Brain health is maintained by immune system activity

the-scientistDramatic advances in understanding how brain health is maintained by the immune system are described in an excellent article published recently in The Scientist that accompanies the brief video presentation by neuroscientist Michal Schwartz shown below. Only recently has it been recognized that brain immune function is integrated with the systemic immune system.

Until recently, the brain and the spinal cord were considered immune-privileged sites, strictly cordoned off from immune cells unless something went terribly wrong. Researchers knew, for example, that multiple sclerosis (MS) was caused by T cells that breach the selective border called the blood-brain barrier (BBB), enter the CNS, and attack the myelin sheath covering neurons. Even microglia, specialized macrophage-like immune cells that scientists had recognized as normal CNS residents since the 1960s, were mainly studied in the context of disease.”

Now the pervasive role of the immune system in brain function and maintenance is being observed:

“But over the past two decades, researchers have recognized that the entire immune system is very much a part of a functional CNS, with vital roles in cognition, injury repair, neurodegenerative disease, and sensory systems. Microglia pervade the CNS, including the white and gray matter that constitute the organ’s parenchyma. Other immune cells, including T cells, monocytes, and mast cells, reside in the brain and spinal cord’s outer membranes, known as the meninges, and circulate in cerebrospinal fluid (CSF).”

Immune cells in the brain help repair damage

It was formerly thought that immune cell activity in the brain was only harmful.

Macrophages, for example, can damage neurons by secreting cytokines, proteases, or reactive oxygen species, but in rat and mouse models of spinal cord injury, they also produce transforming growth factor-beta (TGFβ), which promotes wound healing,5 and interleukin 10 (IL-10) which helps resolve inflammation. By the late 2000s, researchers recognized that different subtypes of macrophages can benefit neuronal growth in rodents, and that some were critical to recovery. Views also began to change on the clinical side after the 2004 Corticosteroid Randomization After Significant Head Injury (CRASH) study showed that corticosteroids didn’t help brain injury patients recover, but increased their risk of disability and death.”

Cells of the adaptive immune system residing in the tissue lining of the ventricles can also assist in repair.

Her team also showed that T cells present in this lining, called thechoroid plexus, secrete cytokines such as interferon gamma (IFNγ), which allows selective passage of CD4+ T cells and monocytes from the blood into CSF within the ventricles.  In a model of spinal cord bruising, mice deficient for the IFNγ receptor had reduced immune cell trafficking across the choroid plexus and poor recovery of limb movement. And last year, Kipnis’s team reported that IL-4 produced by CD4+ T cells in the CNS signals neurons to regrow axons after spinal cord or optic nerve injury.”

Immune cells in the brainAn intact blood-brain barrier (BBB), however, is essential:

“His team also found that microglia reinforce the BBB, which is composed of endothelial cells, pericytes, and astrocytes. Microglia fill in spaces left by astrocytes killed or damaged during injury. Without a robust barrier, McGavern says, unwanted immune cells may flood the parenchyma and do more harm than good.”

Immune cells residing in the CSF and choroid plexus

Immune cells residing in the CSF and choroid plexus

Brain needs both anti-inflammatory and pro-inflammatory activity for cognition

Neuroinflammation is well known to be a core feature of neurodegenerative disorders, but inflammatory immune activity is also required for healthy cognition.

“…Rivest used two-photon microscopy to monitor monocytes in blood vessels of living mouse brains, and he watched as the cells migrated toward and cleared amyloid-β deposits within veins. When the researchers selectively depleted monocytes, the mice developed more amyloid-β plaques in the cortex and hippocampus. And when they knocked out the innate immune signaling protein MyD88, which mediates signals from several monocyte-activating receptors, the mice also experienced more amyloid-β accumulation, accompanied by accelerated cognitive decline.”

Even in the classic disease of neuroinflammation, MS, immune cell activity is necessary:

“Rivest’s team found that microglia-forming monocytes are beneficial in a model of MS, where microglia are found within the inflammatory lesions. Last year, the researchers reported that inhibiting monocytes from entering the CNS reduced the clearance of damaged myelin and impeded proper remyelination.”

Evidence for the immune system’s role in preventing neurodegeneration continues to mount:

“Schwartz has similarly found evidence for the immune system’s ability to protect against neurodegeneration. Last year, she and her colleagues reported that the choroid plexus epithelium was less permissive to immune cell trafficking in a mouse model of Alzheimer’s disease than in wild-type mice, due to anti-inflammatory signals produced by regulatory T cells (Tregs). They found that depleting Tregs in Alzheimer’s mice allowed macrophages and CD4+ T cells into the brain, reduced the number of amyloid-β plaques, and improved cognition. Similarly, blocking the T-cell checkpoint protein PD1, which normally supports Treg survival while suppressing the activity of other T cells, reduced amyloid-β plaques in mouse brains and improved the animals’ scores in a learning and memory water maze test.”

Clinicians should be alert to evaluate and support balance

Too much neuroinflammation is clearly adverse.

“But there’s a reason that scientists have believed that immune activity contributes to Alzheimer’s damage: microglia, perhaps best known for trimming back synapses, have the potential to become overzealous, and excessive synapse pruning can cause neural damage in a variety of CNS diseases. By blocking the cells’ proliferation in mice, Diego Gomez-Nicola of the University of Southampton in the U.K. has successfully alleviated symptoms of Alzheimer’s disease, amyotrophic lateral sclerosis, and prion disease. And earlier this year, Beth Stevens of the Broad Institute and her colleagues reported that inhibiting a protein that tags synapses for microglial pruning halted over-pruning and loss of synapse signaling strength in two mouse models of Alzheimer’s disease.”

Regulation of stress is critical

Stress has a major effect on which way the ‘two-edged sword’ swings.

“Kipnis says regulation of stress may be linked to T cells’ role in learning. Stress can signal macrophages to secrete proinflammatory cytokines, some of which block a protein called brain-derived neurotrophic factor (BDNF), which astrocytes need to support learning and memory. CD4+ T cells in the meninges make more IL-4 cytokine after mice have been trained in a water maze—a stressful exercise for the animals—suggesting the signaling molecule might let macrophages know when the brain is dealing with the stress of learning something new, not the stress of an infection. “They tell macrophages, ‘Don’t overshoot,’” says Kipnis. In mice whose meninges are depleted of CD4+ T cells and thus deficient for IL-4, macrophages secrete proinflammatory factors unchecked in times of stress, disrupting their ability to learn and form memories.”

But excess suppression of inflammatory activity in the brain could have unwanted consequences as in the case of mast cells:

“Best known for their involvement in allergic responses in the upper airway, skin, and gastrointestinal tract, mast cells have been found in the meninges as well as in perivascular spaces of the thalamus, hypothalamus, and amygdala. They are known to quickly recruit large numbers of other immune cell types to sites of inflammation, and to play a role in MS. But mast cells also release serotonin into the hippocampus, where the molecule aids neurogenesis, supports learning and memory, and regulates anxiety.”

A ‘goldilocks zone’ for immune activity in the brain

As in every condition clinical evaluation must embrace the whole context…

“Thus, like microglia, mast cells are a double-edged sword when it comes to neural health. It’s a reflection of the entire immune system’s love-hate relationship with the CNS, Kipnis says. “Saying the immune system is always good for the brain, it’s wrong; saying it’s always bad for the brain, it’s wrong. It depends on the conditions.”

Neuroscientist Michal Schwartz — Breaking The Wall Between Body and Mind


Stunning discovery links brain and immune system

NatureLong established scientific dogma asserts that there is no direct connection by vessels between the brain and immune system, yet the link between systemic inflammation, brain inflammation and neurodegeneration is vividly evident in clinical practice (see Systemic inflammation drives brain neurodegeneration and numerous related posts). Now investigators report in the prestigious journal Nature the stunning discovery of a central nervous system lymphatic system connecting the brain and immune system in a paper entitled Structural and functional features of central nervous system lymphatic vessels.

“One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes.”

Changes the landscape of neuroimmunology

Brain inflammation, a key factor in neuropsychiatric and neurodegenerative disorders, is linked directly to systems-wide immune function.

The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.”

Neuroinflammation’s mechanism re-defined

Neuroscience NewsAutism and bipolar disorder, Alzheimer’s and MS, and every other neuroinflammatory brain based disorder must be considered in this light. A commentary entitled Researchers Find Missing Link Between the Brain and Immune System in Neuroscience News states:

“That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer’s disease to multiple sclerosis.”

Quoting lead author Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA’s Center for Brain Immunology and Glia (BIG):

“Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels…It changes entirely the way we perceive the neuro-immune interaction…We believe that for every neurological disease that has an immune component to it, these vessels may play a major role.

Metabolic purpose of sleep

ScienceThe discovery of lymphatic vessels providing brain drainage reminds of the remarkable research entitled Sleep Drives Metabolic Clearance from the Adult Brain, published in the competing journal Science, that brilliantly demonstrates the metabolic purpose of sleep. The authors state:

“The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.”

In other words, they demonstrated that brain cells shrink during sleep to increase the interstitial space by a whopping 60%, and further showed that this results in marked increase drainage of toxic metabolites through the ‘glymphatic‘ system. This paper was published before the stunning discovery of the brain’s own lymphatic system.

Proteins linked to neurodegenerative diseases, including β-amyloid (Aβ), α-synuclein, and tau, are present in the interstitial space surrounding cells of the brain. In peripheral tissue, lymph vessels return excess interstitial proteins to the general circulation for degradation in the liver. Yet despite its high metabolic rate and the fragility of neurons to toxic waste products, the brain lacks a conventional lymphatic system. Instead, cerebrospinal fluid (CSF) recirculates through the brain, interchanging with interstitial fluid (ISF) and removing interstitial proteins, including Aβ. The convective exchange of CSF and ISF is organized around the cerebral vasculature, with CSF influx around arteries, whereas ISF exits along veins. These pathways were named the glymphatic system on the basis of their dependence on astrocytic aquaporin-4 (AQP4) water channels and the adoption of functions homologous to peripheral lymphatic removal of interstitial metabolic byproducts. Deletion of AQP4 channels reduces clearance of exogenous Aβ by 65%, suggesting that convective movement of ISF is a substantial contributor to the removal of interstitial waste products and other products of cellular activity. The interstitial concentration of Aβ is higher in awake than in sleeping rodents and humans, possibly indicating that wakefulness is associated with increased Aβ production. We tested the alternative hypothesis that Aβ clearance is increased during sleep and that the sleep-wake cycle regulates glymphatic clearance.”

The convective movement of brain interstitial fluid that they describe is only enhanced by lymphatic vessels that drain the brain. Sleep is the time when the brain ‘takes out the trash’.

Tremendous clinical significance

Cranial therapy that restores the amplitude and symmetry of the rhythmic expansion and contraction the skull associated with the circulation of cerebrospinal spinal fluid (CSF) and lymphatic exchange in the brain can be appreciated in this context along with the immunological implications. Further commenting in Neuroscience News:

“The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer’s disease. “In Alzheimer’s, there are accumulations of big protein chunks in the brain,” Kipnis said. “We think they may be accumulating in the brain because they’re not being efficiently removed by these vessels.” He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there’s an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist.”

Maps of the lymphatic system

Cannabis suppresses the immune system

A study just published in the European Journal of Immunology resolves how Cannabis sativa (marijuana) suppresses the immune system. The authors state:

“Cannabinoid receptor activation by agents such as Δ9-tetrahydrocannabinol (THC) is known to trigger immune suppression. Here, we show that administration of THC in mice leads to rapid and massive expansion of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) expressing functional arginase and exhibiting potent immunosuppressive properties both in vitro and in vivo.”

Myeloid-derived suppressor cells (MDSC) are a class of white blood cells that act to regulate the immune system by suppressing immune activity. While their expansion can help to reduce the inflammation and pain of autoimmunity, in cancer they suppress immune system activity in the environment of a tumor. The authors further state:

“Use of selective antagonists SR141716A and SR144528 against cannabinoid receptors 1 and 2, respectively, as well as receptor-deficient mice showed that induction of MDSC was mediated through activation of both cannabinoid receptors 1 and 2. These studies demonstrate that cannabinoid receptor signaling may play a crucial role in immune regulation via the induction of MDSC.”

In other words, THC stimulates cannabinoid receptors 1 and 2 which triggered the proliferation of the immune suppressing MDSC. This is also likely to be at least part of the mechanism by which THC can cause an increase in susceptibility to opportunistic infections. Although this may be a rational therapy for organ transplantation where immune suppression is called for, it makes the use of marijuana worrisome for conditions where a deficient immune response needs support such as most cancers.

Depression is linked to immune system changes

Current Psychiatry ReviewsThis may seem like a “no-brainer”, but many are still poorly informed about the biological dimension of depression that can be evaluated and treated with a functional medicine approach. This paper recently published in the journal Current Psychiatry Reviews is a reminder. The authors state: “Epidemiological findings indicate a connection between depressive symptoms and changes in status of the immune system in depressed patients…medical treatment of depressed patients may be adjusted by more specific knowledge about the interaction between neuroimmunology and depression.”

Ever wonder what the appendix does?

In this interesting article from the Journal of Evolutionary Biology, the mammalian cecal appendix is shown to be a “a safe-house for symbiotic gut microbes, preserving the flora during times of gastrointestinal infection”. Try to hold onto yours by maintaining a healthy microbiome (microbial ecology) and gut immune function.

Fever suppression reduces antibody response to vaccination

Please do not interpret this post as a blanket endorsement of vaccination; this is a complex topic that demands a sophisticated understanding of immune system regulation and the knowledge and clinical experience to apply it on an individual basis. However, this study just published in The Lancet is of interest because it confirms that antipyretic (fever suppressing) medications must be used judiciously (after vaccination or otherwise), because they suppress the body’s disease fighting immune response. “Although febrile reactions significantly decreased, prophylactic administration of antipyretic drugs at the time of vaccination should not be routinely recommended since antibody responses to several vaccine antigens were reduced.”