We usually think of immunology and neuroscience as disparate disciplines, each with its own language, concerns, and interesting molecules. Despite some overlap—the role of inflammation in Alzheimer’s disease has attracted sustained attention—researchers in the two fields have historically gone their own ways.
But convergence is at hand, to judge from a recent afternoon at the New York Academy of Sciences in lower Manhattan. In a four-hour symposium, researchers presented convincing evidence that the central nervous system and immune systems are closely intertwined.
“Classic immune molecules do business in the brain. They play important roles in plasticity and other processes,” said Ken Jones of Lundbeck Research USA, one of the conference organizers. Conversely, “signaling systems that were always known to reside in the brain are also found in the immune system.”
Although the brain is traditionally assumed to be “immune privileged”—protected from systemic inflammation, as from other perturbations, by the blood-brain barrier—there‘s a growing appreciation that the barrier does in fact allow access to immune cells and mediators originating elsewhere in the body. In addition, cells in the brain, microglia in particular, secrete immune molecules of their own.
“The two systems have one language, and have been talking to each other all along,” says Jones. “And now we’re beginning to listen.”
As became clear in the course of the afternoon, the conversation is “bidirectional,” as Raz Yirmiya, professor and director of the Interdepartmental Program in Psychobiology at the Hebrew University of Jerusalem, put it. The brain can stimulate or depress immune activity via sympathetic/parasympathetic and neuroendocrine pathways. At the same time, inflammatory proteins—cytokines—transmit information to the brain through the bloodstream and by stimulating nerve endings in the periphery.
It’s a sensitive conversation, researchers emphasized. Immune molecules apparently play the villain in neurodegenerative and some psychiatric disorders. But they also protect the body against infection and malignancy, and are vital to normal moment-to-moment brain operations.
Reports at the symposium suggested how far researchers have come in tracing the molecular pathways that link immune and nervous system function and dysfunction: Far enough to identify intriguing new targets for drug development—in some cases, leading to clinical trials.
In sickness and in health
Yirmiya described work in his laboratory demonstrating the role of immune proteins in basic neurophysiological functions. “I’d argue that cytokines are involved in all the major dilemmas facing neurons: to fire or not to fire. To change or not to change. Even to be or not to be.”
Low levels of the cytokine interleukin-1 (IL-1) are vital for memory and learning: Concentrations of IL-1 rise in the mouse hippocampus 24 hours after fear conditioning, while mice in which IL-1 signaling is genetically derailed fail to show the learned response. Injecting an IL-1 receptor antagonist after a learning exercise impairs memory by interfering with long-term potentiation.
But excess IL-1 hurts memory too. In humans, even a modest jolt to the immune system—such as a rubella vaccination or just enough endotoxin to raise body temperature by .5⁰ C—impairs our ability to remember a story or recall a figure. The devastation of memory in neurodegenerative diseases such as Alzheimer’s appears linked, in part, to chronic overproduction of IL-1. When mice bred to develop an Alzheimer’s-like condition were injected with astrocytes genetically altered to block IL-1 receptors, it restored their memory.
The effect of IL-1 and similar immune mediators on learning and other cognitive functions can be described as “an inverted U-shaped curve,” Yirmiya said.
The downside of the curve
Other presentations emphasized the role of inflammation in neurodegeneration, and emerging strategies to block it.
Malú Tansey, associate professor of physiology and member of the Center for Neurodegenerative Disease at Emory University School of Medicine, summarized evidence for immune involvement in the loss of dopaminergic neurons in Parkinson’s disease. It may be that diverse triggers of Parkinson's—genetic factors, environmental exposure, and chronic systemic disease—“converge on microglial activation, which then sets off a cycle of inflammation and cell death,” she said.
Although a number of immune mediators probably act together, tumor necrosis factor (TNF) appears to play a critical role, Tansey said.
Researchers in her laboratory have used a genetically engineered TNF inhibitor to prevent neurodegeneration induced by the neurotoxin 6-hydroxydopamine (6OH), a mouse model for PD. If the drug was injected into the brain two weeks after 6OH, while damage was already underway, neuron loss halted at that point. “It offered protection even in the progressive cell death phase,” Tansey said.
That inflammation plays a role in Alzheimer’s disease seems clear, but the molecular details are not. Shi Du Yan, professor of pathology and surgery at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain of Columbia University, described research linking beta-amyloid, immune activation, and neurodegeneration through the receptor for advanced glycation products (RAGE).
This receptor can be found on cell membranes throughout the body, including the brain’s microglia. When it binds to any one of a number of proteins, it activates the inflammatory response, and appears to play a role in such chronic diseases as diabetes and atherosclerosis.
One of these proteins is amyloid beta. In mice bred to produce amyloid beta and to have abundant RAGE, brain levels of cytokines are high and the animal's memory declines rapidly. But introducing a molecule that blocks RAGE activation reduces cytokine production, prevents neurodegeneration, and preserves cognitive function, Yan said. (A clinical trial testing a RAGE inhibitor to treat Alzheimer’s is currently in progress.
More surprising than links to neurological diseases, perhaps, is the apparent role of inflammation in a psychiatric disorder—major depression. The evidence is substantial enough to have led to a clinical trial, said Andrew Miller, professor of psychiatry and behavioral sciences at Emory University School of Medicine.
Medically ill people get depressed at 5-10 times the rate in the general population, and more generally, the “sickness behavior” associated with systemic infection—fatigue, loss of appetite, loss of interest or pleasure in activities—virtually duplicates the symptoms of depression.
The effect of inflammatory mediators on the central nervous system probably evolved as an adaptive strategy, targeting regions “to shut the organism down and conserve energy to fight infection,” he said.
These are the same regions involved in depression. Brain imaging research in Miller’s lab suggests that cytokines are active in dopamine-rich areas in the basal ganglia that regulate reward and motivation, he said.
Blood levels of these inflammatory mediators—interleukin-6 (IL-6) and tumor necrosis factor (TNF) in particular—go up in people with depression. “The degree of elevation correlates with the severity of the depression,” Miller said. “Those who are resistant to treatment [about one-third of patients don’t respond to standard antidepressants] are particularly likely to have inflammatory markers.”
Blocking cytokines may be an effective antidepressant strategy: In one large study, people psoriasis treated with etanercept, a biological drug that targets TNF, experienced significant relief of depressive symptoms, independent of improvement in the skin disorder.
A study is in progress at Emory to test infliximab, a TNF inhibitor often prescribed for rheumatoid arthritis and Crohn’s disease, as therapy for treatment-resistant depression. At enrollment, Miller observed, about two-thirds of the patients had blood levels of C-reactive protein (a sign of immune system activation) high enough to meet standard criteria for inflammation. The researchers expect to start reporting results this spring, he said.