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


Systemic inflammation drives brain neurodegeneration

Frontiers in Cellular NeuroscienceIn a richly valuable paper published recently in Frontiers in Cellular Neuroscience the authors describe the ways in which systemic inflammation causes neurodegeneration in the brain associated with cognitive decline and a host of neuropsychiatric disorders. In the short term this manifests the anorexia, malaise, depression, and decreased physical activity known as sickness behavior (SB) that occurs with inflammation due to infection. Permanent cognitive and behavioral changes due to neurodegeneration occur when inflammation is chronic. Discerning and targeting the causes of inflammation offers opportunities for treatment.

Neuroimmune modulation

The nervous system senses inflammation directly and can exert control through the vagus nerve:

“The efferent axis of neuroimmune control is better understood after the cholinergic anti-inflammatory pathway (CAP), a cholinergic reflex system that regulates inflammation via the vagus nerve that stimulates the splenic nerve to release noradrenaline. Noradrenaline in turn stimulates a subset of acetylcholine (ACh)-producing splenic T-cells (CD4+CD44hiCD62Llo) to release ACh, which binds to α7 nicotinic receptors on the surface of macrophages, resulting in down-regulation of TNF by blocking the nuclear translocation of nuclear factor kappa B (NF-κB). Thus far, this is a unique scenario in which an immune cell acts as interneuron in a reflex system. Electrical as well as chemical stimulation of the CAP have been shown to decrease the inflammatory burden and increase survival of experimental sepsis.”

The a cholinergic response expressed through the vagus nerve can wind down inflammation and protect against neurodegeneration.

Sickness behavior

Transient inflammation, such as associated with a cold or flu, produces behavioral symptoms of the same character as those which persist with the chronic systemic inflammation that can drive neurodegeneration.

“The acute effects of systemic inflammation upon cognition and behavior are not limited to the elderly or the critically ill. As we have witnessed in ourselves and those near us, even a minor and self-limited common cold induces a transient syndrome known as sickness behavior (SB) marked by fatigue, depression, lack of drive, malaise, sleep disturbances, decreased physical activity, and social interactions, as well as cognitive impairment. Healthy volunteers develop anxiety, depression, and memory impairment in response to a low dose of lipopolysaccharide (LPS), and the development of such clinical scenario correlates with TNF secretion.”

And patients with chronic infections such as tuberculosis, human immunodeficiency virus (HIV), hepatitis B virus (HVB), and hepatitis C virus (HCV) can have cognitive and behavioral problems due to the persistent inflammatory response.

“This supports the role of large loads of inflammatory cytokines in inducing and sustaining brain dysfunction. Experimentally, NADPH oxidative activity and nitric oxide synthase (iNOS) are induced in the brain shortly after systemic inflammation, potentially leading to NMDA-dependent neurotoxicity”

Sepsis and severe trauma

An overwhelming load of pathogens or severe trauma can unleash an immune inflammatory response that results in neurodegeneration.

“Under normal conditions, inflammation is a well-orchestrated response with constant fine-tuning. Once microorganisms have breached the skin and mucosal barriers, innate immunity is critical in preventing further invasion by launching inflammation. After the infection source has been cleared, the inflammatory response also plays an important role in tissue repair and functional healing. When the source of damage has been controlled, the same mechanisms that initiated and regulated inflammation will dampen the response. Large loads of pathogens, or infection by highly virulent pathogens, can trigger an en-masse systemic response that leads to sepsis and multiple organ failure…The nervous system is particularly vulnerable to damage in response to systemic inflammation.”

Brain milieu changes in response to systemic inflammation

Brain milieu changes in response to systemic inflammation

Inflammation-induced infiltration of immune cells and mediators into the brain leads to profound structural and functional changes. As a consequence, up to 81% of septic patients develop sepsis-associated delirium (SAD), with elderly patients being at particularly high risk. In the elderly, severe sepsis is sufficient to trigger new cognitive decline of sufficient importance as to profoundly interfere with quality of life…Neonatal sepsis is also marked by abnormalities of the white matter (66% of infants in one cohort), and white matter lesions correlate to poorer mental and psychomotor development at 2 years.


“…clearing the trigger of sepsis does not prevent the appearance of persistent brain damage…in a model of endotoxemia in aged rats, a single systemic injection of LPS induced brain inflammation that lasted for at least 30 days…This suggests that even transient bouts of systemic inflammation of only limited significance can cause sustained brain damage.”

Traumatic inflammation also promotes neurodegeneration:

“Severe trauma, as well as surgery can lead to large loads of endogenous pro-inflammatory molecules (damage-associated molecular patterns (DAMPs) being released. A few DAMPs have been shown to induce brain dysfunction in vivo. Of those, TNF and IL-1 can mediate long-standing cognitive and behavioral changes and, in experimental settings, interfering with the effect of TNF reduces the effect of trauma in the formation of contextual memory.”

In this context antioxidants can have neuroprotective effects.

“Experimentally, preemptive administration of the free radical scavenger endarvone before sepsis induction resulted in reduced neuronal damage and blood–brain barrier (BBB) permeability. Administration of the antioxidants N-acetylcysteine and deferoxamine shortly after murine sepsis induction has shown long-term neuroprotective effects.”

Systemic inflammation disrupts brain networks

Human brain connectome

The human brain connectome

The brain is characterized as a ‘small-world’ network with two levels of connection that are susceptible to disruption by inflammation.

“Biological systems, such as the neuronal network of the human brain have “small-world” properties. Small-world networks have two levels of organization. On the local level, groups of neurons specialized in a specific task form functional modules with high short intramodular connectivity. On the global level, different modules are connected through long intermodular connections. The advantage of the latter type of connections is enhanced computational efficiency through parallel processing of information. Anatomically, long intermodular connections are formed by axonal fiber tracts in the white matter. Long fibers are characterized by high energetic “wiring costs”. To provide the energy for the maintenance of these long fibers the brain is relying on a constant energy supply. Recent findings have elegantly identified oligodendrocyte-derived lactate as the main energetic substrates for axonal maintenance. Consistently, disruption of this oligodendrocyte-neuronal metabolic coupling triggered neurodegeneration. Systemic inflammation poses dramatic challenges to the energetic supply of the brain.”

The brain requires a constant stream of nutrients to maintain its ‘wiring’

Autoimmune driven neuroinflammation, among other insults, can disrupt the delivery of nutrients to neurons and contribute to mitochondrial dysfunction.

“To cover its wiring costs the brain is highly reliant on a constant nutrient supply. Nutrient supply through blood vessels can be compromised through vascular pathologies associated with systemic inflammation…Autoimmune disorders have a chronic course of vascular pathology with acute flares. The most common vascular pathology is the autoantibody-associated antiphospholipid syndrome. Patients with antiphospholipid syndrome display cognitive deficits. MRI studies found diffuse infarctions and white matter lesions in these patients…In line with the concept of high “wiring costs” imposed on the brain by long intermodular connections,Hans Lassmann argues that inflammation in MS causes mitochondrial damage and inability of the brain to maintain neuronal processes. The source of mitochondrial damage is radicals formed as a consequence of inflammation in MS.”

Energy crisis for the brain

Systemic inflammation damages connectivity and fuels mitochondrial dysfunction…

“Taken together these findings indicate that systemic inflammation leads to an energy crisis of the brain that reduces its connectivity. Oxidative stress might be the main mediator of this pathology. Thus, inflammation-induced changes in the brain resemble hallmarks of the aged brain where oxidative damage leads to decreased expression of genes associated with synaptic plasticity and increased expression of stress-response genes. Likewise, the brain during systemic inflammation shows hallmarks of neurodegenerative diseases where oxidative stress and mitochondrial damage have consistently been found.”

Balancing act

Normally astrocytes and neurons talk to each other to keep activation of brain immune cells in check. But this can get out of hand in response to a pathogen resulting in serious damage. Balance is maintained, partly by accepting a certain degree of tolerance for pathogens:

“Brain-resident microglia and peripheral immune cells maintain immune surveillance of brain parenchyma, CSF, and perivascular space for infectious agents or damage-associated milieu changes. In the case of brain infection, complete eradication of some invading pathogens can only be achieved at the cost of irreparable damage to brain tissue. To prevent such damage, the immune system has established active mechanisms of pathogen tolerance. Examples for coexistence-prone pathogens are herpes simplex virus type I or Cryptococcus gattii. A growing body of evidence indicates that not only immune tolerance but also resolution of neuroinflammation is a tightly regulated active immunological process. Taken together, anti-inflammatory brain milieu, pathogen tolerance, and resolution of neuroinflammation require a balanced action between different branches of the immune system.”

Dysregulation causing systemic inflammation drives neurodegeneration

There are a number of mechanisms by which dysregulated systemic inflammation promotes neuroinflammation and neurodegeneration. These in include activation of apoptosis through the inflammasome (inflammation signalling chains):

Apoptosis is one of the main drivers of neurodegeneration. Apoptosis and cell death constantly occur under physiological conditions throughout the human body and cell debris is cleared by immune cells mostly without induction of chronic inflammation. However, during systemic inflammation, apoptosis of stressed cells might further exacerbate the underlying pathology. Activators of apoptosis lead to direct or indirect activation of caspases…inflammatory caspases are crucial for the activation of the innate immune system through the inflammasome…Activation of the innate immune system through the inflammasome is a driver of pathology in age-associated and autoimmune neurodegenerative disorders…these finding show an intricate relationship between inflammation and activation of apoptosis”

Microvesicles (MVs) packed with inflammatory messengers are secreted by peripheral and brain immune cells contribute to neurodegeneration:

“Cellular components of innate immunity can pack and secrete inflammatory messengers in microvesicles (MVs). Peripheral macrophages, as well as brain microglia can secrete inflammasome components (caspase-1, IL-1β, and IL-18) in MVs, and the presence of extravesicular inflammatory inducers (e.g., astrocitic ATP) is sufficient to induce the neurotoxicity by the inflammatory load of MVs.”

This correlates with disease activity in multiple sclerosis and also a significant role in Alzheimer’s disease (AD):

“Recent evidence suggest that MVs play a critical role in the spectrum of AD as well. MVs released by activated microglia participate in the neurodegenerative process of AD by promoting the generation of highly neurotoxic soluble forms of β-amyloid. Based on this collective evidence, it is now clear that EVs produced by peripheral myeloid cells, as well as immune brain cells, are novel and potentially critical biomarkers for neuroinflammatory conditions by providing a link between inflammation and neurodegeneration.”

Inflammation leads to neurodegeneration

Inflammation to neurodegeneration

Immune cells and mediators drive neurodegeneration

Immune cells in both the periphery and the brain can cause neuronal apoptosis through multiple pathways that can be targeted for therapy:

“Various triggers of apoptosis have been described with respect to the brain. Neuronal apoptosis can be directly induced by ROS, pro-inflammatory cytokines or activated immune cells…Additionally, damaged mitochondria are a major source of ROS and mediators of apoptosis. Conversely, inactivation of ROS has anti-apoptotic effects. The inflammatory cytokine TNFα and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) directly induce neuronal apoptosis. Additionally, intracerebroventricularly injected TNFα was shown to induce depression-like symptoms. Cytokine mediated induction of apoptosis was also observed by IL-1β.”

Immune cells in the brain and the periphery cause neurodegeneration, with evidence that antiinflammatory interventions can oppose neuronal death.

“Sources of cytokines under systemic inflammation are brain resident, paravascular or peripheral immune cells. Furthermore, activated immune cells can directly induce neuronal cell death. Brain-resident microglia convey neuronal toxicity through various mechanisms including secretion of neurotoxic factors, as well as through activation of cyclooxygenase/prostaglandin E2 (COX/PGE2) pathways. In fact, blocking the COX/PGE2 pathway by experimentally deleting the prostaglandine receptor EP2 increases mitochondrial degradation of β-amyloid, potentially opening a new therapeutic avenue for AD.”

When there is systemic inflammation immune cells in the periphery in the body can gain access to the brain through the blood-brain barrier:

Peripheral immune cells can penetrate the BBB under conditions of systemic inflammation and contribute to brain pathology. Cytotoxic T-cells were shown to be directly neurotoxic in autoimmune and aging-associated neurodegenerative disorders of the CNS. Co-localization of T-cells with neurons and neuron-specific cytotoxicity of T-cells was shown in vivo and in vitro.”

Anti-brain antibodies*

Identification of anti-brain antibodies is a key clinical finding that practitioners in a wide range of disciplines should be alert for.

“B-cell-derived anti-brain antibodies have been identified as drivers of brain pathology in various diseases. In the last decade, an increasing number of anti-brain antibodies has been detected that can affect cognition and behavior…Under pathological conditions, antibodies may penetrate the BBB through different mechanisms including local and systemic inflammation, or antigen mediated endocytosis.”

Anti-NMDA antibodies have been receiving much scrutiny for neuropsychiatric and neurodegenerative disorders.

“Furthermore, NMDA-receptor-specific antibodies to the subunit 2 (GluN2) have been found in a subset of SLE patients with neuropsychiatric symptoms. These antibodies are cross-reactive to DNA…DNA–NMDA receptor antibodies preferentially bind the open configuration of the NMDA receptor and augment NMDA receptor-mediated excitatory postsynaptic potentials…Depending on the antibody concentrations, DNA–NMDA receptor antibodies can cause either neuronal dysfunction by transiently enhancing excitatory postsynaptic potentials or can result in neuronal cell death. This evidence could be of high relevance in terms of reversibility of symptoms…Furthermore, anti-brain antibodies were also shown to induce neuropsychiatric symptoms in patients with other autoimmune disorders such as celiac disease or inflammatory bowel diseases. Taken together, anti-brain antibodies were shown to cause neuropsychiatric pathology in different diseases presenting novel therapeutic options.”

Inflammation disrupts neurogenesis

Both generation of new neurons and the support of synaptic health and plasticity are adversely affected by inflammation and this too is an avenue for treatment.

Neurogenesis is a central mechanism required for neuronal maintenance and adaptive plasticity in the healthy and diseased brain. Inflammatory mediators have various effects on neurogenesis. Impairment of neurogenesis was shown in neurodegenerative diseases such as AD and neuropsychiatric disorders such as depression. Interestingly, approved AD drugs and chronic antidepressant treatment induce neurogenesis. Inflammation and microglial activation is detrimental for neurogenesis that can be restored by anti-inflammatory treatment. Moreover, microglia are not only involved in the maintenance of the neurogenic niche but also in synaptic maintenance. Of interest, systemic immune cells were shown to be involved in regulation of neurogenesis. CD4+ T-cells were shown to promote while CD8+ T-cells impair proliferation of neural progenitor cells…one may speculate that neuropsychiatric symptoms elicited by chronic inflammation may be driven by detrimental changes of neuronal homeostasis. Thus, specific immune modulatory treatment might be beneficial.”

Inflammation is a core issue for brain health, cognition and mood

Case management of neuropsychiatric and neurodegenerative disorders requires discerning and treating the causes of chronic inflammation on an individual case basis. The authors conclude:

Sustained systemic inflammation is a common feature of many autoimmune disorders, and is present in most sepsis survivors. Cognitive impairment is common in sepsis survivors, as well as patients suffering from chronic inflammatory conditions…Moreover, systemic inflammation occurring in a susceptible brain (e.g., patients with AD) may lead to even further disruption in quality of life and activities of daily living. Up to 95% of patients with SLE develop neuropsychiatric dysfunction…In patients with rheumatoid arthritis, the baseline vagal tone of is persistently low, suggesting a possible mechanism for persistent inflammation. Those examples indicate that the normal neuroimmune cross-talk in health can become deleterious during disease, particularly in a primed brain – one with preexistent damage. Recently, cellular, molecular, environmental, and genetic components have been linked to the persistent brain dysfunction of systemic inflammation. Here, we have discussed mechanistic evidence for the intricate interrelation between inflammation and neurodegeneration. Identification of druggable targets derived from these mechanisms holds the promise to prevent long-term disability and improve the quality of life in patients with chronic inflammatory conditions.”

*Note: Transglutaminase-6 antibodies are included in the Wheat/Gluten Proteome Reactivity & Autoimmunity array from Cyrex Laboratories.

Multiple sclerosis, TH17 and vitamin A

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease. Recent studies shed light on its autoimmune component and offer evidence for the use of vitamin A in consideration of the premiere importance of Treg and Th17 or Th40 balance.

Autoimmunity ReviewsAn excellent paper, highly recommended for any practitioner managing autoimmune disorders in general, that was just published in Autoimmunity Reviews examines the balance between pro-inflammatory Th17 cells and regulatory T cells in autoimmune and inflammatory diseases. Commenting on Th17Treg balance in general:

“Th17 and Treg cells have opposite roles in the development of autoimmune and inflammatory diseases. While Th17 cells promote autoimmunity, Treg cells serve to control it and therefore play a very important role in autoimmune pathogenesis by maintaining self- tolerance and by controlling expansion and activation of autoreactive CD4+ T effector cells. The control of Th17/Treg balance appears also critical in the development of these diseases…Developmental pathways of Th17 and Treg cells are reciprocally regulated and can influence the outcome of immune responses, partic- ularly in autoimmune and inflammatory diseases.”

Specifically in regard to multiple sclerosis:

“MS is a chronic inflammatory disease that leads to brain inflammation and that may involve a break in tolerance. Th17 cells are considered to be important in multiple sclerosis pathogenesis. IL-17A gene is overexpressed in biopsy samples taken from the brains of patients with MS and Th17 cells are present in high proportion in active MS lesions. Treg cells are also implicated in MS. It was reported that a disturbance in the development and function of Treg subpopulations and also an altered frequency of Treg cells are associated with disability status in relapsing remitting MS patients. Furthermore, CD39-expressed Treg cells have the potential to suppress IL-17 production and the pathogenic Th17 cells. So in MS pathogenesis, maintaining Th17/Treg balance appears to be critical.”

Balance between Th17 and Treg cellsNo wonder vitamin D has come to the fore lately in the treatment of multiple sclerosis since it is critical for Treg development. The authors conclude with an important statement that embraces all autoimmune conditions in addition to multiple sclerosis:

“Th17 and Treg cells are both implicated in inflammatory and autoimmune diseases. Th17 cells are involved in the induction and propagation of pathologies whereas Treg cells inhibit autoimmunity and are responsible for tolerance against self-antigens. Th17 and Treg cells share common factors, such as TGF-β, that affect their development and generation. The balance between inflammation (Th17 cells) and tolerance (Treg cells) may influence pathology or disease outcomes in autoimmune diseases, including RA and MS. It is though that if this critical balance is deviated in favor of Th17 cells and against Treg cells, the severity of disease could be significantly enhanced. Such contribution justifies developing new therapeutic means to keep an adequate balance between pathogenic Th17 cells and protective Treg cells, for preventing the development and extension of autoimmune and inflammatory diseases.”


Acta Medica IranicaIn light of the above, a paper recently published in the journal Acta Medica Iranica discussing the use of vitamin A to restore Th17/Treg balance in multiple sclerosis is of special interest. The authors note:

“MS is an autoimmune and neurodegenerative disease of the central nervous system. Inflammation in MS leads to both demyelination and axonal loss…The correlation between damage to the central nervous system and inflammatory reactions during progression of the disease can be understood in terms of existing myelin specific autoreactive T cells in the peripheral blood and cerebrospinal fluid (CSF) of MS patients. This “activated state” of myelin-reactive T cells observed in MS patients is associated with up-regulation of adhesion molecules that make these cells more prone to interact with the blood–brain barrier (BBB) and drive an inflammatory response directed against myelin antigens within the CNS. Therefore, any change in immune response induced by CD4+ cells, particularly the imbalance between Th1/Th2 and also Th17/Treg and subsequent changes in their cytokine’s secretion such as IFN-γ, IL-2( Th1), IL-4 (Th2), IL-17(Th17) IL-10 and TGF-β (Treg) can lead to damage and atrophy of the brain…Cytokine changes in MS are characterized by increased levels of IFN-γ, IL-2, and IL- 17 and decreased levels of IL-4, IL-10 and TGF-β.”

So of paramount practical importance…

“CD4+ Treg cells can suppress inflammatory responses and induction or enhancement of creation of their cytokines such as TGF-β represents a potentially interesting option for the treatment of MS. Therefore, therapeutic strategies that lead to shift the immune response reactions from Th1 to Th2 and Th17 to Treg cells may be effective in the treatment of MS. Retinoic acid inhibits Th1 and Th17 polarization and induces the differentiation of Th2 and Treg cells. Other research has demonstrated that all Trans’ retinoic acid (ATRA) causes a shift in gene expression of Th1, and Th17 cytokines and their transcription factors to Th2 and T regulatory cells. This study examines the effect of vitamin A supplementation as synergistic effect on MRI changes, cytokine levels and gene expression in patients with MS.”

(Retinoic acid and ATRA are metabolites of vitamin A.) The authors also state:

Vitamin A and its metabolites such as retinoic acid (RA) regulate immune homeostasis by induction of regulatory T cells. Studies have shown that RA also elicits pro-inflammatory Th1 and Th17 cells’ responses to infection*. Retinoic acid receptor alpha (RARα) is a critical mediator for these effects. These findings demonstrate a functional role for the RA-RARα axis in the development of both regulatory and inflammatory reactions of adaptive immune systemVitamin A deficiency is associated with decreased Th2 responses. Vitamin A supplement inhibits Th1 and promotes Th2 differentiation in vitro and In vivo…Therefore, retinol and its metabolites present promising possibilities to prevent inflammatory reactions, central nervous system degeneration and disease progression.”

Clinical note*: since vitamin A helps fight infection while inducing regulatory T cells to maintain immune balance it is well worthy of consideration in acute, especially mucosal, infections.

Journal of NeuroimmunologyWith these dynamics in mind plus the challenges of nailing a diagnosis of multiple sclerosis, practitioners should be aware of Th40 cells, a new biomarker for MS revealed by a study just now published in the Journal of Neuroimmunology. The authors state:

“Multiple Sclerosis (MS) is a chronic inflammatory, neurodegenerative disease. Diagnosis is very difficult requiring defined symptoms and multiple CNS imaging. A complicating issue is that almost all symptoms are not disease specific for MS. Autoimmunity is evident, yet the only immune-related diagnostic tool is cerebral–spinal fluid examination for oligoclonal bands. This study addresses the impact of Th40 cells, a pathogenic effector subset of helper T cells, in MS.”

They examined MS patients for Th40 cell levels in peripheral blood resulting in findings comparable to autoimmune type 1 diabetes:

“The levels were significantly elevated compared to controls including healthy non-autoimmune subjects and another non-autoimmune chronic disease. Classically identified Tregs were at levels equivalent to non-autoimmune controls but the Th40/Treg ratio still predicted autoimmunity.”


“The cohort displayed a wide range of HLA haplotypes including the GWAS identified predictive HLA-DRB1*1501 (DR2). However half the subjects did not carry DR2 and regardless of HLA haplotype, Th40 cells were expanded during disease. In RRMS [relapsing-remitting MS] Th40 cells demonstrated a limited TCR clonality. Mechanistically, Th40 cells demonstrated a wide array of response to CNS associated self-antigens that was dependent upon HLA haplotype. Th40 cells were predominantly memory phenotype producing IL-17 and IFNγ with a significant portion producing both inflammatory cytokines simultaneously suggesting an intermediary between Th1 and Th17 phenotypes.”

The authors highlight their key conclusions:

  • We describe CD40 as a T cell biomarker, defining Th40 cells, in MS.
  • Th40 cells are significantly elevated regardless of HLA haplotype in MS.
  • Th40 to Treg ratio is more predictive of autoimmunity than either subset alone.
  • Th40 cells from each patient demonstrate unique CNS antigen signatures.

In other words, Th40 cells appear elevated regardless of the genotype of the patient. Unique neuro-antigen autoimmune targets are consistent with the case variability of symptom presentation. Most importantly, the balance between Th40 and Treg cells is decisive, returning us to premiere consideration of interventions that can elevated Treg function.

Multiple sclerosis and gluten

Acta Neurologica ScandinavicaMultiple sclerosis (MS) becomes evident as the silent creeping damage of the immune system’s destruction of myelin crosses the threshold of sensibility. Additional evidence that loss of tolerance to gluten can be a contributing cause in multiple sclerosis is offered in a study published in Acta Neurologica Scandinavica. This deserves reflection because many clinicians seem to disregard that non-celiac gluten sensitivity may present with no other symptoms. The authors state:

“Multiple changes in antibodies against various antigens are found in multiple sclerosis (MS)… We wanted to measure immunoglobulin A (IgA) antibodies to some common food antigens in MS and also IgG against gliadin and gluten.”

They measured serum IgA antibodies were measured against gluten, gliadin, lactoglobulin, lactalbumin, casein and ovalbumin in patients with multiple sclerosis and unafflicted controls. They added measurements of IgG for gluten and gliadin. The data showed a very strong correlation in multiple sclerosis with the antibodies for gluten and milk:

Highly significant increases compared with controls were found for IgA and IgG antibodies against gliadin and gluten. IgA antibodies against casein were significantly increased. Anti-endomycium and anti-transglutaminase antibodies were negative.”

Clinical note: The absence of anti-transglutaminase antibodies means of course that these are non-celiac cases, rather the reaction to gluten was fueling multiple sclerosis.

The authors’ conclusion brings to the mind the issue of compromised intestinal barrier function (‘intestinal permeability’):

“The data presented indicate that there may be a possible moderately increased uptake of some specific proteins from the gut in MS compared with controls.”

Migraine and histamine intolerance, with a link to MS

Journal of the Neurological SciencesMigraine case management requires assessment of multiple contributing causes, and there is mounting evidence that histamine intolerance contributes to migraine and other neuroinflammatory disorders. A study just published in the Journal of the Neurological Sciences presents evidence that treating insufficient DAO activity (diamine oxidase, the enteric enzyme that breaks down histamine) can be an effective therapy for migraine. The authors state:

Histamine has been considered as a chemical mediator of migraine. The degradation is done in two different pathways. One of the enzymes that allow this process is the diamino-oxidase (DAO)… The aim of this study is to identify the prevalence of the deficit in the activity of DAO in patients with migraine, and test the supplementation of this enzyme in a randomized controlled double- blind trial.”

They randomized patients with four to fourteen migraine attacks per month between to receive either placebo or DAO three times per day during one month. Their outcome measures included reduction in hours of pain and the use of other migraine medication. DAO supplementation was effective for migraine in their study subjects:

“We studied 137 patients with migraine, and find the deficit of DAO activity (<80 HDU/ml) in 119 (87%). One hundred patients were randomized and included in the intention- to-treat analysis. Between run-in and first month of treatment, the mean number of hours of pain decreased in both groups but with significant difference in the final control in the group treated with DAO compared with placebo. The use of the acute antimigraine drug was significantly reduced in the DAO but not in placebo group. There were no adverse events in either group.”

Since excess histamine can produce inflammation in the central nervous system and DAO ‘digests’ histamine (see earlier post titled Histamine intolerance), the authors’ conclusion stands to reason:

Deficit in the activity of DAO is very prevalent in population with migraine. The supplementation with the enzyme is effective and safe as a preventive therapy for migraine.”


The Journal of Headache and PainClinicians should be aware that neuroinflammation and loss of immune tolerance can affect more than one nervous system ‘target’ at a time. An interesting case report published in The Journal of Headache and Pain describes multiple sclerosis presenting as a worsening of migraine symptoms:

Multiple sclerosis (MS) is a chronic autoimmune disease that targets myelinated axons in the central nervous system. Headache has been reported as a subtle symptom of the onset of MS, with a variable frequency of 1.6–28.5%; however, it remains unclear whether headache is a true symptom of MS onset. Here, we report the case of a female patient who had a history of migraine without aura and experienced worsening of migraine-headache symptoms as the initial manifestation of MS.”

Subsequent to the initial presentation of migraine the patient developed typical full-blown MS neurological deficits (bilateral numbness of the lower legs, unsteady gait, difficulty in defecation, and urine retention for the past week, etc.). The diagnosis of MS was then confirmed by MRI. Interestingly…

“The cerebrospinal fluid (CSF) analysis performed after admission to exclude other possible infectious causes showed no white cells and normal glucose (70 mg/dL) and protein (26 mg/dL) levels. CSF tests were negative for virus isolation and for Gram stain and culture. No oligoclonal bands were found. Serum analyses for presence of rheumatoid factor (RF), antibodies against nuclear antigen, and anticardiolipin immunoglobulins G and M yielded negative results; in addition, the levels of the C3 (90.7 mg/dL) and C4 (18.5 mg/dL) complement were normal. Furthermore, the anti-HIV and rapid plasma reagin (RPR) tests were negative. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were <0.10 mg/dL.”

Hyperintense MRI lesions of MSPractitioners should notice that the above laboratory markers, including CRP and ESR, were normal in the presence of raging neuroinflammation. The authors advise clinical vigilance:

“To our knowledge, there is no description in the literature of patients presenting with worsening migraine symptoms without neurological signs as the first episode of MS. When the initial symptoms of MS are worsening migraines and changes in headache patterns, they may be discounted as a recurrent event and ignored. Our study suggests that it is important to consider the possibility of MS in patients with worsening migraine symptoms accompanied by episodes of focal deficit and to follow-up these patients regularly.”

They comment on the role of stress in triggering inflammation:

“Many factors can trigger migraine attacks, such as changes in weather, drugs, alcohol, caffeine withdrawal, stress, fatigue, lack of sleep, hormonal therapy, diet, and hunger. In our case, none of the above-mentioned factors was found. We hypothesize that stress causes inflammation in general, and particularly in MS, because stress-related neuropeptides activate the excretion of inflammatory molecules by microglia and mast cells. Although no obvious stress was observed in our case, a hidden stress may have caused the acute MS attacks. As observed in our case, MS may be considered as one of the differential diagnoses of acute-migraine-like episodes.”

Clinicians should bear in mind the authors’ summary of findings:

We conclude that MS with periaqueductal grey matter involvement may present with worsening migraine. It is important to be cautious if any secondary causes exist, especially when the patient has a history of migraine without aura. MS should be one of the differential diagnoses in young women showing a change in headache pattern or poor clinical drug response to migraine treatment accompanied by episodes of focal neurological deficit. Failure to recognize MS may lead to inappropriate treatment and worse prognosis; early diagnosis in patients with MS is essential to improve their clinical outcomes and quality of life.”


Fluids and Barriers of the CNSIn addition to the fact that histamine intolerance can contribute to migraine, a recent study published in the journal Fluids and Barriers of the CNS offers evidence that histamine levels are also increased in multiple sclerosis:

“Multiple sclerosis (MS) is a complex autoimmune disease with inflammation and demyelination within the central nervous system (CNS). Histamine is an ubiquitous inflammatory mediator of numerous physiological processes. Histamine and its receptors have been implicated in multiple sclerosis (MS) disease pathogenesis. We prospectively enrolled 36 MS patients and 19 age and gender-matched healthy volunteers for cerebrospinal fluid (CSF) histamine analysis.”

They found a significant association between histamine levels and MS:

CSF histamine levels in MS patient samples were significantly higher (median: 35.6 pg/ml) than in controls (median: 5.5 pg/ml). In addition, histamine increased with age.”

The tendency for histamine to increase with age is one of the reasons why we tend to have more inflammation and chronic symptoms as the years go by.

This finding links histamine intolerance, migraine and multiple sclerosis. The authors conclude:

“Histamine may be an important factor for both the initiation and maintenance of chronic inflammatory diseases of the central nervous system… This observation encourages a deeper investigation of the role of GM-CSF, granulocytes, macrophages and histamine in MS. Further, histamine may be investigated as diagnostic marker for MS and other inflammatory CNS diseases.”


European Journal of ImmunologyThose who wish to dig deeper into the mechanism by which histamine contributes to autoimmune inflammatory diseases of the central nervous system including MS will appreciate a paper published in the European Journal of Immunology showing that two specific histamine receptors are involved in pathogenesis:

“Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which histamine (HA) and its receptors have been implicated in disease pathogenesis. HA exerts its effects through four different G protein-coupled receptors designated H(1)-H(4). We previously examined the effects of traditional single HA receptor (HR) knockouts (KOs) in experimental allergic encephalomyelitis (EAE), the autoimmune model of MS. Our results revealed that H(1) R and H(2) R are propathogenic, while H(3) R and H(4) R are antipathogenic. This suggests that combinatorial targeting of HRs may be an effective disease-modifying therapy (DMT) in MS. To test this hypothesis, we generated H(1) H(2) RKO and H(3) H(4) RKO mice and studied them for susceptibility to EAE.”

In other words, they produced two sets of study subjects, one without H(1)and H(2) receptors, the other without H(3)and H(4) receptors and found that neuroinflammation was much less severe when the former pair were ‘turned off’:

“Compared with wild-type (WT) mice, H(1) H(2) RKO mice developed a less severe clinical disease course, whereas the disease course of H(3) H(4) RKO mice was more severe. H(1) H(2) RKO mice also developed less neuropathology and disrupted blood brain barrier permeability compared with WT and H(3) H(4) RKO mice. Additionally, splenocytes from immunized H(1) H(2) RKO mice produced less interferon(IFN)-γ and interleukin(IL)-17.”

IL-17, of course, is a ‘hallmark’ autoimmune cytokine. The authors advance the reduction of histamine signalling as a ‘disease-modifying therapy for MS:

“These findings support the concept that combined pharmacological targeting of HRs may be an appropriate ancillary DMT in MS and other immunopathologic diseases.”

Autoimmune inflammation can elevate serum 1,25-dihydroxy vitamin D

PLOS ONEAutoimmune inflammation, though a pervasive scourge, seems to often elude diagnosis. I have found that patients with an autoimmune component to their case often have elevated 1,25-dihydroxy vitamin D (calcitriol). This is not the 25-hydroxy vitamin D3 (cholecalciferol metabolite) that we always test to determine vitamin D3 sufficiency. Often with normal and even low vitamin D3 levels, patients with various degrees of active autoimmunity are testing for elevated 1,25-dihydroxy vitamin D levels. Now research published in PLOS One (Public Library of Science) shows how autoimmune inflammation and elevated 1,25-dihydroxy vitamin D are associated. The authors sought to elucidate the mechanism by which 1,25-Dihydroxyvitamin D3 suppresses autoimmune inflammation:

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) suppresses autoimmunity and inflammation; however, the mechanism of its action has not been fully understood. We sought in this study to determine whether the anti-immune/anti-inflammatory action of 1,25(OH)2D3 is in part mediated through an interplay between 1,25(OH)2D3 and toll-like receptor (TLR)7/8 signaling.”

To do so they used experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis, and found that…

1,25(OH)2D3 treatment prior to and/or following experimental autoimmune encephalomyelitis (EAE) induction effectively reduced inflammatory cytokine expression in the spinal cord and ameliorated EAE. These effects were accompanied with a reduction in expression of several TLRs with the most profound effect observed for TLR8. The expression of TLR8 adaptor protein MyD88 was also significantly reduced by 1,25(OH)2D3.”

Moreover, 1,25(OH)2D3 also reduced the inflammatory expression of monocytes (white blood cells that becomes activated as macrophages:

“1,25(OH)2D3 treatment not only significantly reduced TLR8 expression but also the expression or activity of MyD88, IRF-4, IRF-7 and NF-kB in monocytes challenged with TLR8 ligands.”

Bear in mind that NF-kB is a ‘final common pathway’ for inflammation in autoimmunity. And regarding the clinically important pro-inflammatory cytokines TNF-α and IL-1β:

“As a result of inhibition on TLR8 signaling cascade at various stages, 1,25(OH)2D3 significantly diminished the TLR8 target gene expression (TNF-α and IL-1β).”

In their conclusion the authors focus on the implied mechanism for the anti-inflammatory effects of 1,25(OH)2D3:

“In summary, our novel findings suggest that TLR8 is a new target of 1,25(OH)2D3 and may mediate the anti-inflammatory action of 1,25(OH)2D3. Our findings also point to a destructive role of TLR8 in EAE and shed lights on pathogenesis of multiple sclerosis.”

Clinical note: If you’ve read this far you probably know how I felt on seeing this, considering all the patients I’m seeing with elevated lab results for 1,25(OH)2D3. In a personal e-mail communication the corresponding author Xuezhong Qin, Ph.D., Associate Professor in the Division of Regenerative Medicine at Loma Linda University School of Medicine states:

Serum 1,25D is frequently elevated in patients with autoimmune inflammatory diseases such as IBD. It is likely this is caused by activated macrophages which express [a] high level of CYP27b1.”

I encourage clinicians to measure 1,25-dihydroxy vitamin D (calcitriol) in their patients for whom autoimmunity seems likely as a meaningful metric for case management and to add to the body of knowledge on autoimmune inflammation.

Depression, aging and brain inflammation: indications for sustainable treatment

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Depression and aging, not only diminished cognitive function but the level of physiological competence throughout the body, have brain inflammation in common. This fact is of premiere importance when designing rational treatment plans for both depression and high functioning longevity. Consider an important paper just published in the journal Depression and Anxiety which the authors the association of major depression and suicidal ideation with inflammatory biomarkers:

Depression and Anxiety“Patients with major depressive disorder (MDD) who attempt or complete suicide have elevated inflammation compared to nonsuicidal patients with MDD. However, greater severity of depression and the medical lethality of suicide attempts could account for such elevated inflammation in suicide attempters and suicide completers…To clarify, we measured inflammatory markers in patients with MDD with and without high levels of suicidal ideation and in nondepressed controls (N = 124). Levels of suicidal ideation, depression severity, and recent suicide attempts were assessed by structured clinical interviews. A composite score including the inflammatory markers tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and C-reactive protein (CRP) was used as an inflammatory index.”

Their data showed a correlation supporting their striking conclusion:

“Patients with MDD and high suicidal ideation had significantly higher inflammatory index scores than both controls…Suicidal ideation may be uniquely associated with inflammation in depressed patients.”


Comprehensive PsychiatryWe should bear in mind that these inflammatory cytokines and CRP are not specific for depression. Moreover, there is a strong association between psychological stress and trauma and inflammatory biomarkers. A study just published in Comprehensive Psychiatry adds to the body of evidence supporting the relationship between depression, inflammation and stress:

“Taking into consideration the previous evidence of revealing the relationship of early life adversity, major depressive disorder (MDD), and stress-linked immunological changes, we recruited 22 MDD patients with childhood trauma exposures (CTE), 21 MDD patients without CTE, and 22 healthy controls without CTE, and then utilized a novel cytokine antibody array methodology to detect potential biomarkers underlying MDD in 120 peripheral cytokines and to evaluate the effect of CTE on cytokine changes in MDD patients.”

Their data showed a particular correlation between major depression with childhood trauma and inflammatory cytokines:

“Depressed individuals with CTE (TD patients) were more likely to have higher peripheral levels of those cytokines. Severity of depression was associated with plasma levels of certain increased cytokines; meanwhile, the increased cytokines led to a proper separation of TD patients from normal controls during clustering analyses. Our research outcomes add great strength to the relationship between depression and cytokine changes and suggest that childhood trauma may play a vital role in the co-appearance of cytokine changes and depression.”


Progress in Neuro-Psychopharmacology and Biological PsychiatryInflammatory cytokines come into play with bipolar disorder too as expressed in a paper published in Progress in Neuro-Psychopharmacology and Biological Psychiatry:

“An emerging body of evidence points to impairments in neuroplasticity, cell resilience and neuronal survival as the main neuropathological correlates of BD. It has been suggested that inflammatory cytokines, particularly TNF-α may play a critical role in this process.”

They examined evidence suggesting that TNF-α may regulate brain cell loss related to bipolar disorder:

“Current evidence suggests that an increase in serum levels of TNF-α takes place during manic and depressive episodes.”

And we’ll see that it is crucial for clinicians to be aware of the central role played by nuclear factor kappa-beta (NF-kB) in driving inflammatory cytokines in the brain in both depression and aging.


American Journal of PsychiatryMen with depression and history of early life stress are featured in a study published in The American Journal of Psychiatry. They evaluated innate immune system activation following psychosocial stress in patients with major depression and increased early life stress by measuring plasma interleukin (IL)-6, lymphocyte subsets, and DNA binding of nuclear factor (NF)-kB in peripheral blood mononuclear cells in medically healthy male subjects with current major depression and increased early life stress and comparing them to nondepressed male comparison subjects before and after completion of a stress test. They found that…

“Trier Social Stress Test-induced increases in IL-6 and NF-κB DNA-binding were greater in major depression patients with increased early life stress and independently correlated with depression severity…Male major depression patients with increased early life stress exhibit enhanced inflammatory responsiveness to psychosocial stress, providing preliminary indication of a link between major depression, early life stress and adverse health outcomes in diseases associated with inflammation.”


PNAS Vol 105 No 2Many reading this are aware that the proinflammatory cytokine IL-1β is a ‘mother cytokine’ in the inflammatory cascade involved in most autoimmune inflammation. The authors of a fascinating study published in PNAS (Proceedings of the National Academy of the Sciences of the USA) demonstrate that IL-1β impairs neurogenesis in the hippocampus of the adult brain. Bear in mind that the hippocampus is the primary locus for short-term memory and adrenal regulation, and is a therapeutic target in the treatment of depression. The authors state:

“The profound consequences of stress exposure, defined as disturbances of physiological homeostasis, include a detrimental impact on certain aspects of brain function. In particular, uncontrollable stress is a major contributing factor for neuropsychiatric disorders such as major depression and posttraumatic stress disorders. Alterations at the cellular level in the hippocampus have been linked to the pathophysiology of stress-related mood disorders. Many studies demonstrate that stressful experiences suppress hippocampal neurogenesis, which could contribute to the hippocampal atrophy observed in depressed patients. In contrast, antidepressant treatment increases hippocampal neurogenesis, blocks the antineurogenic effects of stress, and reduces or even reverses hippocampal atrophy. Recent studies demonstrate that new hippocampal neurons are required for the actions of antidepressants in behavioral models of depression and anxiety with some exceptions.”

By administering exogenous IL-1β they compiled in vivo and in vitro evidence that stress exerts its effects on the hippocampus through activation of IL-1β signaling:

“Here, we demonstrate an essential role for the proinflammatory cytokine IL-1β. Administration of IL-1β or acute stress suppressed hippocampal cell proliferation. Blockade of the IL-1β receptor, IL-1RI, by using either an inhibitor or IL-1RI null mice blocks the antineurogenic effect of stress and blocks the anhedonic behavior caused by chronic stress exposure. In vivo and in vitro studies demonstrate that hippocampal neural progenitor cells express IL-1RI and that activation of this receptor decreases cell proliferation via the nuclear factor-κB signaling pathway. These findings demonstrate that IL-1β is a critical mediator of the antineurogenic and depressive-like behavior caused by acute and chronic stress.”


PNAS Vol 107 No 6Now we move further into the clinically extremely important role of nuclear factor-κB (NF-κB) signaling in autoimmune and brain inflammation. In a study also published in PNAS the authors build on the earlier insights regarding IL-1β and note:

“Exposure to stress and depression can result in atrophy of limbic brain regions that control emotion and mood, including inhibition of neurogenesis in the adult hippocampus…A role for proinflammatory cytokines is supported by a recent report that IL-1β signaling is necessary and sufficient for the antineurogenic and behavioral effects of stress. One possible signaling cascade that could mediate the effects of IL-1β is NF-κB, which is activated by IL-1β and other cytokines both in peripheral immune cells and in the brain. Chronic stress enhances the activation of NF-κB in response to inflammatory stimuli, and social stress increases NF-κB signaling in healthy subjects and produces an exaggerated response in depressed patients…In the present study, we investigate the role of NF-κB in the cellular and behavioral responses to acute and chronic stress. The results demonstrate that the inhibition of neurogenesis by stress occurs via activation of NF-κB in NSCs and that stress-induced anhedonia, a core symptom of depression, is dependent on NF-κB.”

Stress, depression, IL-1β and NF-κBTheir conclusion points to NF-κB signaling as a particularly important therapeutic target, especially considering that there are natural agents that can help:

Stress inhibition of neurogenesis in the adult hippocampus, which has been implicated in the prodepressive effects of stress, is blocked by administration of an inhibitor of NF-κB. Further analysis reveals that stress activates NF-κB signaling and decreases proliferation of neural stem-like cells but not early neural progenitor cells in the adult hippocampus. We also find that depressive-like behaviors caused by exposure to chronic stress are mediated by NF-κB signaling. Together, these data identify NF-κB signaling as a critical mediator of the antineurogenic and behavioral actions of stress and suggest previously undescribed therapeutical targets for depression.


Journal of NeuroscienceThen how fascinating is it that researchers publishing in The Journal of Neuroscience demonstrate that darkness (light deprivation), known to induce depression, does so through the NF-κB signaling pathway:

Depression has been tightly linked to disturbances of circadian rhythms, and alterations in emotional states have been found to affect circadian rhythms. Seasonal affective disorders, a subtype of major depressive disorders related to seasonal variations in natural light levels, occur at higher prevalence in the more northern latitudes, in regions with extended periods of restricted sunlight…Disturbed day–night cycles and altered sleep patterns are also known to affect the rhythmic intradiem oscillations of elements of the immune system, such as IL-6. Interestingly, elevated inflammatory parameters, including IL-6, are also frequently observed in depressed patients…We therefore decided to use a particular case of circadian disruption, light deprivation in the DD paradigm, and to examine the potential involvement of inflammatory signaling in the associated depressive state.”

Their data showed not only IL-6 activity, but that NF-κB signaling again plays a pivotal role in depression induced by light deprivation:

“We find that after 4 weeks of DD, mice display depression-like behavior, which is paralleled by reduced hippocampal cell proliferation. This chronobiologically induced depressive state is associated with elevated levels of plasma IL-6 (interleukin-6) and IL-6 and Il1-R1 (interleukin 1 receptor, type I) protein levels in the hippocampus and also alters hippocampal protein levels of the clock genes per2 and npas2. Using pharmacological blockers of the NF-κB pathway, we provide evidence that the effects of DD on depression-like behavior, on hippocampal cell proliferation, on altered expressional levels of brain and plasma IL-6, and on the modulation of clock gene expression are mediated through NF-κB signaling. Moreover, NF-κB activity is enhanced in hippocampal tissue of DD mice. Mice with a deletion of IL-6, one of the target genes of NF-κB, are resistant to DD-induced depression-like behavior, which suggests a pivotal role for this cytokine in the constant darkness mouse model of depression.”


Brain, Behavior, and ImmunityAnd increased NF-κB pathway signaling is also reported in women suffering childhood abuse-related post-traumatic stress disorder in a study published in the journal Brain, Behavior, and Immunity:

“In addition to neuroendocrine changes PTSD pathophysiology may also involve dysfunction of the innate immune inflammatory system. PTSD patients have been found to exhibit increased concentrations of circulating inflammatory markers such as C-reactive protein and interleukin-6, suggesting dysfunction of the innate immune inflammatory system.”

So the authors examined NF-κB activity obtained from 12 women with childhood abuse-related PTSD and 24 healthy controls. They also measured glucocorticoid sensitivity of monocytes in a clever wsy by observing the amount of dexamethasone needed to suppress lipopolysaccharide-induced tumor necrosis factor-alpha production by 50%. Sure enough, NF-κB was pivotal here too:

Women with PTSD displayed increased NF-κB pathway activity compared to controls that was positively correlated with PTSD severity (determined by PTSD symptom severity scale). Increased NF-κB pathway activity was associated with increased whole blood monocyte DEX IC50 (i.e. decreased sensitivity of monocytes to glucocorticoids) across all participants.”

In other words, the PTSD symptoms were promoted by immune inflammatory acitivity hinging on NF-κB signaling. The authors conclude:

“These findings suggest that enhanced inflammatory system activity in participants with childhood abuse-related PTSD is observable at the level of NF-κB, and that in general decreased immune cell glucocorticoid sensitivity may contribute to increased NF-κB pathway activity. Enhanced inflammation may contribute to co-morbid somatic disease risk in persons with childhood abuse-related PTSD.”


Journal of NeuroinflammationMore evidence that NF-κB plays a key role in central nervous system inflammation is offered by a study published in the Journal of Neuroinflammation. The authors observe by way of background:

Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system (CNS). The development of autoimmune diseases such as MS requires the coordinated expression of a number of pro-inflammatory genes. These factors…encompass a variety of cytokines, chemokines, adhesion molecules as well as other inflammatory factors…Nuclear factor (NF-) kappaB (NF-κB) is essential for both innate and adaptive immunity…and is involved in many inflammatory processes…The transcriptional activation of the NF-κB pathway is controlled by the inhibitor of NF-κB, IκB…Besides the involvement of NF-κB in T-cell proliferation and activation, it is also a key element in coordinately controlling gene expression during monocyte/macrophage activation. In particular the macrophage-derived cytokines interleukin-1beta (IL-1 β) and tumor necrosis factor-alpha (TNF-α), are potent activators of NF-κB. In turn, their expression is controlled by NF-κB thus resulting in a positive feedback loop. Hence, NF-κB signalling pathways may play a pivotal role in activating myeloid cell function during autoimmune inflammation. In addition to its central mediatory function in cytokine expression, NF-κB in myeloid cells may be induced by physical as well as oxidative stress to cells, e.g. via the inducible nitric oxide synthase (iNOS) or cyclooxygenase-2 (COX-2).”

The authors shed light on the role of NF-κB in CNS inflammation by examining experimental autoimmune encephalomyelitis (MOG-EAE, a well established experimental model for autoimmune demyelination of the CNS) in mice whose NF-κB inhibitor IκB was rendered genetically inactive. They found that…

“…loss of IκB in monocytes and macrophages leads to constitutive expression of NF-κB. In turn, this results in an increased expression of NF-κB regulated monocyte/macrophage cytokines and subsequently enhanced macrophage infiltration and iNOS expression in the spinal cord…Thus macrophage derived, NF-κB dependent cytokines may play a pivotal role in the pathogenesis of EAE and determine the outcome of autoimmune inflammation in the CNS without interfering with Th1 and Th17 T-cell responses. Our findings suggest that NF-κB in myeloid cells is a master regulator for regulation of inflammation and tissue damage in autoimmune inflammation of the CNS.”

Consider how surprisingly decisive the NF-κB activity is since it determined the outcome of the autoimmune inflammation without modifying the Th17 response. These authors conclude:

“In summary, myeloid cell derived NF-κB plays a crucial role in autoimmune inflammation of the CNS and drives a pathogenic role of monocytes and macrophages independently from T-cells.”


PNAS Vol 109 No 45T-helper (Th) 17 cells and the proinflammatory cytokine IL-17 are a ‘common pathway’ in autoimmunity. While the previous paper showed that NF-κB can drive autoimmune inflammation by other means as well, another study recently published in PNAS shows that NF-κB also promotes Th17 differentiation. The authors state:

IL-17–producing CD4 T cells play a key role in immune responses against extracellular bacteria and autoimmunity. Nuclear factor κB (NF-κB) is required for T-cell activation and selected effector functions, but its role in Th17 differentiation is controversial.”

They used genetic models to demonstrate that NF-κB signaling controls survival and proliferation of activated T cells, and has an additional role in promoting completion of Th17 differentiation. Specifically the CARD-containing MAGUK protein 1 (CARMA1)is an adapter TCR/NF-κB signaling, resulting in the production of the pro-inflammatory cytokines IL-17A, IL-17F, IL-21, IL-22, IL-23R, and CCR6…

“Consistent with these data, CARMA1-KO [knockout] mice were resistant to experimental autoimmune encephalomyelitis…Our results demonstrate that TCR/CARMA1/NF-κB controls completion of Th17 differentiation by enabling chromatin accessibility of Th17 effector molecule loci.”

Annals of The New York Academy of Sciences Vol 1179Moreover, NF-κB and pro-inflammatory cytokines contribute to major depression by altering glucocorticoid receptor function as presented in a paper published in the Annals of The New York Academy of Sciences:

“Data suggest that the activation of immune responses and the release of inflammatory cytokines may play a role in the pathophysiology of major depression. One mechanism by which cytokines may contribute to depression is through their effects on the glucocorticoid receptor (GR)…Relevant to the GR, cytokines have been shown to decrease GR expression, block translocation of the GR from cytoplasm to nucleus, and disrupt GR-DNA binding through nuclear protein-protein interactions. In addition, cytokines have been shown to increase the expression of the relatively inert GR beta isoform.

Clinicians take note: this is an important dimension to consider in assessing HPA and adrenocortical function and cortisol effectiveness. Cortisol levels might be looking OK but not working properly. Regarding NF-κB:

“Specific cytokine signaling molecules that have been shown to be involved in the disruption of GR activity include p38 mitogen-activated protein kinase…and signal transducer and activator of transcription (STAT)5, which binds to GR in the nucleus. Nuclear factor-κB (NF-κB) also has been shown to lead to GR suppression through mutually inhibitory GR-NF-κB nuclear interactions.”


“Interestingly, several antidepressants have been shown to enhance GR function, as has activation of protein kinase A (PKA). Antidepressants and PKA activation have also been found to inhibit inflammatory cytokines and their signaling pathways, suggesting that drugs that target both inflammatory responses and the GR may have special efficacy in the treatment of depression.”


Inflammation in the hypothalamus drives aging throughout the body

Nature Vol 496 No 7448To top it all off, there is emerging evidence that inflammation enacted by NF-κB in the brain, specifically the hypothalamus, drives many aspects of aging throughout the body. In what has been described as “a major breakthrough in ageing research”, by David Sinclair, a molecular biologist at Harvard Medical School, researchers publishing in the esteemed journal Nature reveal how…

“…the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IκB kinase-β (IKK-β), nuclear factor κB (NF-κB) and related microglia–neuron immune crosstalk.”

Using several models they were able to slow aging and extend lifespan by preventing aging-related hypothalamic or brain IKK-β and NF-κB activation. They also demonstrated that IKK-β and NF-κB inhibit gonadotropin-releasing hormone (GnRH), a ‘master switch’ hormone for the whole body, causing a decline in hypothalamic GnRH. Moreover, they showed that GnRH treatment ameliorated aging-impaired neurogenesis and slowed down aging. Commenting on this study, another author reporting in the same journal noted:

“The area of the brain that controls growth, reproduction and metabolism also kick-starts ageing…Dongsheng Cai, a physiologist at Albert Einstein College of Medicine in New York, and his colleagues tracked the activity of NF-κB…They found that the molecule becomes more active in the brain area called the hypothalamus as a mouse grows older…Further tests suggested that NF-κB activity helps to determine when mice display signs of ageing. Animals lived longer than normal when they were injected with a substance that inhibited the activity of NF-κB in immune cells called microglia in the hypothalamus. Mice that received a substance to stimulate the activity of NF-κB died earlier. “We have provided scientific evidence for the concept that systemic ageing is influenced by a particular tissue in the body,” says Cai.”

NF-kB activation in neurons in the hypothalamusDavid Cai, the lead author, also states:

Inflammation involves hundreds of molecules, and NF-κB sits right at the center of that regulatory map…The mice showed a decrease in muscle strength and size, in skin thickness, and in their ability to learn — all indicators of aging. Activating this pathway promoted systemic aging that shortened the lifespan.”

Also noted by David Sinclair:

“…a key finding is that blocking the effects of NF-κB produced anti-ageing effects even when it was done in middle age.”

The authors state in their conclusion:

“…the hypothalamus has a programmatic role in ageing development via immune–neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems.”

And in another comment in the same edition of Nature:

Inflammation-activated signalling pathways in the brain’s hypothalamus control the production of ageing-related hormones. This finding provides a link between inflammation, stress responses and systemic ageing.”

This installment presents a few drops from an ocean of science implicating brain inflammation as a key factor in cognitive and emotional disorders and global impairments in physiological competence, including loss of function associated with aging. Forthcoming posts will present studies demonstrating resources for sustainable treatment of NF-κB driven inflammation and autoimmunity.

Vitamin D is an independent risk factor for multiple sclerosis

Yet more evidence for the importance of immune regulation by vitamin D is presented in a paper just published in the journal Neurology. This study investigates the association between vitamin D and central nervous system (CNS) demyelination, the pathological process by which the fatty conductive nerve ‘insulation’ is damaged in disorders like multiple sclerosis. The authors set out to…

“…examine whether past and recent sun exposure and vitamin D status (serum 25-hydroxyvitamin D [25(OH)D] levels) are associated with risk of first demyelinating events (FDEs) and to evaluate the contribution of these factors to the latitudinal gradient in FDE incidence in Australia.”

Over a period of three years they compared 216 subjects aged 18–59 years with a FDE to 395 controls matched for age, sex, and study region who had no CNS demyelination. Besides self-reported sun exposure by life stage the gathered objective measures of skin type and sun related damage, along with vitamin D status. Not surprisingly…

Higher levels of past, recent, and accumulated leisure-time sun exposure were each associated with reduced risk of FDE… Higher actinic skin damage and higher serum vitamin D status were independently associated with decreased FDE risk. Differences in leisure-time sun exposure, serum 25(OH)D level, and skin type additively accounted for a 32.4% increase in FDE incidence from the low to high latitude regions.”

There was a 93% decrease in first demyelinating events for every 10 nmol/L increase in serum 25(OH)D). The authors conclude:

Sun exposure and vitamin D status may have independent roles in the risk of CNS demyelination. Both will need to be evaluated in clinical trials for multiple sclerosis prevention.”

Should you take Vitamin D for multiple sclerosis?

Current Neurology & Neuroscience ReportsThe ‘full-disclosure’ answer is that it depends upon what your lab tests reveal, taking into consideration that people with autoimmune disease may require higher amounts due to polymorphisms (genetic variants) of the vitamin D receptor. But as this paper published last month in Current Neurology & Neuroscience Reports begins:

“A relationship between vitamin D and several diseases, including multiple sclerosis (MS), has recently received interest in the scientific community. Vitamin D appears to have important actions beyond endocrine function, particularly for the immune system. Risk of development of MS, as well as disease severity, has been associated with vitamin D in a variety of studies.”

The authors conclude their review by stating:

“Given the current evidence of the potential benefits of vitamin D, it appears to be reasonable and safe to consider vitamin D supplementation at dosing adequate to achieve normal levels in patients with MS.”

The autoimmune aspect of cardiovascular disease and Th17/Treg imbalance

Clinical ImmunologyCardiovascular disease, an inflammatory disorder, is a leading cause of death and the autoimmune component is one of the most important and in general practice, overlooked, aspects. Consider this paper published not long ago in the journal Clinical Immunology. As the authors state,

Atherosclerosis is a chronic inflammatory disease regulated by T lymphocyte subsets.” [‘T lymphocyte subsets’ refers to the different categories of lymphocytes that participate in immune reactions.]

Regulatory T cells (Treg) ‘referee’ the immune response and quiet inflammation. Vitamin D is necessary for their production. Th1 refers to the lymphocytes that express the ‘innate’, cell-mediated aspect of the immune response; Th2 is the ‘adaptive’, humoral (antibody) mediated aspect. Th17 cells are a more recently recognized subtype that play a potent role in the immune system’s inflammatory attack.

“Recently, CD4+CD25+Foxp3+ regulatory T (Treg) cells and Th17 cells have been described as two distinct subsets from Th1 and Th2 cells and have the opposite effects on autoimmunity. Th17/Treg balance controls inflammation and may be important in the pathogenesis of plaque destabilization and the onset of acute coronary syndrome [ACS, including unstable angina (UA) and acute myocardial infarction (AMI)].”

The authors investigated this by assessing Th17/Treg functions by cell numbers, related cytokine secretion and their  transcription factors in patients suffering from heart attacks, angina and control subjects free of heart disease. Their data made a strong impression:

“The results demonstrated that patients with ACS revealed significant increase in peripheral Th17 number, Th17 related cytokines (IL-17, IL-6 and IL-23) and transcription factor levels and obvious decrease in Treg number, Treg related cytokines (IL-10 and TGF-β1) and transcription factor (Foxp3) levels as compared with patients with SA and controls. Results indicate that Th17/Treg functional imbalance exists in patients with ACS, suggesting a potential role for Th17/Treg imbalance in plaque destabilization and the onset of ACS.”

In other words, the inflammatory process of cardiovascular disease that culminates in the rupture of a vulnerable plaque, which is the precipitating event for a heart attack, expresses this Th17/Treg functional imbalance.

Biochemical and Biophysical ResearchYou may have read earlier posts discussing oxidized LDL (ox-LDL) as a fundamental feature of cardiovascular disease and a valuable laboratory marker. This fascinating paper published recently in the journal Biochemical and Biophysical Research Communications that reports on the relationship between ox-LDL and Th17/Treg balance.

Oxidized low-density lipoprotein (ox-LDL) is an instrumental factor in atherogenesis…CD4+CD25+ regulatory T (Treg) cells and Th17 cells, subsets of T-helper cells, play important roles in peripheral immunity and their imbalance leads to the development of tissue inflammation and autoimmune diseases…To explore the shift of Th17/Treg balance in ACS [acute coronary syndrome] patients and the effect of ox-LDL on the balance, we examined the frequencies of Th17 and Treg cells, key transcription factors and relevant cytokines in patients with AMI [acute myocardial infarction = heart attack], UA [unstable angina], stable angina (SA) and controls.”

What did their data show about the connection between these immune cells and inflammatory cardiovascular disease?

“Our study demonstrated that ACS patients have shown a significant increase of Th17 frequency, RORγt expression and serum Interleukin 17 (IL-17), and a obvious decline of Treg frequency, Foxp3 expression, suppressive function, and serum IL-10. Serum ox-LDL positively correlated with the frequency of Th17 cells and negatively correlated with the frequency of Treg cells…. Treg and Th17 cells from ACS patients were significantly more susceptible to ox-LDL-mediated alterations.

Take a moment to appreciate the profound significance of this for the evaluation and treatment of cardiovascular disease. Cholesterol levels can be high in the absence of CVD, but when it is damaged by oxidation it somehow participates in the inflamed lesions of the vessel wall that are the basic characteristic of condition…

“Th17/Treg numerical and functional imbalance exists in ACS patients, and ox-LDL has a direct effect on Th17/Treg imbalance which may contribute to the occurrence of ACS.”

Scandinavian Journal of ImmunologyHow else might Th17/Treg imbalance manifest in cardiovascular disease? A study published this year in the Scandinavian Journal of Immunology reveals its role in idiopathic dilated cardiomyopathy, a fairly common cause of heart failure (the enlarged heart fails to pump properly).

“To assess whether Treg/Th17 balance was broken in patients with idiopathic dilated cardiomyopathy (DCM). We studied 25 patients who were diagnosed as idiopathic DCM (18 men and seven women, mean age 35.6 ± 5.2) and 25 normal persons (18 men and seven women, mean age 33.8 ± 4.9). Then, we detected Treg/Th17 functions on different levels including cell frequencies, related cytokine secretion and key transcription factors in patients with idiopathic DCM and controls.”

What did their data show?

“The results demonstrated that patients with idiopathic DCM revealed significant increase in peripheral Th17 number, Th17-related cytokines (IL-17, IL-6, IL-23) and transcription factor (RORγt) levels and obvious decrease in Treg number, Treg-related cytokines (TGF-β1 and IL-10) and transcription factor (Foxp3) levels when compared to normal persons. Results indicated that Treg/Th17 functional imbalance existed in patients with idiopathic DCM, suggesting a potential role for Treg/Th17 imbalance in the development of idiopathic DCM.”

NephrologyWe can also see that this is a mechanism promoting adverse cardiovascular events when uric acid increases in the bloodstream, such as when people undergo dialysis, from a paper published not long ago in the journal Nephrology.

Adverse cardiovascular events resulting from accelerated atherosclerosis are the leading cause of mortality in uraemic patients on maintenance haemodialysis (MHD). Chronic inflammation due to antigen-specific responses is an important factor in the acceleration of atherosclerosis...The aim of the present study was to assess the Treg/Th17 pattern in uraemic patients on MHD and to explore the significance of Treg/Th17 imbalance in the development and outcome of acute cardiovascular events.”

Their findings offer fascinating insight into the link between uric acid and cardiovascular inflammation:

“Patients with uraemia exhibited an obvious imbalance of Treg/Th17 function when compared to the normal control group, displaying increased peripheral Th17 frequency, Th17-related cytokines (interleukin [IL]-17, IL-6 and IL-23) and RORγt mRNA levels. These patients also displayed decreased Treg frequency, Treg-related cytokines (IL-10, transforming growth factor-β1) and Foxp3 mRNA levels…It was also observed that the imbalance of Treg/Th17 was not only consistent with the cardiovascular disease but also correlated with a microinflammatory state.”

Clinicians and patients should bear their concluding point in mind:

“This Th17/Treg imbalance might act synergistically with microinflammation on immune-mediated atherosclerosis and contribute to the high incidence of adverse cardiovascular events.”

Clinical & Experimental ImmunologyI would like to note the evidence that Th17/Treg imbalance also plays a role in autoimmune disease associated with organ transplantation since a case this year involving autoimmune attack on the nerves regulating the heartbeat followed by another autoimmune inflammatory reaction to the pacemaker (Dressler’s syndrome). The authors of a paper published in Clinical and Experimental Immunology state:

“…it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD [autoimmune disease] or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL-6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection…”

They sum up their extensive review by concluding:

Interleukin 17 is a pleiotropic cytokine with multiple proinflammatory functions that is likely to be involved in either the causation or progression of inflammatory diseases and transplant rejection in humans. Regulatory T cells are an anti-inflammatory lineage of T cells… It is possible that acute flares of autoimmune diseases or acute episodes of transplant rejection may be explained by a change in the relative dominance of these pathways…”

European Journal of ImmunologyWhat resources can we turn to for correcting Th17/Treg imbalances? A fascinating paper just published in the European Journal of Immunology explains how the proinflammatory cytokine IL-6 (Interleukin-6) is a regulator of Th17/Treg.

“IL-6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL-6 has a very important role in regulating the balance between IL-17-producing Th17 cells and regulatory T cells (Treg). The two T-cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T-cell responses.”

The authors explain the pivotal role played by IL-6 in determining the relative balance of autoimmune inflammation-promoting Th17 versus the anti-inflammatory Treg cells:

“IL-6 induces the development of Th17 cells from naïve T cells together with TGF-β; in contrast, IL-6 inhibits TGF-β-induced Treg differentiation. Dysregulation or overproduction of IL-6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology.”

Their conclusion offers a welcome insight in that we have evidence-based physiological interventions that act to regulate IL-6:

“Given the critical role of IL-6 in altering the balance between Treg and Th17 cells, controlling IL-6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases.”

Mucosal ImmunologyFurther evidence for the pivotal role of IL-6 in regulating T17 and Treg balance is found in an interesting paper published in the journal Mucosal Immunology that points out the same process in inflammatory bowel disease:

T helper (Th)17 cells have been shown to play a role in the pathogenesis of inflammatory and autoimmune diseases including inflammatory bowel diseases (IBD). It is now well established that although transforming growth factor (TGF)-beta alone induces FoxP3+ regulatory T (Treg) cells, TGF-beta and interleukin (IL)-6, acting in concert, induce differentiation of mouse naive T cells into Th17.”

Going a step further, they were able to discern that IL-6 can act alone in promoting the development of Th17 cells:

“We found that upon activation, Treg cells induce CD4+CD25- naive T cells or Treg cells themselves to differentiate into Th17 in the presence of IL-6 alone without exogenous addition of TGF-beta.”

Journal of ImmunologyAnother clue to some of the therapies we can use is suggested by a study published in the Journal of Immunology on the ability of retinoic acid (RA), a metabolite of Vitamin A, to inhibit the expression of IL-6. The authors first observe:

“The de novo generation of Foxp3+ regulatory T (Treg) cells in the peripheral immune compartment and the differentiation of Th17 cells both require TGF-β, and IL-6 and IL-21 are switch factors that drive the development of Th17 cells at the expense of Treg cell generation.”

The authors elucidate the pathways by which Treg can be promoted and IL-6 inhibited by retinoic acid (RA):

“Herein we show that RA enhances TGF-β signaling…and this results in increased Foxp3 [Treg] expression even in the presence of IL-6 or IL-21. RA also inhibits the expression of IL-6R{alpha}…and thus inhibits Th17 development. In…experimental autoimmune encephalomyelitis…RA suppresses the disease very efficiently by inhibiting proinflammatory T cell responses, especially pathogenic Th17 responses.”

Their conclusion is well worth keeping in mind when we are researching a treatment plan for the autoimmune component of cardiovascular disease or any other autoimmune condition:

“These data not only identify the signaling mechanisms by which RA can affect both Treg cell and Th17 differentiation, but they also highlight that in vivo during an autoimmune reaction, RA suppresses autoimmunity mainly by inhibiting the generation of effector Th17 cells.”