning up they would do,” Carrithers says. “Some people thought the mice would get more ill, but we found that it protected them and they either had no disease or a very mild case.”
In follow-up experiments, regular mice that do not express the human gene were treated with the NaV1.5 macrophages after the onset of symptoms, which include weakness of the back and front limbs. The majority of these mice developed complete paralysis of their hindlimbs. Almost all of the mice that were treated with the Na1.5 macrophages regained the ability to walk. Mice treated with placebo solution or regular mouse macrophages that did not have NaV1.5 did not show any recovery or became more ill. In treated mice, the research team also found the NaV1.5 macrophages at the site of the lesions, and found smaller lesions and less damaged tissue in the treated mice.
Because the NaV1.5 variation is present in human immune cells, Carrithers says, “The questions are, ‘Why are these repair mechanisms deficient in patients with MS and what can we do to enhance them?’’’ He says the long-range goal is to develop the NaV1.5 enhanced macrophages as a treatment for people with MS.
The study is being published in the June issue of the Journal of Neuropathology and Experimental Neurology.
(Source: med.wisc.edu)
Going live – immune cell activation in multiple sclerosis
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to examine individual cells and their activity directly in the tissue. The development of new microscopes and fluorescent dyes in recent years has brought this scientific dream tantalisingly close. Scientists from the Max Planck Institute of Neurobiology in Martinsried have now presented not one, but two studies introducing new indicator molecules which can visualise the activation of T cells. Their findings provide new insight into the role of these cells in the autoimmune disease multiple sclerosis (MS). The new indicators are set to be an important tool in the study of other immune reactions as well.
Inflammation is the body’s defence response to a potentially harmful stimulus. The purpose of an inflammation is to fight and remove the stimulus – whether it be disease-causing pathogens or tissue. As an inflammation progresses, significant steps that occur thus include the recruitment of immune cells, the interactions of these cells in the affected tissue and the resulting activation pattern of the immune cells. The more scientists understand about these steps, the better they can develop more effective drugs and treatments to support them. This is particularly true for diseases like multiple sclerosis. In this autoimmune disorder cells from the body’s immune system penetrate into the central nervous system where they cause massive damage in the course of an inflammation.
In order to truly understand the cellular processes involved in MS, scientists ideally need to study them in real time at the exact location where they take place – directly in the affected tissue. In recent years, new microscopic techniques and fluorescent dyes have been developed to make this possible for the first time. These coloured indicators make individual cells, their components or certain cell processes visible under the microscope. For example, scientists from the Max Planck Institute of Neurobiology have developed a genetic calcium indicator, TN-XXL, which the cells themselves form, and which highlights the activity of individual nerve cells reliably and for an unlimited time. However, the gene for the indicator was not expressed by immune cells. That is why it was previously impossible to track where in the body and when a contact between immune cells and other cells led to the immune cell’s activation.
Now the Martinsried-based neuroimmunologists report two major advances in this field simultaneously. One is their development of a new indicator which visualises the activation of T cells. These cells, which are important components of the immune system, detect and fight pathogens or substances classified as foreign (antigens). Multiple sclerosis, for example, is one of the diseases in which T cells play an important role: here, however, they detect and attack the body’s brain tissue. If a T cell detects “its own” antigen, the NFAT signal protein migrates from the cell plasma to the nucleus of the T cell. “This movement of the NFAT shows us that the cell has been activated, in other words it has been ‘armed’,” explains Marija Pesic, lead author of the study published in the Journal of Clinical Investigation. “We took advantage of this to bind the fluorescent dye called GFP to the NFAT, thereby visualising the activation of these cells.” The scientists are thus now able to conclusively show in the organism whether an antigen leads to the activation of a T cell. The new indicator is an important new tool for researching autoimmune diseases and also for studying immune cells during their development, during infections or in the course of tumour reactions.
In parallel to these studies, the neuroimmunologists in Martinsried developed a slightly different, complementary method. They modified the calcium indicator TN-XXL to enable, for the first time, T cell activation patterns to be observed live under the microscope, even while the cells are wandering about the body. When a T cell detects an antigen, a rapid rise in the calcium concentration within the cell ensues. The TN-XXL makes this alteration in the calcium level apparent by changing colour, giving the scientists a direct view of when and where the T cells are being activated.
"This method has enabled us to demonstrate that these cells really can be activated in the brain," says a pleased Marsilius Mues, lead author of the study which has just been published in Nature Medicine. Until now, scientists had only suspected this to be the case. In the animal model of multiple sclerosis, scientists are now able to track not only the migration of the T cells, but also their activation pattern in the course of the disease. Initial investigations have already shown, besides the expected activation by antigen detection, that numerous fluctuations in calcium levels also take place which bear no relation to an antigen. “These fluctuations can tell us something about how potent the T cell is, how strong the antigen is, or it may have something to do with the environment,” speculates Marsilius Mues. These observations could indicate new research approaches for drugs – or they could even show whether a drug actually has an effect on T cell activation.