The human immune system often has a troubled relationship with the brain; the brain is an “immune privileged” area, where only one type of immune cell, called microglia, reside. Invading bacteria, viruses, and toxins can enter the brain by breaching the blood-brain barrier, the tightly packed layer of cells in blood vessel walls that governs the transfer of substances from blood to the brain. When this occurs, immune cells then rush into the brain to fight the invaders off.
Sometimes, however, immune cells mistake normal brain tissues as invaders and attack them. This occurs in multiple sclerosis, for instance, in which immune cells go overboard and attack the essential myelin insulation surrounding axons in the brain and central nervous system. The immune system also launches an attack against the amyloid proteins that build up in the brains of patients with Alzheimer’s disease; this attack is so aggressive that it provokes inflammation that damages neurons. A similar process may occur in Parkinson’s disease (see Movement Disorders).
The most significant advances in neuroimmunology in 2006 identified how certain immune cells become transformed to attack myelin in multiple sclerosis. Other research investigated how the immune system might serve to prevent or even reverse the degeneration of Alzheimer’s disease.
In multiple sclerosis, the gaps that develop in the myelin covering of nerve cell axons after repeated immune system attacks disrupt neural signaling. This disruption produces an array of symptoms. Until recently, scientists assumed that such myelin attacks were waged by faulty immune helper T cells (called TH1 cells), which ordinarily alert the immune system to the presence of bacteria or viruses within a cell. However, researchers discovered in 2005 that another helper T cell, TH17, plays a crucial role in initiating an autoimmune attack on myelin. The TH17 cells are produced when immature T cells are exposed to the combination of two other molecules, according to a Nature study by researchers at Harvard Medical School in Boston, led by Estelle Bettelli.1 One of these molecules is a signaling protein known as transforming growth factor-beta (TGF-beta). The other is an inflammation-promoting immune molecule called interleukin-6 (IL-6), which is released by T cells. Mice deficient in IL-6 had no TH17 cells and did not develop a mouse version of multiple sclerosis.
Moreover, Yoichiro Iwakura and Harumichi Ishigame found that a molecule called interleukin-23 (IL-23), a growth factor, transforms immature T cells into TH17 cells.2 Their work, published in the Journal of Clinical Investigation, revealed that by blocking IL-23, they could significantly suppress the development of animal versions of multiple sclerosis and another autoimmune disease called inflammatory bowel disease. Taken together, these two studies suggest that therapies that block the transformation of immune T cells into TH17 cells might be effectively used in at least some autoimmune disease, including multiple sclerosis.
Target of an Autoimmune Attack
In another inflammatory disease called neuromyelitis optica, the immune system attacks the myelin around the optic nerve, producing partial or total blindness. Although neuromyelitis optica is sometimes mistaken for an early manifestation of multiple sclerosis, scientists recently discovered that an antibody known as NMO-IgG, which mistakenly attacks the myelin in neuromyelitis optica, does not exist in patients with multiple sclerosis. This finding suggests that neuromyelitis optica is a distinct disease.
Research also suggests a role for NMO-IgG in transverse myelitis, a disease in which the immune system attacks the myelin around axons in the spinal cord, causing movement problems or paralysis. Brian Weinshenker and colleagues at the Mayo Clinic reported in Annals of Neurology that about 40 percent of patients with extensive transverse myelitis test positive for NMO-IgG, and more than half of those who test positive experience a relapse within one year.3 Those without the antibody in their blood do not experience relapse.
Before this discovery, physicians could not identify which of these patients, including those with transverse myelitis, were at risk for a recurrent autoimmune attack on the spinal cord. Now, by testing for this biomarker, they can identify those at risk for relapse and consider starting immunosuppressive treatments.
But what does the NMO-IgG autoimmune antibody attack? Researchers at the Mayo Clinic led by Vanda Lennon discovered in 2006 that NMO-IgG mistakenly targets aquaporin-4, a recently discovered protein in the central nervous system that enables water to move in and out of cells.4 Aquaporin-4 is produced in the brain primarily by star-shaped cells called astrocytes, which bolster the blood-brain barrier, dispose of noxious substances in the blood, and prevent them from passing into the brain.
High levels of aquaporin-4 are found in the optic nerve, spinal cord, and certain brain stem areas—targets attacked by the immune system of patients with neuromyelitis optica. This suggests that NMO-IgG might leak from blood vessels at those locations, find aquaporin-4, and attack it. In any case, the finding that NMO-IgG is a reliable marker for the disease represents a major advance in diagnosis of neuromyelitis optica.
Controlling the Immune Response
A runaway immune response in the brain can cause multiple sclerosis, lupus, and other diseases—but how does the immune system get out of control?
Chemokines send signals among cells and regulate the deployment of immune cells known as leukocytes. A team led by Richard M. Ransohoff reported in Nature Neuroscience that fractalkines, an unusual variant of chemokines, are essential for keeping immune reactions in the brain under control.5 By releasing fractalkines, immune cells in the brain (the microglia) quell the tendency of other cells involved in an immune response to overreact.
Ransohoff found that mice lacking the gene for fractalkines appear normal but suffered much greater damage to their neurons during vigorous inflammatory reactions in mouse models of human diseases including Parkinson’s disease and amyotrophic lateral sclerosis (Lou Gehrig’s disease).
|Immune system control problems: Mice lacking the gene for the fractalkine receptor protein, bottom, a protein found on brain inflammatory cells, show increased microglia activity over time (from left to right), causing greater neuron damage during mouse models of human diseases. (Image courtesy of Richard Ransohoff) |
The Immune System and Alzheimer’s
The immune system identifies the beta-amyloid particles that accumulate in the brains of people with Alzheimer’s disease as foreign invaders that must be destroyed. The result is inflammation, which certainly aggravates the disease and may even cause it. A clinical trial of a therapeutic vaccine to deplete those plaques had to be stopped in 2002 because the immune reaction caused severe brain inflammation in some participants.
But the immune T cells that caused that inflammation still might be effectively and safely recruited as allies in a fight against those plaques, according to Michal Schwartz and colleagues at the Weizmann Institute of Science in Israel. In a paper published in Proceedings of the National Academy of Sciences, the researchers described how they therapeutically immunized mice bred to develop amyloid plaques by giving them glatiramer acetate (GA), an immune system modulator (trade name “Copaxone”) that has been used to treat multiple sclerosis. The therapy, which stimulates T cells, reduced the plaque burden in the mice and promoted the growth of cells in the hippocampus, resulting in improved memory and learning.6 The scientists believe the therapy achieved this effect by stimulating microglial cells to express a hormone called insulin-like growth factor-1 (IGF-1) instead of the destructive cytokine called tumor necrosis factor-alpha (TNF-alpha), which triggers inflammation. By fine-tuning the immune response in this way, the authors believe, such therapies could stimulate an attack against beta-amyloid in the brain without triggering destructive inflammation.
Schwartz also demonstrated that when immune T cells are injected into the brains of mice, they contribute to the birth of neurons in certain areas, including the hippocampus, which is devastated by Alzheimer’s disease. She and her group compared the brains of two groups of mice in a stimulating environment full of toys and novel objects: normal mice and mice with severe combined immune deficiency (SCID), which left them with virtually no T cells. While the normal mice displayed vigorous neurogenesis in the hippocampus, where short-term memories are generated, the SCID mice that lacked T cells displayed almost none.
A different approach to Alzheimer’s that involves suppressing inflammation also showed promise in 2006. Researchers led by Edward Tobinick at the University of California, Los Angeles, conducted a six-month pilot study in which they administered etanercept, a therapy that counters TNF-alpha and is effective at suppressing inflammation in arthritis, to 15 patients with moderate to severe Alzheimer’s.7
The weekly injections significantly improved the mental function of the participants. The study bolsters the theory that inflammation in itself is a major contributor to the dementia of Alzheimer’s, and that suppressing it would help slow or even prevent mental decline.
Researchers at Case Western Reserve University, however, challenged the widespread hypothesis that the amyloid plaques characteristic of Alzheimer’s and the inflammation they trigger are the cause of the disease. Instead, they argue that symptoms result from oxidative stress, the increased production of oxidants, which they believe destroys neurons. In a report in Current Alzheimer Research, Hyoung-gon Lee, Mark Smith, George Perry, and colleagues argue that the plaques represent the brain’s attempt to alleviate oxidative stress.8 They believe that attempting to cure Alzheimer’s by eliminating plaques from the brain is fundamentally misguided. A more effective approach, they say, would involve finding the causes of oxidative stress and minimizing them. Meanwhile, Northwestern University Medical School researchers led by Abdelhak Belmadani discovered that chemokines, in addition to sending signals that regulate leukocytes, regulate the migration of neural progenitor cells to any site of inflammation in the brain, including the widespread inflammation caused by Alzheimer’s. When inflammation injures nerve cells, astrocytes activate chemokines, which then direct adult neural progenitor cells to the site of inflammatory injury.
This finding could point the way to drugs that might contribute to the recovery of the brain after injury by encouraging this migration of neural progenitor cells to the site of injury, where they could develop into new neurons, the Northwestern researchers write in the Journal of Neuroscience.9 This could conceivably help rebuild a hippocampus that had been damaged by Alzheimer’s.
Other research has implicated microglia in neuropathic pain, a chronic and frequently excruciating condition in which pain persists long after the injury, infection, or toxin that triggered it has cleared (also discussed in the Pain section).
Neuropathic pain may result after injury to “peripheral” nerves (those outside the brain and spinal cord). When pain does occur, microglial cells, the only immune cells that reside in the brain and spinal cord, are activated. They release brain-derived neurotrophic factor, which intensifies pain signals between microglia and neurons, according to researchers at the University of Toronto led by Michael Salter.
This process disrupts the normal suppression of pain, making neurons hypersensitive even in the absence of painful stimuli. The researchers reported their findings in the European Journal of Physiology.10 The research suggests the signaling components of microglial cells may be promising therapeutic targets for reducing chronic peripheral nerve pain.
Elsewhere, researchers at Columbia University Medical Center applied for a patent to develop drugs that would block chronic pain by turning off an enzyme known as protein kinase G (PKG). They reported in the journal Neuroscience that the activity of PKG contributes to neuronal hyperexcitability, which results in the production of persistent pain signals.11 They found that turning off the PKG switch stopped the pain, which makes the enzyme an ideal target for drugs.
|Microglia mediate pain: After injury to peripheral nerves, microglia in the dorsal horn of the spinal cord become activated, making neurons hypersensitive and creating a sensation of pain even when no painful stimulus is present. (Image coutesy of Simon Beggs) |
Youthful brains rewire themselves vigorously in response to injury. Although such rewiring, called plasticity, becomes progressively slower with age, researchers at Harvard Medical School have found that an immune system protein known as paired-immunoglobulin-like receptor-B (PirB) may gradually inhibit plasticity over time, stabilizing brain connections. A team led by Josh Syken reported these findings in Science.12
They found that mice deprived of PirB exhibited greater rewiring ability throughout life. That suggests that finding a way to reduce PirB might help to re-establish connections among neurons damaged by spinal cord injury, stroke, or other trauma.
Depression Can Lead to Inflammation
Researchers at the Emory University School of Medicine in Atlanta found that the immune systems of depressed men with early life stresses produce exaggerated inflammatory responses to stress that may contribute to poor health outcomes from inflammatory diseases.
Exposure to stress generally results in an increase in the production of interleukin-6 (IL-6), which promotes inflammation. The researchers, led by Drs. Andrew H. Miller and Christine Heim, tested 28 men, half of them diagnosed with major depression and early life stress. After they were subjected to tasks such as solving math problems and public speaking, which increase stress, blood samples were tested for the presence of IL-6.
Although IL-6 increased in all participants, levels rose almost twice as high in the depressed group, the researchers reported in the American Journal of Psychiatry.13 The study provides preliminary indication of a link between major depression, early life stress, and health outcomes.