Dramatic 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.”
An 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
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
Alzheimer’s disease is not a unitary condition but variable in causation at the individual level like all complex chronic disorders. Neuroinflammation, metabolic damage, vascular compromise, accumulation of noxious debris (amyloid β and tau), impairments in brain CSF and lymphatic drainage and other causes can all variously contribute to Alzheimer’s and other dementias. Now original research recently published in the journal Radiology demonstrates that leakiness of the blood-brain barrier (BBB) can permit an environment hostile to neuronal health that contributes to cognitive decline, Alzheimer’s and other dementias. The authors state:
“Evidence is increasing that impairment of the cerebral microvasculature is a contributing factor in the pathophysiology of Alzheimer disease (AD). However, the exact pathway remains unclear. Results of histologic evaluation and albumin sampling studies show that an increased permeability of the blood-brain barrier (BBB) is likely a key mechanism.”
An intact blood-brain barrier is essential for brain health
The BBB is a collection of cells and other structures in the cerebrovascular wall that when healthy permits only privileged access into the brain from the extra-cerebral blood compartment.
“It regulates the delivery of important nutrients to the brain through active and passive transport mechanisms and prevents neurotoxins from entering the brain. It also has a clearance function, meaning that it removes surplus substances from the brain. A well-functioning BBB is essential to keeping the brain tissue in a healthy condition. Results of previous studies suggest that deterioration of the BBB can cause an ill-conditioned environment for neuronal cells and other pathologic changes such as small-vessel abnormality, protein deposits, inflammation, and neuronal cell death. These changes eventually may lead to cognitive decline and dementia.”
Early Alzheimer’s shows abnormal BBB permeability
Blood-brain barrier degradation has earlier been demonstrated in advanced Alzheimer’s disease. Here the authors examined whether or not BBB leakage contributes to the early stages of disease.
“To investigate whether BBB leakage contributes to the early pathophysiology of AD, we hypothesized that patients with early forms of AD already show increased BBB permeability in comparison with age-matched control subjects. For this pilot study, we used a dedicated dynamic contrast-enhanced MR imaging acquisition protocol with dual-time resolution that separates the filling of the blood vessels from the leakage. We also investigated differences in local blood plasma volume fraction, and the relationship between BBB permeability and global cognition.”
The analyzed data for patients diagnosed with mild cognitive impairment (MCI) due to AD or patients or patients with early AD (a continuum of cognitive decline who had been referred by general practitioners because of memory concerns, in comparison with healthy controls. Individuals with dementia of vascular origin were excluded, as were those with major cardiovascular and neuropsychiatric disorders, Parkinson’s, MS, trauma, major structural abnormalities of the brain, and alcohol or drug abuse. They indeed demonstrated a marked distinction between their study subjects and controls:
“The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total GM (grey matter) and cortex but not in the WM, normal-appearing WM, deep GM, or WM hyperintensities…When adjustments were made for all covariates, the patients exhibited a significantly higher leakage volume in the WM and GM and also in the normal-appearing WM, deep GM, cortex, but not in WM hyperintensities…The median blood plasma volume was significantly lower in the patients than in the control subjects in all tissue classes.”
BBB leakage rate shown on the right, with some periventricular hot spots
BBB leakage in early Alzheimer’s is widespread
The leakage is not due to vascular abnormalities, and leakage volume was even more striking than rate:
“The results of this study showed increased BBB leakage in patients with early AD. The leakage was globally distributed throughout the cerebrum and was associated with declined global cognitive performance. By using dynamic contrast-enhanced MR imaging with dual-time resolution, we found an increased BBB leakage rate in the GM of patients with early AD. By also showing very subtle BBB impairment in the WM, leakage volume proved to be even more sensitive to the differences in BBB leakage than was the leakage rate. Not only did this show that the differences between patients with early AD and healthy control subjects were in the extent of the BBB leakage rather than the rate (ie, strength), but it also showed that the leakage was widespread rather than localized to a single tissue class such as WM hyperintensities, normal-appearing WM, or cortex. In addition, the BBB impairment did not fully originate from vascular abnormality, because adding diabetes and other noncerebral vascular diseases to the analysis model did not change the results. This suggested that the BBB impairment stemmed from the AD abnormality instead of from vascular comorbidities.”
Breakdown in tight junctions like the intestinal barrier
The intestinal barrier, critical for healthy immune system regulation, loses integrity with a breakdown of the tight cellular junctions. So too with the blood-brain barrier.
“The leakage observed in this study can be explained as a breakdown of the BBB tight junctions. It has been shown in rodents that tight junction damage allows gadolinium leakage through the BBB. The regions with high BBB leakage were diffusely distributed throughout the brain, showing that BBB tight junctions were globally impaired. This could have allowed the passage of small and lipophilic molecules that could not cross a healthy BBB. The loss of tight junctions also changes cell polarity, which influences the expression of transporter complexes and thus indirectly affects active transport across the BBB. Therefore, both passive and active transport mechanisms may be impaired in patients with early AD, possibly disturbing homeostasis.”
Toxic accumulations in the brain and cognitive impairment
The authors have demonstrated that BBB leakage tracks cognitive impairment in early Alzheimer’s:
“We found that cognitive decline was associated with stronger BBB leakage, and both the patients with MCI and those with early ADshowed increased BBB leakage. These observations suggest that BBB impairment may be a contributing factor in the early pathophysiology of AD. A possible mechanism is that loss of tight junctions impairs the filter function of the BBB, leading to a toxic accumulation of substances in the brain. This, combined with the altered active transport systems, might add up to a substantial effect on neuronal function that eventually leads to dementia.”
BBB and amyloid β
Clearance of amyloid β is also impaired:
“…amyloid β is actively transported across the BBB, whereas gadolinium leaks passively through the tight junctions. Previous work with positron emission tomographic data has shown that clearance of amyloid β is also impaired in patients with AD. An impaired clearance of amyloid β would mean that the BBB is impaired in different ways, contributing to the pathologic cascade leading to AD.”
“Therefore, BBB leakage may help to provide a biomarker for early diagnosis, or at least a marker indicating vulnerability for the development of dementia. Successful prediction of dementia eventually might lead to optimized treatment, delay, or even prevention of the disease.”
Early diagnosis is key here, and for those of us without dynamic gadolinium contrast-enhanced MR imaging at hand I highly recommend the Blood Brain Barrier Permeability™ screen from Cyrex Labs (Array 20) which offers the clinician the ability to detect early changes in BBB permeability. Clinicians experienced in rehabilitation of the gut barrier will be familiar with resources to evaluate and remediate inflammation and other insults to the blood-brain barrier.
The authors conclude:
“…in this pilot study, MR imaging was used to show global, diffusely distributed BBB leakage in patients with early AD, which suggests that a compromised BBB is part of the early pathology of AD and might be part of a cascade of pathologic events that eventually lead to cognitive decline.”
“Patients with early Alzheimer disease have significantly more tissue characterized by blood-brain barrier leakage than do healthy control subjects, both in the normal-appearing white matter and in the gray matter.
Blood-brain barrier leakage in the gray matter correlates with lower scores on the Mini-Mental State Examination.”
Severe fatigue, associated with chronic fatigue syndrome (CFS) or another disorder, has as a core underlying cause chronic inflammation. A valuable paper recently published in BMC Medicine illuminates the role of immune activation and peripheral inflammation with subsequent neuroinflammation and mitochondrial damage as key clinical features. The authors state:
“The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.”
Fatigue triggered by acute infection or ongoing autoimmunity
In either case, immune cells in the brain are activated and persist as chronic neuroinflammation, the linchpin of fatigue.
“There is copious evidence establishing the causative role of peripheral immune activation and inflammation, evidenced by elevated levels of proinflammatory cytokines in the genesis of debilitating fatigue in neuro-inflammatory, autoimmune and inflammatory disorders. Activation of pathogen recognition receptors by pathogen associated molecular patterns leads to the production of nuclear factor NF-kappaB and subsequent production of proinflammatory cytokines by the myeloid differentiation primary response gene (88) (MYD88), which is a universal adapter protein that is used by almost all Toll-like receptors (TLRs) in dependent and independent pathways. Systemic inflammatory stimuli, resulting from the presence of proinflammatory cytokines in the peripheral circulation, enter the brain via a number of routes activating microglia and astrocytes inducing the production of proinflammatory cytokines and other neurotoxins leading to an environment of neuroinflammation. This sequence of events ultimately underpins the genesis of fatigue and other signs and symptoms associated with acute pathogen invasion. Many people suffering from a range of neuroimmune and autoimmune diseases also suffer from debilitating or intractable fatigue.
They point out that chronic immune activation and systemic inflammation are associated with debilitating fatigue in conditions as diverse as multiple sclerosis, Alzheimer’s and Parkinson’s disease, major depression, systemic lupus erythromatosis (SLE), Sjogren’s syndrome, and rheumatoid arthritis.
Elevated cytokines, oxidative and nitrosative stress (O and NS) and NF-kappaB
They note that viral and bacterial infections are not always the trigger, and that other factors including environmental toxins can promote chronic inflammation.
“One of the key drivers in the development of chronic immune activation in the absence of bacteria or virus infection is the development of chronic inflammation as evidenced by elevated levels of cytokines and oxidative and nitrosative stress (O and NS) and characterized by activated NF-kappaB. Indeed, the production of proinflammatory cytokines and other inflammatory molecules by macrophages and other sentinel cells, even in the absence of pathogen invasion, and the subsequent activation of NF-kappaB are early events in the genesis of chronic inflammation. Activation of this transcription factor leads to the upregulation of cytokines and O and NS. These players can engage in a feed-forward manner to maintain and amplify chronic inflammation and immune activation in a TLR radical cycle.”
In other words, in many conditions associated with fatigue there is a self-maintaining feedback loop of chronic inflammation that sustains activation of NF-kappaB (nuclear factor kappa beta), thus promoting chronic and persistent inflammatory damage. Hence the great clinical importance of the benign agents available to clinicians that help wind down NF-kappaB activity.
Damaging the intestinal barrier systems
Loss of barrier integrity of the intestinal mucosa (and the blood-brain and respiratory barriers) is a major contributor to the loss of immune tolerance and maintenance of chronic inflammation and associated fatigue.
“Chronically elevated levels of NF-kappaB, proinflammatory cytokines and O and NS, in turn, lead to a disruption of epithelial tight junctions in the intestine allowing translocation of gram-negative bacteria, containing lipopolysaccharides, into the circulation, which can further amplify the TLR-radical cycle by acting as a pathogen-associated molecular pattern (PAMP). Translocation of bacterial lipopolysaccharides (LPS) from the gut and engagement with TLRs, due to a state of increased intestinal permeability driven by the effector molecules of chronic inflammation is another cause of chronic immune activation that may play a role in major depression, CFS, neuro-inflammatory disorders and some systemic autoimmune disorders.”
See a brief animation of the TLR signaling chain in inflammation at the bottom. TLR activation is a key step in inflammation that produces fatigue:
“Given the established association between chronic inflammation and the genesis of incapacitating fatigue, the TLR-radical cycle can potentially explain the development of incapacitating fatigue in patients suffering from these and other illnesses. This association may be explained by chronically increased levels of proinflammatory cytokines and reactive oxygen and nitrogen species (ROS/RNS) produced by the TLR-radical cycle upon stimulation by PAMPs and DAMPs. We have reviewed previously that some proinflammatory cytokines, including IL-1β, TNF-α and IL-6, and increased O and NS processes may cause fatigue in some vulnerable individuals.”
Mitochondrial dysfunction and fatigue
Disruption of the capacity to produce energy at the cellular level and depletion of ATP further contribute to fatigue. Multiple sclerosis offers one example:
“Mitochondrial dysfunction likely plays a major role in the progression of MS. Electron transport chain (ETC) complex I, complex III and complex IV activity is grossly reduced in normal appearing gray matter and in normal tissue within the motor cortex in patients suffering from this illness. There is also direct evidence of globally impaired energy production and longitudinal depletion of ATP levels leads to increased levels of physical disability.”
Inflammatory and oxidative damage to mitochondria also figures in chronic fatigue and major depression:
“Multiple lines of evidence demonstrate the existence of mitochondrial dysfunction in many, but by no means all, patients afforded a diagnosis of CFS. These abnormalities include loss of mitochondrial membrane integrity and oxidative corruption of translocatory proteins. Other findings include abnormal muscle mitochondrial morphology and defective aerobic metabolism uncharacteristic of muscle disuse. There is also accumulating evidence that inflammation and subsequent mitochondrial dysfunction drive the symptoms of major depression.”
Mitochondial dysfunction and glutathione depletion in autoimmunity
Fatigue in autoimmune disorders occurs from neuroinflammation and when the capacity to produce energy is derailed.
“Localized or global mitochondrial dysfunction is also an invariant feature of autoimmune diseases. Persistent mitochondrial membrane hyperpolarization and increased O and NS production combined with depleted levels of glutathioneand ATP is an invariant characteristic of T cells in SLE. The release of DAMPS into the systemic circulation, consequent to necrosis, acts as a mechanism by which localized mitochondrial pathology can lead to self-perpetuating systemic inflammation which, in turn, amplifies mitochondrial dysfunction in a vicious feed-forward loop. The association between chronic oxidative stress, systemic inflammation and mitochondrial dysfunction and chronic oxidative stress is also firmly established in Sjogren’s syndrome. There is also evidence of widespread nitric oxide (NO)-induced inhibition of complex III and V of the ETC in patients with rheumatoid arthritis. The causative role of chronic inflammation and oxidative stress and mitochondrial dysfunction is explained by the presence of elevated levels of ROS and RNS in such environments. These entities cause damage to proteins, DNA and lipid membranes. NO and peroxynitrite have the capacity to inhibit crucial enzymes within the ETC and can inactivate crucial enzymes in the tricarboxylic acid cycle leading to, often critical, reductions in the generation of ATP. Peroxynitrite, in particular, also has a destructive influence on the mitochondrial membrane leading to the loss of potential difference between the outer and inner membrane needed to manufacture ATP. The products of lipid peroxidation driven by elevated levels of ROS are also toxic to mitochondrial membranes. It is noteworthy that inhibition of the ETC leads to the formation of even higher concentrations of oxygen radical species which, in turn, leads to further impairment of mitochondrial function.”
Chronic fatigue syndrome
CFS has multiple causes that combine in varying ways for each individual.
“Pathological levels of fatigue unrelated to activity and not relieved by rest is a mandatory requirement for a diagnosis of chronic fatigue syndrome under the current internationally accepted diagnostic guidelines. The original diagnostic criteria contained another mandatory element, namely a clinical picture whereby the patient’s global symptoms represent a unitary illness with a single pathogenesis and pathophysiology. It is more likely that a diagnosis of CFS represents a spectrum of illnesses where different pathophysiological processes converge to produce a very similar phenotype.”
Immune dysregulation and present with different types of imbalances with chronic fatigue:
“Numerous research teams have reported a wide range of peripheral immune abnormalities in people afforded a diagnosis of CFS…now data reveal that while some patients present with a Th2 profile and a preponderance of anti-inflammatory cytokine production, others present with a Th1 or possibly Th17 profile, with the synthesis of proinflammatory cytokines being dominant…We have reviewed previously that patients with CFS and Myalgic Encephalomyelitis (ME) show different cytokine profiles, for example, a Th1-like pattern, with increased levels of IFN-γ, IL-2, IL-12 and IL-2 receptor, or a Th2-like pattern, with increased levels of IL-10, IL-4 and IL-5, or combinations thereof. Two recent studies reported evidence of activated TLR4 receptors. The causative relationship between chronic inflammation and the development of fatigue is perhaps strongest in patients afforded a diagnosis of CFS, with many studies demonstrating a significant positive correlation between surrogate markers of inflammation, oxidative stress and symptom severity.”
And addressing these causal patterns can afford relief:
“Miwa and Fujita (2010) demonstrated that a rapid decline in inflammation and oxidative stress of patients corresponded with a decline in severity of fatigue and amelioration of their entire symptom profile.”
Major depression and fatigue
It is now well established that major depression is a disorder characterized by chronic neuroinflammation:
“The existence of increased levels of circulatory proinflammatory cytokines in these patients is now a textbook truism…Fatigue of variable severity occurs in practically 100% of people with a diagnosis of depression. It is worthy of note, however, that a systematic review reported that almost 80% of patients still experienced chronic debilitating levels of exhaustion following treatment of their depression. This is perhaps to be expected given that several studies have now demonstrated that antidepressants have no positive modulatory effects on fatigue.”
Chronic inflammation, oxidative damage, intestinal barrier permeability and mitochondrial dysfunction all can contribute to depression:
“There is copious evidence of chronically activated T cells with Th1, Th2 and Th17 patterns of differentiation…Chronic systemic inflammation and oxidative stress play a major role in the etiology of depression. Elevated levels of redox-damaged DAMPs, including oxidized low density lipoprotein, oxidized phospholipids, and malondialdehyde (MDA)-adducts are also consistently found in patients suffering from this illness. Compromised epithelial barrier integrity is also a finding in depression and the resulting bacterial translocation into the systemic circulation is intimately involved in the pathogenesis of the disease. Mitochondrial dysfunction affects neuronal function, synaptic plasticity, energy metabolism and neurotransmitter release and, hence, it is not surprising that there is increasing evidence that mitochondrial dysfunction and inflammation drive the symptoms of major depression. Gardner and Boles highlighted the fact that research has failed to confirm a consistent relationship between serotonin levels and depression and that compromised bioenergetics should become a focus of research into the pathogenesis of the illness.”
Inflammation in the periphery can fire up inflammation in the brain
There is cross-talk between the rest of the body and the central nervous system that promotes neuroinflammation and fatigue. As this continues the pathways become primed to maintain dysfunctional inflammation even in the absence of the original triggering stimuli.
“There is now copious evidence that chronic or intermittent inflammation…can worsen or trigger neuroinflammatory or neurodegenerative processes via the induction of primed microglia. Briefly, prolonged or intermittent peripheral inflammation and immune activation act to prime microgliawhich thereafter become exquisitely sensitive to future inflammatory stimuli. Once microglia have achieved this sensitized status, subsequent peripheral inflammation and proinflammatory cytokine production mediated by a number of insults (for example, biotoxin exposure or pathogen invasion) provokes an exaggerated response from microglia and the production of excessive concentrations of neurotoxic molecules, such as nitric oxide, peroxinitrite, prostaglandins, cyclo-oxygenase 2 and cytokines. The secretion of these neurotoxins and alarmins leads to the activation of astrocytes and the combined activation of these glial cells provokes dysregulation of brain homeostasis, development of chronic neuroinflammation and neurotoxicity.”
Neuronal (vagal) and cytokine signaling from the periphery to the brain are involved, with disruption of the blood-brain barrier….
“Both humoral and neuroendocrine routes mediate proinflammatory signaling to the brain. The neural route operates via the dorsal motor nucleus of the afferent vagus nerve. The humoral route is facilitated by circulating proinflammatory cytokines that communicate their presence to the brain via direct and indirect routes. Such pathways involve engagement with specific transporters in the blood brain barrier (BBB)…The cumulative effects of proinflammatory cytokines and activated astrocytes cause disruption of the BBB allowing abnormally high numbers of activated T cells and B-cells to circulate between the peripheral immune system and the brain, acting as more channels of communication between the peripheral and central immune system. It should be noted that cytokines are able to diffuse from the CNS into the bloodstream as well.”
Gender, hormones and inflammation
There are important sex-related differences in autoimmune predilection associated with the immunomodulatory roles of sex hormones.
“An increased incidence rate in women is observed in most autoimmune disorders…Estrogen, progesterone and testosterone play important immunomodulatory roles and influence the quantity and pattern of cytokine secretion by antigen presentation cells and T lymphocytes and immunoglobulin production by B cells. Sex hormones also regulate the Th1/Th2 balance of the immune system, the production of regulatory T cells and the functionality of granulocytes and natural killer cells.”
Clinicians should remember that, while estrogens are neuroprotective at physiological levels, they can promote autoimmune inflammation when excessive.
“…Thus, excessive estrogens but less androgens may favor activation of B cells, a Th2-like response and increased numbers of autoimmune cells and, thus, autoimmune responses.”
Inter-related mechanisms produce fatigue
Clearly, a systems biomedicine perspective is required to grasp the dynamics, and peripheral inflammation plays a key role.
“It is of interest that levels of peripheral inflammation, oxidative stress and TNF-α also display a positive correlation with objective markers of disease activity and disability levels and that levels of proinflammatory cytokines correlate positively with levels of fatigue. The existence of gray matter atrophy before the advent of white matter abnormalities, and the existence of metabolic abnormalities before the advent of gray matter pathology, rather argues against the proposition that the chronic peripheral immune activation and oxidative stress seen in early disease is secondary to the release of inflammatory mediators from the CNS. These observations, coupled with data demonstrating that the severity of neuro-inflammation depends on the level of peripheral immune activation and that inflammation drives the development of disease, emphasizes the likely causative role of peripheral pathology. The strong association between the severity of fatigue and disability and the level and geographical distribution of glucose hypometabolism and gray matter hypoperfusion strongly indicates that these elements are driven by generic rather than disease specific pathology…There is also evidence demonstrating that the severity of fatigue is associated with the degree of white matter hyperintensities in people with SLE and evidence that the neuropathology in Sjogren’s syndrome is immune mediated. The widespread mitochondrial dysfunction seen in people with autoimmune diseases could also make a significant contribution to the development of fatigue…Given that many such patients also display evidence of peripheral immune activation, oxidative stress, gray matter pathology, glucose hypometabolism, hypoperfusion and metabolic abnormalities in the prefrontal cortex, basal ganglia and elsewhere, it would seem reasonable to investigate all such patients for the presence of these abnormalities. Standard MRI is unlikely to be helpful but other approaches discussed in the main body combined with serum measures of immune activation and oxidative stress may well bear fruit.”
Clinical bottom line
Practitioners need to view the complex and dynamic interactions at play for case analysis and treatment planning.
“..the multifactorial triggers that cause secondary fatigue by activating the networks/pathways in those disorders, including viral and bacterial infections, bacterial translocation, psychosocial stressors, exposure to adjuvants, nicotine dependence, sex- and gender-related factors, and so on. Towards this end, a systems biomedicine approach is essential to delineate the genetic and molecular signature of fatigue in these disorders and the non-linear interactions between the many pathways, networks, and trigger and genetic factors that underpin secondary fatigue.”
And the authors conclude by mentioning a short list from among the varied therapeutic resources already in use:
“Multi-targeting these interlinked dysfunctions may show benefit in these diseases. For example, a number of antioxidant compounds have demonstrated efficacy in modifying pathways leading to chronic inflammation, oxidative stress and immune dysregulation at relatively high doses for a long duration. N-acetyl-cysteine is an example of a multi-target therapeutic approach having the capacity to decrease the levels of ROS/RNS, increase the levels of cellular antioxidants, such as reduced glutathione, and normalize the production of proinflammatory cytokines and immune cell functions. This supplement has demonstrated the capacity to improve fatigue and disease activity in SLE, CFS and major and bipolar depression. Omega-3 polyunsaturated fatty acids (PUFAs) and zinc are also very effective antioxidants and anti-inflammatory compounds and supplementation has produced clinical benefit in patients diagnosed with depression and chronic fatigue syndrome…Curcumin, another nutraceutical with anti-inflammatory and antioxidative effects, is useful in the treatment of depression and rheumatoid arthritis. Coenzyme Q10 is another powerful antioxidant and anti-inflammatory compound which also has positive effects on mitochondrial function and which displays disease modifying effects in Parkinson’s disease and produced clinical benefit in patients with a diagnosis of CFS. Other approaches aimed at upregulating antioxidant defenses include N acetylcysteine, methylfolate and dimethyl fumarate, with the latter displaying disease modifying properties in MS . Methylfolate produces a similar quantum of benefit in MDD as antidepressants and can often be effective in treatment-resistant depression.”
Of course for these and many more therapies clinicians should shun a ‘try this, try that’ approach and employ the abundant objective laboratory resources to target specific needs on an individual case basis. The authors conclude:
“It is concluded that there are sufficient robust multiple lines of evidence to support the proposition that the severe fatigue and profound disability experienced by people with the neurodegenerative, neuro-immune and autoimmune diseases discussed here is largely driven by peripheral immune activation and systemic inflammation either directly or indirectly by inducing mitochondrial damage.”
Traumatic brain injury(TBI) even in it’s milder forms can initiate a process of chronicneuroinflammation that causes a range of chronic neurodegenerative disorders. The authors of a paper just published in Neuropsychiatric Disease and Treatment detail the secondary injury cascades that exacerbate the damage and can lead to chronic traumatic brain injury.
“Mild TBI, sometimes referred to as concussion, is the most prevalent TBI. Although TBI has been traditionally considered an acute injury, accumulating clinical and laboratory evidence has recognized the chronic pathology of the disease. Indeed, TBI can manifest many symptoms of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease…Accumulating laboratory and clinical evidence has implicated neuroinflammation in both acute and chronic stages of TBI, suggesting this secondary cell death pathway may be the key to the disease pathology and treatment…”
Neuroinflammation in traumatic brain injury stands out as a target of inquiry:
“Here, we focus on neuroinflammation, which closely manifests immediately after TBI onset, and equally important, it persists in the chronic stages of the disease, making it an appealing target for understanding TBI pathology and its treatment.”
Mild traumatic brain injury may cause a variety of symptoms to persist
Clinicians need to be alert to a range of possible symptoms long after the original injury.
“Most patients fully recover in a couple hours or days, although it may take a couple of weeks. However, depending on the severity of the injury, there are some cases in which victims do not recover and the symptoms persist for years….Clinical manifestations of mild TBI consist of a combination of physical and neuropsychiatric symptoms, which include behavioral and cognitive disorders…Of the physical symptoms of TBI, headaches are the most common, with around 25%–90% of post–mild TBI patients reporting it. Dizziness and nausea are other common symptoms, along with fatigue, sleep disruption, hearing problems, and visual disturbances. As a result of damage to the frontal or temporal lobe, TBI patients are also prone to seizures, which may present a challenge for diagnosis and treatment (ie, differential diagnosis between TBI and epilepsy).”
Chronic cognitive and behavioral disorders from mild traumatic brain injury
The cascade of neurodegenerative effects stemming from mild traumatic brain injury are tragically life altering.
“Cognitive disorders after TBI primarily include attention deficit, memory problems, and executive dysfunction. Attention deficit is very common and interferes with other functions, making daily tasks harder than before…These include irritability, mood changes, aggression, impulsivity, self-centered behavior, and poor persistence.Other symptoms related to TBI are depression (sadness, low energy and motivation, not liking oneself, hopelessness), anxiety, and posttraumatic stress disorder. In addition, as noted earlier, TBI may increase the risk of developing Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative diseases in the long term.”
Primary and secondary waves of injury
Both short and long term cascades of damage occur when the brain is subject to trauma.
“The initial insult first leads to a primary injury caused by the mechanical damage from shearing, tearing, and/or stretching of neurons, axons, glia, and blood vessels…The primary injury triggers a secondary wave of biochemical cascades, together with metabolic and cellular changes. This occurs within seconds to minutes after the traumatic insult and can last for days, months, or years. It often leads to progressive neurodegeneration and delayed cell death, exacerbating the damage from the primary injury. The secondary wave is mainly detected in the injury site and surrounding tissue, although neurodegeneration in brain areas located far from the primary impact has recently been recognized…
The secondary wave consists of excitotoxicity, oxidative stress, mitochondrial dysfunction, blood–brain barrier (BBB) disruption, and inflammation. All these processes contribute to neurological deficits separately, but at the same time, these cell death processes interact, worsening the progressive outcome of TBI.”
Excitotoxicity in traumatic brain injury
Substances released by damaged neurons cause brain cells to be stimulated to death.
“…injured nerve cells secreting large amounts of intracellular glutamate into the extracellular space…overstimulates the AMPA and NMDA receptors of surrounding nerve cells. These receptors stay activated, allowing an influx of sodium and calcium ions into the cell. The high concentration of calcium ions in the cytosol leads to the activation of protein phosphatases, phospholipases, and endonucleases. Eventually, the DNA is fragmented, and structures and membranes of the cell are deteriorated. This results in cell death through a hybrid form of apoptosis and necrosis. The overstimulation of glutamate receptors also results in the increased production of nitric oxide, free radicals, and pro-death transcription factors.”
ROS in traumatic brain injury
A damaging increase in free radical reactive oxygen species (ROS) and reactive nitrogen species (RON), which are normally kept at a low level in the brain by antioxidants and enyzmes, also contributes to neuronal cell death.
“After TBI, a significant increase in ROS and impairment of antioxidants that lower the levels is seen. When the generation of ROS/RON is too large, it leads to major cell dysfunction, as its oxidative capabilities damage all biomolecules. ROS cause lipoperoxidation of the cell membrane, which results in the dysfunction of many structures and organelles, such as the mitochondria and oxidizing proteins that affect membrane pores. It may also fragment DNA, causing mutations. ROS are also related to the infiltration of neutrophil, which induces an inflammatory response that, in turn, increases the generation of ROS. Overall, oxidative stress cascade results in large neuronal cell death.”
Mitochondrial dysfunction in mild TBI
Mitochondrial dysfunction, typically a contributing factor to neurodegeneration in general, also plays a role in neuronal cell death and chronic loss of brain function following traumatic brain injury.
“After TBI, the stabilizing mechanisms of levels of ROS become impaired, resulting in increased concentrations. Lipid peroxidation-mediated oxidative damage to the mitochondrial membrane negatively affects its structure and function. The mitochondria also works as a calcium ion buffer, releasing and absorbing the ions as needed to maintain homeostasis. However, when the calcium ion load becomes too large from excitotoxicity, the function of the mitochondria becomes impaired. The mitochondrial permeability transition pore, associated with the mitochondrial inner membrane, is a calcium ion-dependent pore. With the excess calcium ions, the pore stays active, disrupting the mitochondrial membrane potential. Without a membrane potential, the mitochondria is unable to produce ATP, and the ATP synthase may actually consume ATP instead of producing it. With mitochondrial break down, toxins and apoptotic factors are released into the cell, activating the caspase-dependent apoptosis. This causes the cell to commit suicide.”
Blood-brain barrier disruption
Loss of blood brain barrier (BBB) integrity also contributes to brain cell death following TBI.
“BBB dysfunction is related to neuronal cell death and cognitive decline and limits the effectiveness of therapies. Its dysfunction triggers many other secondary injuries, including cell death, oxidative stress, and inflammation, causing the brain to swell, with higher intracranial pressure and ischemia. The primary injury disrupts the tight junctions, allowing an influx of peripheral immune cells and circulating factors (albumin, thrombin, and fibrinogen). These events affect the interaction between BBB endothelial cells and astrocytic glial cells, further contributing to the effects of BBB dysfunction by increasing its permeability. One of the underlying mechanisms regarding BBB dysfunction after TBI is the up-regulation of protein matrix metallopeptidase 9 (MMP-9). This digests the tight junctions, disrupting its proper function. BBB breakdown also allows an influx of larger molecules such as leukocytes that increase the osmotic force in the brain. This results in edema and higher intracranial pressure, which are directly related to ischemia and further cell death.”
Neuroinflammation, the ‘big enchilada’
Red line = damaging neuroinflammation, Green solid = pro-survival inflammation, green dotted = treatment, arrow = initiation of treatment.
Brain inflammation may be the leading contributor to accelerated loss of brain cells in most forms of neurodegeneration. In traumatic brain injury it is triggered immediately after impact and can continue for many years.
“After the initial injury, an endogenous inflammatory response is triggered to defend the injury site from invading pathogens and to repair the damaged cells. The complement is activated to perform these functions and recruits inflammatory cells into the intrathecal compartment. The activation of the complement is also accompanied by the infiltration of neutrophils, monocytes, and lymphocytes across the BBB. These secrete prostaglandins, free radicals, proinflammatory cytokines, and other inflammatory mediators that, in turn, up-regulate the expression of chemokines and cell adhesion molecules. This results in immune cells and microglia mobilizing into the brain parenchyma.”
While the microglial cells perform important positive functions that limit damage and sequester the injured tissue, they fire up neuroinflammation by over-reacting. This is particularly true of the M1 phenotype of glial cells.
“…microglial activation in TBI is excessive, and proinflammatory cytokines such as tumor necrosis factor (TNF)- , IL-1 , IL-6, IL-12, and interferon are released. The up-regulation of these cytokines increases the permeability of the BBB by higher expression of cell adhesion molecules in the endothelial cells and by an increased production of chemokines. This results in an increased inflammatory response. Sustained microglial activation also produces neurotoxic molecules and free radicals, which lead to other mechanisms of secondary cell death…In addition, activated microglial cells increase the expression of major histocompatibility complex class II (MHCII ), which is directly correlated to neurodegeneration.”
Astrocytes too exert beneficial effects by increasing brain-derived neutrophilic factors (BDNF) and regulating extracellular glutamate to reduce excitotoxicity. However…
“…when the presence of astrocytes is too large and they become overactivated, it can lead to detrimental effects in the brain. The astrocytes secrete inhibitory extracellular matrix, building a dense physical and chemical barrier surrounding the injury site (glial scar), which encapsulates and isolates the axons. This protects the remaining healthy brain from the neurotoxic environment of the injury site, but it also interferes and prevents the regeneration and repair of the damaged tissue.”
What to do?
A rational treatment plan should include the various remedial measures that target all of these processes:
Wind down glutamate excitotoxicity
Oppose oxidative stress
Support mitochondrial function
Help repair the blood-brain barrier
These processes play a role in neurodegeneration from other causes besides traumatic brain injury. The clinician should have a repertoire of remedial measures at hand to address them. Past and future posts report on advances in treatment. Calming neuroinflammation plays a premiere role.”
“It takes considerably more time for the inflammatory cells to reach the injured brain and contribute to the secondary cell death damage than it takes other secondary death mechanisms, such as glutamate excitotoxicity. This delayed onset provides an extended window of opportunity in which treatments can be administered, greatly increasing the chances of a successful intervention and preventing further damage.”
One cardinal point must be kept in mind: there is a beneficial ‘housecleaning’ side to neuroinflammation so antiinflammatory therapies should not be overdone.
“Immune cells, astrocytes, cytokines, and chemokines are all necessary components for brain repair, and it is their excessive levels that contribute to the secondary cell death damage in TBI…When considering treatments for neuroinflammation in TBI, it is important to note that inflammation has both beneficial and detrimental effects. Prior studies have shown that high doses of antiinflammatory agents actually lead to worse outcomes. In addition to inhibiting the detrimental effects of neuroinflammation, these robust treatments may also retard the beneficial ones.”
Judicious application of natural anti-inflammatory agents to minimize side-effects along with other measures guided by objective measurements is a standard for treating traumatic brain injury that can be applied to other neurodegenerative disorders as well.
Brain-immune interactions control inflammation and the response to stress. An exciting study with tremendous practical significance was just published in the Journal of Neuroimmunology that shows how vagal nerve activity, which can be measured in the clinic by heart rate variability analysis (HRV), is a key moderator of the brain-immune web and determines the immune and physiological responses to acute stress. Highlights include:
Vagal tone indexed by heart rate variability reflects biological regulatory capacity.
Vagal tone is linked with flexible immune and physiological stress responses.
Frontal-striatal network mediates effects of vagal tone on stress responses.
The authors note:
“The bidirectional communication between the immune and nervous systems is considered to involve neural pathways that link these systems and expression of receptors for ligands such as cytokines and neurotransmitters. The brain produces immune-regulatory effects, and immunity has sensory functions (Haddad, 2008). Specifically, descending neural influences on immunity include neural innervation of lymphatic organs (Madden et al., 1995), expression of receptors for neurotransmitters on immune cells (Levite, 2008; Tracey, 2009) and differential left versus right hemisphere influences on immunity (Davidson et al., 1999; Sumner et al., 2011). Ascending immune-to-brain pathways include immune signals entering brain regions that lack a blood-brain barrier (BBB), prostaglandins on both sides of the BBB that mediate inflammatory signals, and an immune-to-brain conversion of inflammatory information by the vagus nerve (Ek et al., 1998; Dantzer et al., 2000; Davidson et al., 2001; Tracey, 2009).”
Fortunately there is increasing interest in understanding the brain-immune web and how the brain modulates the immune system during acute stress. Earlier studies have shown that the brain regions involved in executive functions and stress coping also modulate adaptive immune activities, and are responsible for making the physiological response to stress flexible and appropriate. The authors observe:
“Such associations between the neural and immune systems may depend on and be affected by a third variable, relevant to both systems, specifically tonic activity of the vagus nerve (Thayer and Sternberg, 2010). The vagus nerve expresses receptors for interleukin-1, enabling it to convert immune to nerve information via ascending acetylcholine signals to the brain stem (Ek et al., 1998). In return, the descending vagus modulates the activity of peripheral leukocytes and inflammation via the HPA axis and neural routes that inhibit cytokine production by macrophages (Tracey, 2009). Importantly, brain regions regulating activity of the vagus nerve partly overlap with brain regions involved in immune regulation, including the medial prefrontal cortex (MPFC) and DLPFC (Lane et al., 2009; Ohira et al., 2009). Given the strategic location of the vagus nerve mediating between the periphery and the brain and given its neuroimmunomodulatory roles, we hypothesized that tonic activity of the vagus nerve, indexed by heart rate variability (HRV) in a resting state, moderates transient brain–immune relationships accompanying acute stress.”
“…it was previously reported that individuals with a higher resting HRV showed faster recovery in their acute stress responses of immune, neuroendocrine, and cardiovascular parameters (Weber et al., 2010). These data suggest that higher resting HRV is associated with context-appropriate responses including adaptive recovery after termination of stress, and that the autonomic and endocrine systems mediate the associations between brain and immunity.”
Correlations between regional cerebral blood flow with proportion of natural killer cells and concentration of adrenocorticotropic hormone in high heart rate variability group.
So they set out to investigate whether vagus nerve activity as measured by HRV modulates brain-immune associations including the autonomic nervous system and endocrine (HPA) responses to acute stress. They subjected their study subjects to a learning task that has been proven to psychological and physiological stress and serve as a valid acute stressor for study purposes. The participants underwent PET scans of the brain, had blood sampled after each stress for the ratio of NK cells (natural killer cells) and helper T cells, and amounts of norepinephrine as an index of sympathetic activity and ACTH as an index of endocrine (HPA) activity. Their findings are fascinating:
“There were two main findings of the present study. First, low tonic vagal activity (low resting HRV) was associated with blunted responses in NK cells, norepinephrine, and ACTH to an acute stressor, whereas high tonic vagal activity (high resting HRV) was associated with more sensitive responses in those physiological parameters. Second, low and high tonic vagal activity was related to a qualitatively different neural matrix associated with immune, sympathetic, and endocrine changes. While low HRV participants showed only a correlation between ACTH and activity in the VLPFC, high HRV participants showed stronger associations between their brain activities and NK cells and ACTH. Specifically, in the high HRV participants, NK cell proportions were correlated with activity in the rostral ACC which is a portion of the MPFC and the dorsal striatum (nucleus caudate). The ACTH levels of the high HRV participants correlated with activation in the insula, OFC, cerebellum, and dorsal ACC. To the best of our knowledge, this is the first study to demonstrate thattonic vagal activity moderates brain–immune and brain–neuroendocrine associations accompanying acute stress.”
They discuss some of the important implications of their findings:
“Importantly, we observed that high HRV participants showed…associations between NK cell proportions and activity in [several brain regions]…By contrast, in low HRV participants, NK cell proportions showed no correlation with brain activity. These findings suggest that in individuals with high tonic vagal activity, immune responses to stress are associated with a higher and more complex regulatory neural network that…may enable regulation of NK-cell responses.”
“The observation that individuals with high HRV initially showed a reduced NK cell response to an ongoing stressor during the initial learning task suggests that high HRV reflects the ability to habituate to stress. This is consistent with a previous finding by Weber et al. (2010) indicating that individuals with high HRV recovered cardiovascular, endocrine, and immune responses more rapidly after termination of an acute stressor than individuals with low HRV…By contrast, low HRV individuals demonstrated blunted immune, sympathetic, and endocrine reactivity to the stressor. These data suggest a greater physiological adaptability of in high HRV individuals and a potential moderating role of the vagus nerve in neuroimmuno-endocrine responses to stress.”
It was a similar story for the excitatory neurotransmitter norepinephrine:
“Changes of norepinephrine due to stress showed a similar pattern to that in NK cells, with an initial decrease followed by increase after reversal of contingency between options and outcomes in the high HRV group, compared to a more blunted reactivity in the low HRV group.”
And for ACTH (adrenocorticotrophic hormone produced in the pituitary that stimulates adrenal production of cortisol):
“Values of ACTH showed a continuous decrease in the high HRV group, reflecting a habituation process, but not in the low HRV group.”
For clinicians reading this who wisely do HRV assessments in their practice:
“…rating of subjective stress at baseline (before measurement of baseline HRV) did not differ between the low and high HRV groups. This suggest that baseline HRV, which was measured before the experimental procedure, might reflect the basic characteristics of an individuals’ vagal tone, rather than individual differences in phasic reactivity of HRV affected by anticipatory anxiety.”
In other words, this implies that heart rate variability assessments really does give us objective data about the patient’s vagal and parasympathetic resources. Other insights that emerge include:
…low HRV participants had some impairment in the connections between the brain and peripheral physiology, with consequent differential patterns in physiological responses to the stressor…The high HRV group manifested greater sensitivity in their immune and physiological responses and greater association and possibly regullation by the brain over these responses. Although whether this is an adaptive response is an open question, it is possible that a high tonic vagal activity is a prerequisite for top-down rapid regulation of immune, autonomic, and endocrine responses to acute stress. By contrast, lower vagal activity may result in slower recovery (Weber et al., 2010) or lack of changes of immune responses to environmental challenges, possibly because of impairment in neuro-immune circuits.”
And regarding the premiere factor of inflammation:
“An impaired regulation of immune responses can result in inflammation,which is etiologic to various chronic diseases, such as coronary-artery disease, cancer, and dementia, in which the vagus nerve was recently postulated to play a protective role via regulation of multiple basic processes (De Couck et al., 2012).”
Summing up their findings regarding vagal actvity as measured by HRV and the brain-immune response to stress:
“…our study revealed that tonic vagal nerve activity may be an important determinant of neuro- immune and neurophysiological associations and the regulation of the multisystem responses under acute stress.”
Since we can easily measure vagal (parasympathetic) tone in the clinic with HRV and we have sustainable interventions to increase vagal activity (BioCranial Therapy and many others), it’s hard to overemphasize the practical significance of this research.
Professor Yehuda Shoenfeld of the Zabludowicz Center for Autoimmune Diseases, Tel-Aviv University is one of the world’s leading authorities on autoimmune disease. His talk on ASIA—autoimmune sydrome induced by adjuvants (used to magnify the immune response to vaccines)—was distributed recently by the BMC Medical division of the open access publisher BioMed Central.
Prof. Shoenfeld does not argue against the immense benefits of vaccines, but explains briefly why clinicians must be aware of the potential for autoimmune complications in a percentage of the population that may be predisposed. Morever, he discusses how the process in ASIA is relevant also for the loss of tolerance involved in conditions such as environmental and chemical sensitivity, chronic fatigue syndrome (CFS), fibromyalgia, narcolepsy, sick building syndrome, reactions to silicon implants, Gulf War syndrome and others.