Summary: Adjuvants are agents added to vaccines to heighten the immune system response to the primary antigen. The video below presents an excellent lecture by one of the world’s leading experts in autoimmunology. He explains how adjuvants can trigger autoimmune reactions that manifest, months or years later, as autoimmune diseases. His exposition, richly illustrated by published case studies, is valuable for all clinicians regardless of specialty. Practically any tissue in the body, including the brain and vascular system, can be a target for autoimmune attack.

Autoimmunity seems to be the medical issue of our time as environmental and other factors promote a loss of immune tolerance to chemicals, toxic and benign, and to self. The resulting chronic inflammation underlies many conditions beyond the strictly defined autoimmune diseases such as MS, SLE and rheumatoid arthritis. Autoimmune inflammation can play a major role in cardiovascular disease, depression, fibromyalgia and chronic fatigue, migraine, loss of normal apoptosis (leading to malignancy), etc.

Professor Shoenfeld Yehuda, MD, FRCP is head of the Zabludowicz Center for Autoimmune Diseases of Sheba Medical Center (affiliated with Tel-Aviv University), the incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases at Tel-Aviv University, editor-in-chief of the journal Autoimmunity Reviews, and co-editor of the Journal of Autoimmunity. While celebrating vaccination as one of the greatest gifts of medicine in modern times, he explains the mechanism by which adjuvants can trigger autoimmunity. Also in this fascinating lecture he discusses some of the environmental, genetic, endocrine and immune factors that create a susceptibility to autoimmunity in general.

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There are many ways to fall prey to simplistic linear thinking when desperately seeking solutions to complex problems. Chronic Fatigue Syndrome can be a devastating illness; as attractive as a viral culprit may be to some, there is abundant evidence that attributing this complex condition to a singular cause unrealistically ignores the complexity of CFS and related conditions. A study just published in the Journal of Virology is the most recent ‘nail in the coffin’ for the notion that CFS is caused by the XMRV virus. The authors state:

“Chronic fatigue syndrome (CFS) is a multi-system disorder characterized by prolonged and severe fatigue that is not relieved by rest…Recently CFS has been associated with xenotropic murine leukemia virus-related virus (XMRV) as well as other murine leukemia virus (MLV)-related viruses, though not all studies have found these associations.”

They analyzed blood samples from 100 CFS patients and 200 self-reported healthy volunteers using molecular, serological and viral replication assays. Interestingly, they also analyzed samples from patients in the original study that attracted so much media attention when it reported XMRV in CFS. What were the results?

“We did not find XMRV or related MLVs, either as viral sequences or infectious virus, nor did we find antibodies to these viruses in any of the patient samples, including those from the original study. We show that at least some of the discrepancy with previous studies is due to the presence of trace amounts of mouse DNA in the Taq polymerase enzymes used in these previous studies.”

Attention to their conclusion may prevent clinicians and CFS sufferers from a fruitless diversion:

“Our findings do not support an association between CFS and MLV-related viruses including XMRV and off-label use of antiretrovirals for the treatment of CFS does not seem justified at present.”

This is a thorough and detailed study, but is there any other evidence to support the assertion that we shouldn’t depend on XMRV as a linear viral cause for CFS? A study recently published in the journal Retrovirology also finds no association in cases across the US:

“Here we tested blood specimens from 45 CFS cases and 42 persons without CFS from over 20 states in the United States for both XMRV and MuLV. The CFS patients all had a minimum of 6 months of post-exertional malaise and a high degree of disability, the same key symptoms described in the Lombardi et al. study. Using highly sensitive and generic DNA and RNA PCR tests, and a new Western blot assay employing purified whole XMRV as antigen, we found no evidence of XMRV or MuLV in all 45 CFS cases and in the 42 persons without CFS. Our findings, together with previous negative reports, do not suggest an association of XMRV or MuLV in the majority of CFS cases.”

Additional research published shortly after in the same journal came up with the same negative results for both CFS and prostate cancer in Japan:

“To evaluate the risk of XMRV infection during blood transfusion in Japan, we screened three populations–healthy donors (n = 500), patients with PC (n = 67), and patients with CFS (n = 100)–for antibodies against XMRV proteins in freshly collected blood samples. We also examined blood samples of viral antibody-positive patients with PC and all (both antibody-positive and antibody-negative) patients with CFS for XMRV DNA.”

Their data led them to the following conclusion:

“Our data show no solid evidence of XMRV infection in any of the three populations tested, implying that there is no association between the onset of PC or CFS and XMRV infection in Japan.”

A study recently published in PLoS ONE (Public Library of Science) goes a step further in examining the issue. The authors state:

“The novel human gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV), originally described in prostate cancer, has also been implicated in chronic fatigue syndrome (CFS). When later reports failed to confirm the link to CFS, they were often criticised for not using the conditions described in the original study. Here, we revisit our patient cohort to investigate the XMRV status in those patients by means of the original PCR protocol which linked the virus to CFS.”

In addition to the PCR protocol used in the original study, the authors also assayed the sera of CFS patients for the presence of both the xenotropic virus envelope protein and a serological response to it. What did their data show?

“The results further strengthen our contention that there is no evidence for an association of XMRV with CFS, at least in the UK.”

Subsequent research also conducted in the UK and published in PLoS examined a highly susceptible cohort of patients for XMRV virus:

“We extracted peripheral blood DNA from a cohort of 540 HIV-1-positive patients (approximately 20% of whom have never been on anti-retroviral treatment) and determined the presence of XMRV and related viruses using TaqMan PCR.”

Even for this very vulnerable group XMRV was not proven to be a concern:

“In view of these negative findings in this highly susceptible group, we conclude that it is unlikely that XMRV or related viruses are circulating at a significant level, if at all, in HIV-1-positive patients in London or in the general population.“

The authors of a study just published in the Annals of Neurology go a step further in investigating whether XMRV could be a causative agent in CFS. Having acknowledged the pre-existing research, they state:

“A useful next step would be to examine cerebrospinal fluid, because in some patients CFS is thought to be a brain disorder. Finding a microbe in the central nervous system would have greater significance than in blood because of the integrity of the blood–brain barrier.”

The brain is at the core of the experience of fatigue; if the virus were to show up anywhere it should be there. What did they find?

“We examined cerebrospinal fluid from 43 CFS patients using polymerase chain reaction techniques, but did not find XMRV or multiple other common viruses, suggesting that exploration of other causes or pathogenetic mechanisms is warranted.”

Just because a virus may be found in the body of a patient with CFS or any other condition does not mean that it is a significant causal factor for their complaint. The authors of a paper published in the British Medical Bulletin undertook a survey of…

“…All papers including the wording XMRV were abstracted from the NIH library of medicine database and included in the analysis.”

They make the point that…

“An increasing number of papers now refute the association of XMRV with human disease in humans although there is some evidence of serological reactivity to the virus. While it is unlikely that XMRV is a major cause of either prostate cancer or CFS, it can infect human cells and might yet have a role in human disease.”

But there is a big difference between being present in human cells and being a cause of disease. This is illustrated by a fascinating study published in the Journal of Virology showing that XMRV does not efficiently replicate and spread in human tissue. The authors state:

“To determine whether XMRV can replicate and spread in cultured PBMCs even though it can be inhibited by A3G/A3F, we infected phytohemagglutinin-activated human PBMCs and A3G/A3F-positive and -negative cell lines (CEM and CEM-SS, respectively) with different amounts of XMRV and monitored virus production by using quantitative real-time PCR.”

They summarize their findings by concluding:

“We found that XMRV efficiently replicated in CEM-SS cells and viral production increased by >4,000-fold, but there was only a modest increase in viral production from CEM cells (<14-fold) and a decrease in activated PBMCs, indicating little or no replication and spread of XMRV…Overall, these results suggest that hypermutation of XMRV in human PBMCs constitutes one of the blocks to replication and spread of XMRV.”

Wishing for a single linear cause that will lend itself to the discovery of a ‘magic bullet’ for conditions that are engendered by a multi-causal systemic web of factors is a flaw that has hindered progress in the treatment of chronic disease. In the case of CFS, dysregulation of the brain-immune axis is a core component. This demands that the clinician integrate a panoramic systems view with a nuanced investigation of individual functional elements. There is a world of science to delve into here; research just published in the journal NMR In Biomedicine offers a taste of the brain aspect. The authors in order to:

“…explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR [magnetic resonance] images has been extended to voxel-based regressions against clinical scores.”

The compared MR signal levels in 25 CFS subjects and 25 normal controls, including such clinical scores as fatigue duration, another score based on the 10 most common CFS symptoms, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24 hour blood pressure monitoring. What did their data show?

“In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T1-weighted MR and white matter volume, group × hemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation. It can be argued that at least some of these changes could arise from astrocyte dysfunction.”

In other words, there were strong correlations between CFS symptoms and pathological changes in the brain. The authors conclude:

“These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS).“

How might such neurodegenerative changes come about? A paper published earlier in Autoimmunity Reviews discusses the autoimmune component of CFS:

“The current concept is that CFS pathogenesis is a multifactorial condition. Various studies have sought evidence for a disturbance in immunity in people with CFS. An alteration in cytokine profile, a decreased function of natural killer (NK) cells, a presence of autoantibodies and a reduced responses of T cells to mitogens and other specific antigens have been reported. The observed high level of pro-inflammatory cytokines may explain some of the manifestations such as fatigue and flu-like symptoms and influence NK activity. Abnormal activation of the T lymphocyte subsets and a decrease in antibody-dependent cell-mediated cytotoxicity have been described. An increased number of CD8+ cytotoxic T lymphocytes and CD38 and HLA-DR activation markers have been reported, and a decrease in CD11b expression associated with an increased expression of CD28+ T subsets has been observed.”

The main point: practitioners and patients should not be seduced by the wish for a ‘magic bullet’ treatment of a single linear cause for complex conditions that require a systems biology perspective. In the case of chronic fatigue syndrome, the brain-immune axis comes to the fore, with all its multifaceted considerations for functional assessment and treatment.

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Most readers here are well aware that osteoporosis results from a failure to maintain the resilient protein matrix (web, or ‘scaffolding’) of bone tissue, and that chronic inflammation is a prime contributor. A paper just published in Current Opinion in Endocrinology, Diabetes and Obesity examines the role of autoimmunity, now so widespread, in skeletal disease in general and osteoporosis in particular. The authors state:

“There is an increased risk of osteoporotic fractures and osteonecrosis often at a young age among patients with certain systemic autoimmune diseases. The loss of bone mineral density and bone integrity seen with these diseases often cannot be explained by traditional risk factors alone…”

The review studies that document that in rheumatoid arthritis the risk of osteoporosis is doubled, the risk for hip fracture is doubled or tripled, and there is a two to six-fold risk of vertebral fracture.

“Reduction in bone mineral density in RA may be influenced by immobility, inflammation associated with osteoclast activation, and medications used to treat the disease such as corticosteroids.”

In the case of lupus…

“Risk factors for osteoporosis in patients with SLE include high disease activity, vitamin D deficiency, renal disease, corticosteroid use, and premature ovarian failure from cytotoxic medications…”

The include a review of vitamin D in skeletal health and note that besides its well-known role in bone metabolism…

“…vitamin D is thought to have an immunomodulatory function, with deficient levels associated with impaired innate immune function and overexuberant adaptive immune function. Markers of inflammation have been associated with increased bone turnover and bone loss, a factor that is thought to be particularly at play among patients with inflammatory diseases. Consequently, low vitamin D levels can lead to accelerated bone loss among patients with inflammatory diseases. Put together, these observations move us beyond the calcitropic effects of vitamin D deficiency among patients with inflammatory diseases, and argue in favor of higher serum levels than are currently accepted.“

Importantly, the mechanisms by which inflammation disrupts skeletal are becoming known:

“Several studies have found an association between pro-inflammatory cytokines which play a role in bone resorption, such as TNF-α, IL-1 and IL-6, and the development of osteoporosis. Epidemiologic studies have shown levels of systemic inflammation to predict bone loss and future fracture. It is becoming clear that T cells play a pivotal role in regulating bone homeostasis through direct interactions with bone marrow, stromal cells and osteoblasts. Once activated, these T cells release osteoclastogenic cytokines and Wnt ligands.”

And it appears that steroid treatment does not undo the skeletal effects of inflammation:

“Among a cohort of 20 patients with SLE who had never been on steroids, osteocalcin levels were significantly lower, the urinary excretion of cross-links were significantly higher than in a non-SLE cohort, suggesting that there is decreased bone formation and increased bone resorption among steroid-naive SLE patients. Although these findings were attributed to the underlying disease, comparable results were detected among a steroid-treated cohort implying that steroid treatment does not undo the skeletal effects of inflammation in SLE as was speculated by some researchers.”

Summing up the studies linking osteoporosis to SLE, the authors state:

“These findings suggest that patients with more active inflammation are at greater risk for bone loss.“

Concerning the importance of vitamin D and autoimmunity, they comment:

“In light of the alarming prevalence of vitamin D deficiency seen worldwide, all patients with autoimmune disease should have at least a baseline screening 25-hydroxyvitamin level to screen for vitamin D deficiency. The only laboratory test usually required to ascertain the patient’s status is the 25-hydroxyvitamin D level with a goal of at least greater than 30 ng/ml.”

Their conclusion is heightened in significance by the sharp increase in autoimmune disorders in recent years:

“Bone loss and damage commonly occurs in patients with systemic autoimmune diseases. We are improving in our ability to diagnose and treat autoimmune diseases and their complications; yet osteoporosis and osteonecrosis remain growing comorbid conditions.”

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Brain development, structure and function can suffer from a number of adverse environmental influences. A paper published in the journal Acta Pædiatrica review some of the environmental risk factors for ADHD.

“Converging evidence from epidemiologic, neuropsychology, neuroimaging, genetic and treatment studies shows that ADHD is a valid medical disorder…The majority of studies performed to assess genetic risk factors in ADHD have supported a strong familial nature of this disorder…However, several biological and environmental factors have also been proposed as risk factors for ADHD, including food additives/diet, lead contamination, cigarette and alcohol exposure, maternal smoking during pregnancy, and low birth weight.“

The authors review numerous studies that examine some these extraneous risk factors. They conclude by stating:

“Although a substantial fraction of the aetiology of ADHD is due to genes, the studies reviewed in this article show that many environmental risk factors and potential gene–environment interactions also increase the risk for the disorder.”

A study published in the journal Neuropediatrics investigates specifically the association between blood levels of mercury and ADHD in Hong Kong children:

“Fifty-two children with ADHD aged below 18 years diagnosed by DSM IV criteria without perinatal brain insults, mental retardation or neurological deficits were recruited from a developmental assessment center. Fifty-nine normal controls were recruited from a nearby hospital. Blood mercury levels were measured by cold vapor atomic absorption spectrophotometry.”

The authors uncovered a significant difference in blood mercury levels between the children with ADHD and the controls (‘normal’ children) which remained apparent after adjusting for age, gender and parents’ occupations:

“Children with blood mercury level above 29 nmol/L had 9.69 times higher risk of having ADHD after adjustment for confounding variables.”

The average blood mercury levels were higher for both the inattentive and combined subtypes of ADHD. Let’s bear in mind that this is one possible causal factor among many, not ‘THE’ cause. The authors conclude by stating:

“High blood mercury level was associated with ADHD. Whether the relationship is causal requires further studies.”

We can see a similar biological mechanism at play when we consider research recently published in Pediatric Allergy and Immunology that examines the association of heavy metals and Tourette syndrome. The authors state:

“Tourette syndrome (TS) is a childhood-onset and relapsing disorder characterized by involuntary simple or complex tics and high co-morbidity with behavioral anomalies…We investigated immunologic alternations and serum heavy metal levels in patients with TS to elucidate the unclarified mechanisms.”

Their findings illuminate a key point:

“In exacerbation, there were reverse CD4/CD8 (in two), higher percentages of natural killer cells (in five) and memory T cells (in eight), diminished lymphocyte activation CD69 marker (in three) and impaired NK cytotoxicity (in six) that showed a trend of lower inhibitory CD94 (NKG2A), activating NKp46, and perforin expression compared to those of patients with stable TS and healthy controls…Serum ASLO, mycoplasma antibody and the levels of heavy metals were not significantly different.”

In other words, the levels of heavy metals were pretty much the same but the immune system reaction to them was different. This is why it is impossible to make absolute statements about sub-acute levels of any heavy metal or toxin. Whether it elicits a dysregulated immune response leading to brain inflammation depends on the individual. The authors note this in their conclusion:

“Our study demonstrated that, in some patients with TS, consistently higher memory T cells and lower cytotoxicity in exacerbation status reflect immune alterations and underscore the potential for immunomodulation or immunosuppressive treatment.”

A paper published not long ago in Annals of Clinical Psychiatry carries the point further. The authors summarize the laboratory findings and other data in evidence for an autoimmune pathogenesis for autism:

“ Autoimmune markers were analyzed in the sera of autistic and normal children, but the cerebrospinal fluid (CSF) of some autistic children was also analyzed. Laboratory procedures included enzyme-linked immunosorbent assay and protein immunoblotting assay.”

Their findings certainly revealed the fire behind the smoke:

“Autoimmunity was demonstrated by the presence of brain autoantibodies, abnormal viral serology, brain and viral antibodies in CSF, a positive correlation between brain autoantibodies and viral serology, elevated levels of proinflammatory cytokines and acute-phase reactants, and a positive response to immunotherapy. Many autistic children harbored brain myelin basic protein autoantibodies and elevated levels of antibodies to measles virus and measles-mumps-rubella (MMR) vaccine. Measles might be etiologically linked to autism because measles and MMR antibodies (a viral marker) correlated positively to brain autoantibodies (an autoimmune marker)—salient features that characterize autoimmune pathology in autism. Autistic children also showed elevated levels of acute-phase reactants—a marker of systemic inflammation.”

Here again we see why it is impossible to argue for an environmental factor (heavy metal, virus, vaccine) as an absolute cause for autism or any other condition. Children at risk are those whose immune system is dysregulated and predisposed to an autoimmune triggering agent.

The authors state in their conclusion:

“The scientific evidence is quite credible for our autoimmune hypothesis, leading to the identification of autoimmune autistic disorder (AAD) as a major subset of autism. AAD can be identified by immune tests to determine immune problems before administering immunotherapy.”

We can also consider mild traumatic brain injury as a kind of ‘environmental risk factor’ for disorders neurodevelopment, learning and behavior. A study just published in the journal Pediatrics tests the link between postconcussion syndrome (PCS) and brain injury:

“Much disagreement exists as to whether postconcussion syndrome (PCS) is attributable to brain injury or to other factors such as trauma alone, preexisting psychosocial problems, or medicolegal issues. We investigated the epidemiology and natural history of PCS symptoms in a large cohort of children with a mild traumatic brain injury (mTBI) and compared them with children with an extracranial injury (ECI).”

The authors followed 670 children with mTBI and 197 children with ECI (non-cranial injury) and used the the Post Concussion Symptom Inventory, Rivermead Postconcussion Symptom Questionnaire, Brief Symptom Inventory, and Family Assessment Device to determine outcomes. Their data led to this conclusion:

“Among school-aged children with mTBI, 13.7% were symptomatic 3 months after injury. This finding could not be explained by trauma, family dysfunction, or maternal psychological adjustment. The results of this study provide clear support for the validity of the diagnosis of PCS in children.“

Environmental factors can be so severe that anyone would be affected. For most, however, the response depends on the individual. A skilled and experienced clinician knows when and where to focus suspicion. In the functional medicine model there are numerous resources available to test objectively when a question about environmental factors needs an answer, followed by the appropriate therapies when indicated.

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Cardiovascular 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.

You 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.”

How 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.”

We 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.”

I 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…”

What 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.”

Further 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.”

Another 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.”

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This paper just published in the journal Brain, Behavior, and Immunity highlights an important principal in clinical practice: even when an acute infection has been cleared by antimicrobial therapy, a chronic autoimmune disorder can develop due to immune dysregulation. The authors begin by noting:

“Some Lyme disease patients report debilitating chronic symptoms of pain, fatigue, and cognitive deficits despite recommended courses of antibiotic treatment. The mechanisms responsible for these symptoms, collectively referred to as post-Lyme disease syndrome (PLS) or chronic Lyme disease, remain unclear. We investigated the presence of immune system abnormalities in PLS by assessing the levels of antibodies to neural proteins in patients and controls.”

Their data showed that…

“Anti-neural antibody reactivity was found to be significantly higher in the PLS group than in the post-Lyme healthy and normal healthy groups.”

Their conclusion:

“The results provide evidence for the existence of a differential immune system response in PLS, offering new clues about the etiopathogenesis of the disease that may prove useful in devising more effective treatment strategies.”

Indeed. This is but one example of chronic conditions following acute infections, and why functional medicine practitioners are concerned with objectively assessing immune system integrity through cytokine analysis, white blood cell subset populations, vitamin D sufficiency, etc.

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There is a connection between how well you can smell, brain damage from autoimmune inflammation, and psychiatric disease. Consider this fascinating paper published in the journal Clinical Immunology in which the authors discuss the “inter-relationship between olfactory impairment, autoimmunity and neurological/psychiatric symptoms in several diseases affecting the central nervous system (CNS) such as Parkinson, Alzheimer’s disease, autism, schizophrenia, multiple sclerosis and neuropsychiatric lupus erythematosus. We suggest that common manifestations are not mere coincidences. Current data from animal models show that neuropsychiatric manifestations are intimately associated with smell impairment, and autoimmune dysregulation, via autoantibodies…”

In another paper published in the journal Autoimmunity Reviews the authors note that “Research in the field of immunology as well as in various brain illnesses is beginning to indicate the increasing relevance of smell in pathophysiology.” They further state “…evidence exists that there may be something unique about the olfactory system that is inextricably related to immunological function. In addition, accumulating evidence confirms the existence of olfactory dysfunction in brain disease, much of which appears at early stages including multiple sclerosis, Alzheimer’s Disease, Parkinson’s Disease, schizophrenia and depression…under certain circumstances, olfactory abnormalities may be associated with autoimmune conditions. Since the organization of the olfactory system is so sensitive, impairment may be noted at an early stage. This may become important in the prediction of certain brain illnesses.”

This paper recently published in the International Journal of Neuroscience focuses specifically on the link between olfaction, autoimmunity and Parkinson’s Disease. They first describe “the immune alterations observed in PD patients…the increase in the innate immune components including complement and cytokines within their substantia nigra and cerebrospinal fluid (CSF). These alterations extended to the adaptive immune response with the elevation of T cells and autoantibodies…in the peripheral blood and CSF of PD patients.” (Just the kinds of things we test for in the functional medicine approach.) They then describe the link between PD, autoimmunity and olfaction: “Smell deficit is one of the earliest signs of PD and a unique observation suggesting olfactory declines to be a consequence of autoimmune mechanisms.”

And the authors of this study published recently in the journal Autoimmunity observe that “Psychiatric diseases are often associated with mild alterations in immune functions (e.g., schizophrenia) as well as autoimmune features. Recent evidence suggests that autoimmune diseases (AD) demonstrate a higher prevalence of psychiatric disorders, such as depression and psychosis, than in the normal population. Patients with AD often have an olfactory impairment as well, based on smell studies… ” They report that olfactory gene receptors have brain functions in addition to smell, and go on to describe the genetic polymorphisms (variations) that link autoimmunity, psychiatric disorders and smell impairment.

The paper that concludes this post is tantalizingly entitled Olfaction—A Window to the Mind. Published not long ago in The Israel Medical Association Journal, it is available here in its entirety. The authors comment that “The sense of smell can provide a natural window to the brain. This window provides an opportunity to examine neural mechanisms and brain function in a non-invasive way.” They then undertake a fascinating review of the field of olfactory studies encompassing aspects ranging from autoimmunity and neuropsychiatric disease to sexual function, addiction, social behavior and the discrimination of self from non-self. Their conclusion is worth bearing in mind: “…assessment of the sense of smell and olfactory impairments is usually overlooked by patients and their clinicians. Given the clinical data reviewed here, clinicians should be encouraged to screen for olfactory impairments, which can help in the early diagnosis of CNS diseases such as Parkinson, dementia and schizophrenia, as well as CNS-autoimmune diseases such as neuropsychiatric lupus.”

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This paper published in the journal Allergy & Immunology discusses the molecular basis of a factor that is crucial for the decisions we make in daily life. This is because our choices and environment change our gene expression as we age, which plays a key role in how we become more prone to autoimmune, inflammatory and malignant disorders as the years go by. In the background there develops a persistent chronic low-grade inflammation. The authors state, “The decline in immunocompetence with age is accompanied by the increase in the incidence of autoimmune diseases. Aging of the immune system… is characterized by…the presence of low-grade chronic inflammation. There is growing evidence that epigenetics, the study of inherited changes in gene expression that are not encoded by the DNA sequence itself, changes with aging. Interestingly, emerging evidence suggests a key role for epigenetics in human pathologies, including inflammatory and neoplastic disorders.” [neoplastic = abnormal growths] They continue to describe the role of key molecular processes such as DNA methylation that we evaluate and treat in our functional medicine approach to chronic disease and aging.

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