Posts tagged tissue damage
Articles and news from the latest research reports.
Multiple sclerosis study reveals how killer T cells learn to recognize nerve fiber insulators
A micrograph of a killer T cell, a white blood cell that destroys germs or cancers, but that can sometimes attack the body’s own normal cells.
Misguided killer T cells may be the missing link in sustained tissue damage in the brains and spines of people with multiple sclerosis, findings from the University of Washington reveal. Cytoxic T cells, also known as CD8+ T cells, are white blood cells that normally are in the body’s arsenal to fight disease.
Multiple sclerosis is characterized by inflamed lesions that damage the insulation surrounding nerve fibers and destroy the axons, electrical impulse conductors that look like long, branching projections. Affected nerves fail to transmit signals effectively.
Intriguingly, the UW study, published this week in Nature Immunology, also raises the possibility that misdirected killer T cells might at other times act protectively and not add to lesion formation. Instead they might retaliate against the cells that tried to make them mistake the wrappings around nerve endings as dangerous.
Scientists Qingyong Ji and Luca Castelli performed the research with Joan Goverman, UW professor and chair of immunology. Goverman is noted for her work on the cells involved in autoimmune disorders of the central nervous system and on laboratory models of multiple sclerosis.
Multiple sclerosis generally first appears between ages 20 to 40. It is believed to stem from corruption of the body’s normal defense against pathogens, so that it now attacks itself. For reasons not yet known, the immune system, which wards off cancer and infection, is provoked to vandalize the myelin sheath around nerve cells. The myelin sheath resembles the coating on an electrical wire. When it frays, nerve impulses are impaired.
Depending on which nerves are harmed, vision problems, an inability to walk, or other debilitating symptoms may arise. Sometimes the lesions heal partially or temporarily, leading to a see-saw of remissions and flare ups. In other cases, nerve damage is unrelenting.
The myelin sheaths on nerve cell projections are fashioned by support cells called oligodendrocytes. Newborn’s brains contain just a few sections with myelinated nerve cells. An adult’s brains cells are not fully myelinated until age 25 to 30.
For T cells to recognize proteins from a pathogen, a myelin sheath or any source, other cells must break the desired proteins into small pieces, called peptides, and then present the peptides in a specific molecular package to the T cells. Scientists had previously determined which cells present pieces of a myelin protein to a type of T cell involved in the pathology of multiple sclerosis called a CD4+ T cell. Before the current study, no cells had yet been found that present myelin protein to CD8+ T cells.
Scientists strongly suspect that CD8+ T cells, whose job is to kill other cells, play an important role in the myelin-damage of multiple sclerosis. In experimental autoimmune encephalitis, which is a mouse model of multiple sclerosis in humans, CD4+ T cells have a significant part in the inflammatory response. However, scientists observed that, in acute and chronic multiple sclerosis lesions, CD8+T cells actually outnumber CD4+ T cells and their numbers correlate with the extent of damage to nerve cell projections. Other studies suggest the opposite: that CD8+ T cells may tone down the myelin attack.
The differing observations pointed to a conflicting role for CD8+ T cells in exacerbating or ameliorating episodes of multiple sclerosis. Still, how CD8+ T cells actually contributed to regulating the autoimmune response in the central nervous system, for better or worse, was poorly understood.
TIP dendritic cells, stained to show their physical features.
Goverman and her team showed for the first time that naive CD8+ T cells were activated and turned into myelin-recognizing cells by special cells called Tip-dendritic cells. These cells are derived from a type of inflammatory white blood cell that accumulates in the brain and the spinal cord during experimental autoimmune encephalitis originally mediated by CD4+ T cells. The membrane folds and protrusions of mature dendritic cells often look like branched tentacles or cupped petals well-suited to probing the surroundings.
The researchers proposed that the Tip dendritic cells can not only engulf myelin debris or dead oligodendrocytes and then present myelin peptides to CD4+ T cells, they also have the unusual ability to load a myelin peptide onto a specific type of molecule that also presents it to CD8+ T cells. In this way, the Tip dendritic cells can spread the immune response from CD4+ T cells to CD8+ T cells. This presentation enables CD8+ T cells to recognize myelin protein segments from oligodendrocytes, the cells that form the myelin sheath. The phenomenon establishes a second-wave of autoimmune reactivity in which the CD8+ T cells respond to the presence of oligodendrocytes by splitting them open and spilling their contents.
“Our findings are consistent,” the researchers said, “with the critical role of dendritic cells in promoting inflammation in autoimmune diseases of the central nervous system.” They mentioned that mature dendritic cells might possibly wait in the blood vessels of normal brain tissue to activate T-cells that have infiltrated the blood/brain barrier.
The oligodendrocytes, under the inflammatory situation of experimental autoimmune encephalitis, also present peptides that elicit an immune response from CD8+ T cells. Under healthy conditions, oligodendrocytes wouldn’t do this.
The researchers proposed that myelin-specific CD8+ T cells might play a role in the ongoing destruction of nerve-cell endings in “slow burning” multiple sclerosis lesions. A drop in inflammation accompanied by an increased degeneration of axons (electrical impulse-conducting structures) coincides with multiple sclerosis leaving the relapsing-remitting stage of disease and entering a more progressive state.
Medical scientists are studying the roles of a variety of immune cells in multiple sclerosis in the hopes of discovering pathways that could be therapeutic targets to prevent or control the disease, or to find ways to harness the body’s own protective mechanisms. This could lead to highly specific treatments that might avoid the unpleasant or dangerous side effects of generalized immunosuppressants like corticosteroids or methotrexate.
(Source: washington.edu)
Johns Hopkins researchers have uncovered strong evidence that mice have a specific set of nerve cells that signal itch but not pain, a finding that may settle a decades-long debate about these sensations, and, if confirmed in humans, help in developing treatments for chronic itch, including itch caused by life-saving medications.
At the heart of their discovery is a type of sensory nerve cell whose endings receive information from the skin and relay it to other nerves in the spinal cord, which then coordinates a response to the stimulus. Published online Dec. 23 in Nature Neuroscience, a report on the research suggests that even when the itch-specific nerve cells receive stimuli that are normally pain-inducing, the message they send isn’t “That hurts!” but rather “That itches!”
Pain and itch are both important sensations that help organisms survive. And pain is arguably more important because it tells us to withdraw the pained body part in order to prevent tissue damage. But itch also warns us of the presence of irritants, as in an allergic reaction. However, “when either of these sensations continues for weeks or months, they are no longer helpful. We even see patients stop taking life-saving medications because they cause such horrible itchiness all over,” says Xinzhong Dong, Ph.D., a Howard Hughes early career scientist and associate professor of neuroscience at the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. “And sometimes when we try to suppress chronic pain, with morphine for example, we end up causing chronic itchiness. So the two sensations are somehow related, and this study has begun to untangle them,” he says.
Because nerve cells send their messages as electrical currents that flow through them just as they would through wires, scientists can plug tiny monitors into individual nerve cells to detect the moment of stimulation. The scientific controversy over pain and itch centers around a group of nerve cells known to respond electrically to painful stimuli such as molecules of capsaicin, the fiery ingredient in chili peppers. A small subset of these nerve cells also responds electrically to itchy stimuli because they have on their surfaces receptors for molecules like histamine. One of these itchy receptors, called MrgA3, binds the anti-malaria drug chloroquine, causing serious itchiness in many patients.
Sensory nerve scientists have not known whether the nerves with itchy receptors and pain receptors were actually sending both types of messages to the brain, or just itch messages. What the current study found is that, in nerves with the itchy receptor MrgA3, electrical signals sent in response to both painful and itchy stimuli are interpreted by the brain as itch.
To reach this conclusion, the researchers first used a genetic trick to label the MrgA3 cells in mice with a glowing protein that allowed them to see the cells under the microscope. Aided by the glow, they were able to plug in those tiny electricity monitors and watch nerve cell responses to different stimuli. The cells transmitted electrical signals when the mice were exposed to itch-inducing chloroquine and histamine, as well as pain-inducing capsaicin and heat. Based on this result, the researchers tentatively concluded that the cells could send both pain and itch signals.
In the next experiment, the researchers monitored the behavioral responses of mice to the different stimuli. As expected, when the tails of normal mice were placed in hot water, they quickly pulled them out; when normal mice were given a bit of chloroquine or histamine, they scratched vigorously with their hind legs.
Then, to examine the role of MrgA3 cells in pain and itch, the scientists selectively killed MrgA3 nerve cells in adult mice and retested their responses. Presumably, the researchers noted, because MrgA3 cells are only a small fraction of all pain-sensing nerve cells, the mice had normal withdrawal responses to painful stimuli like hot water. However, when exposed to itchy stimuli, their scratching responses were reduced to varying degrees depending on the stimulus, most significantly in response to chloroquine. The fact that some stimuli still caused scratching suggested to the scientists that MrgA3 cells are not the only ones in the body that respond to itch. “We were convinced that MrgA3 cells are responsible for much of the sensation of itch, but it wasn’t yet clear whether MrgA3 cells could also relay painful information,” says Dong.
In their final experiments, the scientists used genetic techniques to create mice in which the MrgA3 cells were the only cells in the body capable of responding to capsaicin, that peppery pain-inducing substance. When injected into the cheeks of mice, normal mice massage the area with their forepaws to relieve the hot sensation. When injected into the experimental mice, they vigorously scratched their cheeks with their hind legs, suggesting that this normally painful stimulus had been communicated to the brain—by MrgA3 cells—as itchiness.
"Now that we have disentangled these itchy sensations from painful ones, we should be able to design drugs that target itch-specific nerve cells to combat chronic itchiness," says Dong. "We hope that this will not only provide relief, but also increase people’s faithfulness to their drug plans, particularly for deadly diseases like malaria and cancer."