The immune system is, in a word, a wonderful thing. When activated, the innate immune system produces all sort of molecules that can engulf pathogens (macrophages), tag infectious molecules for destruction (antibodies), and signal cells to become responsive (cytokines). The brain, however, is protected, or “immune privileged.” It has its own set of immune cells and is inaccessible to the peripheral immune system—at least that’s what the dogma says.
Over the past several decades, however, research into the brain’s immune system has shown that there is a lot we have yet to discover.
Dr. Jonathan Kipnis, an immunologist at the University of Virginia, recently published findings that shook the increasingly converging worlds of neuroscience and immunology—that lymphatic vessels line the brain, essentially connecting it to the peripheral immune system. Up until now, scientists didn’t even know these vessels existed. Kipnis and colleagues uncovered them in the meninges (the layer between the skull and the central nervous system (CNS) that includes cerebral spinal fluid and blood vessels) draining immune cells from the cerebrospinal fluid into the deep cervical lymph nodes in the neck.1
“We are looking into the role of these vessels in different neurological disorders,” Kipnis, who is also the director of the university’s Center for Brain Immunology and Glia (BIG), says. “It’s hard to believe they won’t be involved in these.”
The role of microglia
Microglia are one type of glial cell—non-neuronal brain cells that support and maintain healthy neurons. They are known as the “resident macrophages” of the brain, constantly monitoring the CNS for infectious molecules, debris, and damaged neurons. Activated microglia engulf such particles for destruction and also produce various inflammatory and immune signaling molecules to help clear the CNS of toxic substances.
Ordinarily, the only immune cells in the brain are microglia and perivascular macrophages, says Dr. Ben Barres, a neurobiologist at Stanford University and leading researcher of microglia. Barres notes that they probably do many other things that haven’t been discovered yet. “Microglia, especially when activated, make very high levels of different cytokines whose main receptors are on immune cells. So it is difficult to not think that microglia, when activated, powerfully control migration of immune cells [from the peripheral blood] into the brain.”
Immune role in neurodegeneration
Most neurodegenerative diseases involve misfolded proteins that aggregate in neurons and are not cleared properly, leading to neuronal cell death. Increasingly, research is pointing toward overactivation of microglia as a contributing factor toward progression of these diseases.
Multiple sclerosis (MS) is the most well-known neurodegenerative disease influenced by the immune system. In MS, T cells attack and destroy the protecting sheathing myelin cells of neurons from inside the CNS. Under normal circumstances, T cells are only present in the periphery, patrolling the outside of the brain or directing production of immune chemicals that can cross the blood-brain barrier and influence microglia and resident molecules.
Recent research continues to reveal how limited our understanding of the kinds, amounts, and functions of innate and peripheral immune cells in the brain remains. In Alzheimer’s disease, for instance, mouse studies have shown that brain-derived T cells are present.2 In Parkinson’s disease, both CD4+ T cells (helper T cells) and CD8+ T cells (cytotoxic T cells) have been found in the brains of patients, but scientists are not sure if they are activated forms of these cells.3 “There is no need for T cells or B cells or even monocytes to be in the brain, but that doesn’t mean that every time you see a T cell it is there to do something bad,” Kipnis says.
Systemic inflammation can also impact microglial activation. In fact, studies in animals show that peripheral inflammation worsens neurological disease and accelerates its progression. While peripheral inflammatory molecules signal through microglia—that is, they do not enter the brain themselves—they are still impacting microglia function in very important ways.3
Microglia in Alzheimer’s disease
The post-mortem brains of patients who had Alzheimer’s disease (AD) reveal the presence of amyloid plaques, neurofibrillary tangles, neuronal cell loss, and activated glial cells—indicating a role for the innate immune response in the development of this debilitating brain disorder.4 Evidence is mounting that shows progression of AD is actually dependent on microglia losing their ability to function as immune cells5 whereby they promote just the right amount of inflammation and then turn it off when the debris—in this case, amyloid beta plaques—have been done away with.
“They have a lot of plasticity and they respond to the environment in ways that are not necessarily helpful,” Harvard Medical School’s Dr. Joseph El Khoury says. El Khoury has been studying micoglia’s role in AD for over 20 years. They’re a “double-edged sword,” he says. “As amyloid beta interacts with microglia, it changes their gene expression profile. That means they become activated by amyloid, but that activation reduces their ability to clear it.”
Recently, Dr. Katrin Andreasson, professor of neurology and neurological sciences at Stanford University, and her colleagues found that in mice, knocking down expression of a prostaglandin receptor on microglial cells both improved microglia function and reversed memory loss.6 “This is pretty surprising,” Andreasson says. “We’re able to reprogram these microglia to start behaving like healthy young microglia, and they do what they’re supposed to do—take up all accumulating amyloid beta.” Epidemiological data has shown that high levels of prostaglandins are associated with the development of AD.
Further evidence that microglia are involved in AD comes from the discovery that rare mutations in the TREM2 (triggering receptor expressed on myeloid cells) gene have been found to increase Alzheimer’s disease risk significantly.7 TREM2 encodes for a receptor on microglia, and its role is anti-inflammatory— it helps to trigger phagocytosis of amyloid beta peptide and apoptotic neurons without inflammation. Mutations in TREM2 prevent it from doing its job—and contribute to the progression of AD.
Less is known about microglia’s role in other neurodegenerative disorders like Parkinson’s disease or amyotrophic lateral sclerosis (ALS), but scientists believe that some of the same mechanisms are involved for diseases beyond AD.
Microglia in autism
Microglia have recently been linked not only to disease, but also to normal brain development. Recent work from Barres’ and Harvard University’s Beth Stevens’ labs has shown that microglia help prune synapses during early brain development in mice.8 Studies suggest that this process goes awry in the autistic brain,9 and that microglia activation levels are different in the brains of those who are diagnosed with autism compared to the typically developing brain.10
Kipnis’ lab has also linked microglia to learning disorders. Several of his lab’s studies have found that mice lacking brain-patrolling T cells show cognitive impairment11 and that these T cells are actually derived from cervical lymph nodes.12 Preliminary work by members of his lab also shows a similar function for these T cells in normal social behavior, with implications for an immune component in autism.
“The idea is, without immune cells, the mouse is not functioning cognitively as well as mice with T cells,” Kipnis says. Based on other studies, he hypothesizes this somehow occurs through T cells producing an interleukin signaling molecule, IL-4, which then goes on to activate specific neurons.13
Microglia in translation
Neuroimmunology is a burgeoning field, but we’re only just beginning to investigate how the immune system affects brain diseases.
In further elucidating the role of microglia in Alzheimer’s, El Khoury hopes for better tracking tools that leave microglia intact while allowing scientists to follow their movements and visualize their function. With a dire need for new AD therapies, figuring out how the immune system component helps or hinders progression of the disease can’t happen fast enough. Any treatment, El Khoury says, has to “promote [amyloid beta] clearance without causing damage on its own. You have to have a balance.”
Many scientists are already convinced that all neurological disorders have an immune system component—in other words, that all diseases involve inflammatory processes. While this adds a level of complexity to research and treatment, it also has an upside. Brain diseases are notoriously difficult to treat: not only are drug targets elusive, but getting drugs into an organ that is as heavily fortressed as the brain makes it doubly challenging. We already have therapies for some immunological disorders—not to mention a much more thorough understanding of how these diseases progress, in some cases. Treating brain diseases by way of treating the immune components of them could be an effective step toward ameliorating some of their symptoms.
“I don’t think we can efficiently deliver [drugs] into the brain, the technology is not there yet—but with the immune system all this is doable,” Kipnis says. “We may not be able to cure autism or Alzheimer’s, but we may be able to improve quality of life.”
- 1. Louveau A et al. (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337-341. doi: 10.1038/nature14432
- 2. Monsonego A, Nemirovsky A, Harpaz I (2013) CD4 T cells in immunity and immunotherapy of Alzheimer's disease. Immunology 139(4):438-446. doi: 10.1111/imm.12103
- 3. Perry VH (2012) Innate Inflammation in Parkinson’s Disease. Cold Spring Harbor Perspectives in Medicine 2(9). doi: 10.1101/cshperspect.a009373
- 4. Britschgi M, Wyss-Coray T (2007) Systemic and acquired immune responses in Alzheimer's disease. International Review of Neurobiology 82:205-233.
- 5. Gold M, El Khoury J (2015) β-amyloid, microglia, and the inflammasome in Alzheimer's disease. Seminars in Immunopathology 37(6):607-611. doi: 10.1007/s00281-015-0518-0
- 6. Johansson JU et al. (2014) Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models. Journal of Clinical Investigation 125(1):350-364. doi: 10.1172/JCI77487
- 7. Guerreiro R et al. (2013) TREM2 variants in Alzheimer's disease. New England Journal of Medicine 368(2):117-127. doi: 10.1056/NEJMoa1211851
- 8. Schafer DP et al. (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74(4):691-705. doi: 10.1016/j.neuron.2012.03.026
- 9. Tang G et al. (2014) Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits. Neuron 83(5):1131-1143. doi: 10.1016/j.neuron.2014.07.040
- 10. Morgan JT et al. (2010) Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biological Psychiatry 68(4):368-376. doi: 10.1016/j.biopsych.2010.05.024
- 11. Radjavi A, Smirnov I, Kipnis J (2014) Brain antigen-reactive CD4+ T cells are sufficient to support learning behavior in mice with limited T cell repertoire. Brain, Behavior, and Immunity 35:58-63. doi: 10.1016/j.bbi.2013.08.013
- 12. Radjavi A et al. (2014) Dynamics of the meningeal CD4(+) T-cell repertoire are defined by the cervical lymph nodes and facilitate cognitive task performance in mice. Molecular Psychiatry 19:531-532. doi: 10.1038/mp.2013.79
- 13. Walsh JT et al. (2015) MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. Journal of Clinical Investigation 125(2):699-714. doi: 10.1172/JCI76210