Tag Archives: allergy

The important role of autoimmunity in cardiovascular disease

Posted on by
Reply

Summary: Inflammation of the blood vessels is the fundamental factor in cardiovascular diseases including heart attack and stroke. Vascular inflammation due to autoimmunity, a widespread phenomenon, is not encompassed by the ‘traditional’ metabolic risk factors. In the clinic the autoimmune components of vascular disease must be investigated and treated.

The authors of a paper published in the clinical journal Mædica observe:

“Inflammation plays a crucial role in atherogenesis either by local cellular mechanisms or humoral consequences…inflammation and endothelial dysfunction are triggered by cardiovascular risk factors: hypercholesterolemia, hypertension, smoking or diabetes. In other cases inflammation precedes atherosclerotic changes that occur in autoimmune diseases, as systemic lupus erythematosus and rheumatoid arthritis. In these diseases atherogenesis is mostly independent from conventional risk factors. Irrespective of its cause systemic inflammation is correlated with cardiovascular events.”

They also note:

“The pathogenic mechanisms of autoimmune disorders include an important localized or systemic inflammatory response. This may trigger as an “innocent bystander” reaction a peculiar type of endothelial injury that predisposes to atherogenesis. Many of these diseases are associated with early, accelerated atherosclerosis. This can also be due to concomitant presence of conventional risk factors, but is determined mainly by specific autoimmune and pro-inflammatory mechanisms or by specific medication (i.e. long term systemic corticosteroid use). In these cases atherosclerosis occurs in population subgroups traditionally protected from the atherosclerotic process, as young women that develop systemic lupus erythematosus. Atherothrombosis became the main cause of mortality in autoimmune disorders…Endothelial dysfunction found in early stages of athero genesis in autoimmune diseases is independent from traditional risk factors, depends only on the severity of systemic inflammation.”

As stated by the authors of a paper published in The Netherlands Journal of Medicine, autoimmune conditions such as rheumatoid arthritis and SLE have long been known to increase cardiovascular risk:

“Immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis and spondyloarthritis, are associated with increased cardiovascular morbidity and mortality, independent of the established cardiovascular risk factors. The chronic inflammatory state, a hallmark of IMIDs, is considered to be a driving force for accelerated atherogenesis.”

They discuss autoimmunity and cardiovascular disease using as models RA, psoriatic arthritis and ankylosing spondyloarthritis, SLE and role of innate and adaptive immunity, concluding:

“Over the past two decades it has become increasingly clear that chronic inflammation is an independent risk factor for cardiovascular events, with an impact over and above established risk factors. Since IMIDs are protracted disorders, the focus on adequate cardiovascular prevention in these patients is long overdue. Pathophysiologically, chronic inflammation provides a direct link between IMIDs and accelerated atherogenesis.”

A fascinating review article, rich with references to other valuable citations, was published recently in the International Journal of Inflammation that expands on the role of oxidative stress in eliciting an autoimmune response that produces cardiovascular inflammation. The authors state:

“Recently, it has become clear that atherosclerosis is a chronic inflammatory disease in which inflammation and immune responses play a key role. Accelerated atherosclerosis has been reported in patients with autoimmune diseases, suggesting an involvement of autoimmune mechanisms in atherogenesis. Different self-antigens or modified self-molecules have been identified as target of humoral and cellular immune responses in patients with atherosclerotic disease. Oxidative stress, increasingly reported in these patients, is the major event causing structural modification of proteins with consequent appearance of neoepitopes. Self-molecules modified by oxidative events can become targets of autoimmune reactions, thus sustaining the inflammatory mechanisms involved in endothelial dysfunction and plaque development.”

The authors acknowledge the role of infectious agents as instigators of autoimmune activity, but emphasize the role of modified self-antigens:

“Although infectious agents have been associated with the activation of immune mechanisms, evidence exist that the main antigenic targets in atherosclerosis are modified endogenous structures [12]. Atherosclerotic plaques express autoantigens that are targeted by both IgM and IgG. It is likely that these autoimmune responses initially have a beneficial effect facilitating the removal of potentially harmful antigens [13, 14]. However, studies performed on hypercholesterolaemic mice deficient in different components of innate and adaptive immunity uniformly indicate that the net effect of immune activation is proatherogenic and that atherosclerosis, at least to some extent, should be regarded as an autoimmune disease.”

They go on to discuss the roles of oxidized LDL, heat shock proteins, Beta2-glycoprotein I (β2-GPI), and oxidized hemoglobin as oxidized agents that act as autoantigens eliciting an autoimmune response implicated in atherogenesis and cardiovascular disease, then conclude by stating:

“Excessive oxidative stress and low-grade chronic inflammation are major pathophysiological factors contributing to the development of cardiovascular diseases…In addition to pro-inflammatory properties, self molecules modified by oxidative events can become targets of autoimmune reactions, thus sustaining the inflammatory mechanisms involved in endothelial dysfunction and plaque development…Modulation of the immune system could represent a useful approach to prevent and/or treat these diseases.”

An excellent paper published in the journal Nature Reviews Rheumatology (formerly Nature Clinical Practice Rheumatology) discusses the mechanisms of atherosclerosis in autoimmune diseases. The authors note:

“Many components of the immune system are involved in the pathologic processes underlying the development of atherosclerosis: macrophages that develop into foam cells; T cells; autoantibodies; autoantigens that are components of vessel walls and cholesterol particles; and cytokines that are secreted by cells within atherosclerotic plaques, including interleukin (IL)-1, IL-2, IL-6, IL-8, IL-12, IL-10, tumor-necrosis factor, interferon-gamma and platelet-derived growth factor.”

They note evidence for the role of cellular immunity…

“Several autoimmune diseases are characterized as being TYPE 1 T HELPER (TH1) CELL-mediated or TYPE 2 T HELPER (TH2) CELL-mediated conditions. A study in which ApoE-/- mice were treated with pentoxifylline (an inhibitor of the TH1 differentiation pathway) for 12 weeks suggested that atherosclerosis is a TH1-mediated process.”

And the participation of humoral immunity is characterized by antibodies to oxidized LDL cholesterol and to heat-shock proteins (HSPs):

“Oxidized LDL (oxLDL) is the type of LDL cholesterol most likely to be taken up by macrophages that develop into foam cells. Increased levels of anti-oxLDL antibodies have been detected in patients with early-onset peripheral vascular disease, severe carotid atherosclerosis, and angiographically verified coronary artery disease (CAD). In addition, raised levels of oxLDL antibodies were found to be predictive of progression of carotid atherosclerosis, MI, and death…it was found that individuals with atherosclerosis had significantly higher levels of anti-HSP65 antibodies than controls.”

It has long been known that antiphospholipid antibodies (aPL) and anticardiolipin antibodies (aCL) can be associated with cardiovascular disease, and the authors discuss their relation to arterial intima–media thickness (IMT, pathological thickening of the blood vessel wall). They conclude:

“The complex involvement of the immune system in the pathogenesis of atherosclerosis is most evident in patients with autoimmune diseases, but is also important in the general population. Immunomodulation of atherosclerosis carries great potential for future human therapies…

  • Autoimmune rheumatic diseases are characterized by enhanced atherosclerosis, which leads to cardiovascular disease
  • Some forms of atherosclerosis can be detected at the preclinical stage
  • Both cellular and humoral components of the immune system are involved in the pathogenesis of atherosclerosis
  • Classical and nonclassical risk factors for atherosclerosis are associated with accelerated atherosclerosis in autoimmune rheumatic diseases
  • Atherosclerosis can be immunomodulated in experimental models in various ways, which include induction of immune tolerance”

The authors of a paper published in the journal Stroke observe that inflammation plays the critical role in arterial plaque destabilization:

“Inflammation is not only instrumental in the development of human atheromatous plaques, but, importantly, plays a crucial role in the destabilization of internal carotid artery plaques, thus converting chronic atherosclerosis into an acute thrombo-embolic disorder.”

Expanding on this…

“…a complex endothelial dysfunction induced by elevated and modified low-density lipoproteins (LDL), free radicals, infectious microorganisms, shear stress, hypertension, toxins after smoking or combinations of these and other factors leads to a compensatory inflammatory response. Endothelial dysfunction is characterized by decreased nitric oxide synthesis, local oxidation of circulating lipoproteins and their entry into the vessel wall. Intracellular reactive oxygen species similarly induced by the multiple atherosclerosis risk factors lead to enhanced oxidative stress in vascular cells and further activate intracellular signaling molecules involved in gene expression. Upregulation of cell adhesion molecules facilitates adherence of leukocytes to the dysfunctional endothelium and their subsequent transmigration into the vessel wall. As outlined in this review, the evolving inflammatory reaction is instrumental in the initiation of atherosclerotic plaques and their destabilization.”

The authors summarize the stream of events leading to plaque rupture:

“Inflammation plays an important role in the progression of atherosclerosis and ICA plaque destabilization converting a chronic process into an acute disorder with ensuing thrombo-embolism. During atherosclerosis, T cells and macrophages infiltrate the vessel wall triggered by endothelial dysfunction, and locally interact in a synergistic manner. Autoreactive T cells recognize oxLDL, HSP and shared microbial antigens by molecular mimicry and locally release proinflammatory cytokines. Macrophages on stimulation by T-cell-derived cytokines and transformation into foam cells after uptake of oxLDL secrete MMP predisposing the plaques to subsequent rupture. Plaque-associated macrophages, moreover, are an important cellular source of TF. On plaque rupture TF-rich plaque material gets in contact with the circulation and activates the extrinsic coagulation pathway…Vaccination against modified LDL and HSP can slow development of atherosclerotic plaques. Current therapeutics effective in preventing atherosclerosis and stroke such as statins, ASS [aspirin] and renin-angiotensin system inhibitors may exert part of their effects by modulating inflammatory responses in the vessel wall.”

The authors of a review article published in Clinical and Developmental Immunology consider epigenetic mechanisms involved in autoimmune cardiovascular risk. They state:

“Autoimmune diseases (AIDs) have been associated with accelerated atherosclerosis (AT) leading to increased cardio- and cerebrovascular disease risk…many new genes and signalling pathways involved in autoimmunity…have been further detected. Epigenetics, the control of gene packaging and expression independent of alterations in the DNA sequence, is providing new directions linking genetics and environmental factors. Epigenetic regulatory mechanisms comprise DNA methylation, histone modifications, and microRNA activity, all of which act upon gene and protein expression levels. Recent findings have contributed to our understanding of how epigenetic modifications could influence AID development.

In other words, environmental factors that modulate gene expression play a role in ‘turning on’ autoimmunity that promotes heart attacks and strokes. As the authors note:

“It is widely known that AIDs are the result of interaction between predisposing genetic factors, deregulation of the immune system, and environmental triggering factors.”

Of great importance is that these factors can be modified:

“Moreover, epigenetic changes may be reversed. A remarkable example of disease in which epigenetic abnormalities and patterns of inheritance are extremely complex is SLE. The high incidence of twin pairs in which SLE develops in only one of the siblings supports the notion that environmental factors and their involvement in epigenetic modifications could affect the onset of disease.”

And there seem to be differences of autoimmune expression depending on the disease and the individual:

“Significant evidence has shown that there is heterogeneity in the characteristics of vasculopathies underlying different autoimmune diseases such as APS, SLE, RA, and pSS. It has been also shown a relevant heterogeneity with respect to inflammatory risk factors. The data presented in this revision further indicated that epigenetic mechanisms also seem to influence inflammation and cardiovascular disease in those autoimmune conditions.”

The authors of a paper published in Zeitschrift für Rheumatologie (Journal of Rheumatology) note that EULAR (the European League Against Rheumatism) recommends aggressive cardiovascular risk factor management for rheumatoid arthritis, which would be reasonable extrapolate to other autoimmune diseases:

“Beyond the traditional CV risk factors, chronic systemic inflammation has been shown to be a crucial factor in atherosclerosis development and progression from endothelial dysfunction to plaque rupture and thrombosis. Numerous studies have shown that atherosclerosis is not a passive process characterized by accumulation of lipids in the vessel walls, but rather represents active inflammation of the vasculature…According to the recently published EULAR recommendations for CV risk screening and management in patients with inflammatory arthritis, annual CV risk assessment is recommended for all patients with RA. Any CV risk factors identified should be optimally managed. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower CV risk.”

Stroke in young women, particularly in the absence of ‘traditional’ risk factors such as elevated cholesterol, hypertension, metabolic syndrome and obesity, etc. is a great concern. In a paper published recently in the Canadian Journal of Neurological Sciences the authors state:

“In women ages 15-45 years, an additional set of risk factors are important in the pathogenesis of ischemic stroke. Some of these pertain strictly to women, and relate to exogenous hormones and pregnancy. Various other conditions are more common in women, which include migraine with aura, selected vascular disorders and autoimmune conditions. These differences do have implications for management in both the primary and secondary prevention of stroke in this age group.”

Of interest to clinicians is another paper in the same journal drawing attention to the role of the cytokine transforming growth factor-β (TGF-β) in vascular inflammation. The authors investigated polymorphisms of the TGF-β gene in ischemic stroke:

“Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and of cerebrovascular complications. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine with a central role in inflammation. To investigate whether polymorphisms of the TGF-β1 gene can modify the risk of ischemic stroke (IS) in Chinese population, we conduct this hospital-based, case-control study.”

They determined the transforming growth factor-β1 genotype in 450 Chinese patients (306 male and 144 female) with ischemic stroke compared to 450 control subjects (326 male and 124 female).

“Subjects carrying 869TT were susceptible to IS (odds ratio [OR] =1.58). Further analysis of IS data partitioned by gender revealed the female-specific association with 869T/C (OR=2.64).”

While the 869TT genotype of the TGF-β1 gene increased the risk of stroke for both sexes, the increase in risk for stroke was 264% for females.

The authors of an interesting paper published recently in the Endocrine Journal investigate the association of chronic inflammation in autoimmune thyroiditis with endothelial (vascular) dysfunction:

“Our study aims to investigate the presence of the well known preceding clinical situations of atherosclerosis like endothelial dysfunction and inflammation in subclinical hypothyroidism.”

They evaluated 37 patients with subclinical hypothyroidism (29 women, 8 men) in comparison to 23 healthy volunteers (19 women, 4 men) for endothelial dysfunction as measured by brachial artery responses to endothelium-dependent (flow mediated dilation, FMD) and endothelium-independent stimuli (sublingual nitroglycerin (NTG)). They also measured serum TNF-alpha, interleukin-6, and hs-CRP, and estimated insulin resistance by HOMA score. The data make paint an interesting picture:

“There were no significant differences in age, body mass index, waist circumference, HOMA scores. There was a statistically significant difference in endothelium-dependent (FMD) and endothelium-independent vascular responses (NTG) between the patients with subclinical hypothyroidism and the normal healthy controls…The TSH and LDL, IL-6, TNF-alpha and hs-CRP levels in the patient group were significantly higher than those in control group. A positive correlation was found only between endothelium-dependent vasodilation and TNF-alpha, hs-CRP and IL-6, TSH, total cholesterol, LDL and triglycerides. Neither of the groups were insulin resistant and there was not any difference either in fasting insulin or in glucose levels. We found endothelial dysfunction in subclinical hypothyroidism group.”

The vascular inflammation associated with autoimmune thyroiditis stands out in high relief against a background of normal traditional risk factors like BMI, waist circumference and insulin resistance. The authors conclude:

“Our findings suggest that there is endothelial dysfunction and low grade chronic inflammation in SH due to autoimmune thyroiditis. There are several contributing factors which can cause endothelial dysfunction in SH such as changes in lipid profile, hyperhomocysteinemia. According to our results low grade chronic inflammation may be one of these factors.”

Finally, in the journal Circulation Research the authors of a commentary  on a study just published in the Journal of Clinical Investigation ask the question “Is Atherosclerosis an Allergic Disease?“:

“A new report in the Journal of Clinical Investigation adds to the ever-increasing evidence that immunological mechanisms play an important role in atherogenesis. These new observations suggest involvement of IgE and its FcϵR1α receptor in the promotion of atherosclerosis, and specifically in plaque instability and clinical events.”

They further note, importantly…

“In addition, aside from conditions in which there are generalized increases in IgE levels, such as parasitic infections and hyper-IgE syndromes, elevated IgE levels usually reflect allergic-type immune responses.”

This is one mechanism by which food and other allergies contribute to the inflammation of cardiovascular disease. The authors conclude:

“The report by Wang et al and other reports describing the potential importance of mast cells to CVD have provided a compelling case to study the role of IgE in inflammatory conditions such as atherosclerosis. It adds to the growing evidence of the importance of immune function in atherogenesis and in particular of the role that immunoglobulins play, both through antigen-specific interactions and antigen-independent regulatory roles.”

Bottom line: In clinical management of cardiovascular disease the autoimmune components should be investigated and addressed with a rational treatment strategy.

Yeast growth in the gut aggravates arthritis and allergies

Posted on by
1

It is a cardinal principle in functional medicine to examine the gut in any case of autoimmune or allergic disease. No wonder, considering that 60-80% of the immune system tissue in the body is the lymphoid tissue packed around the intestines. This principle is illustrated by an interesting study recently published in the journal Medical Mycology:

“We examined whether Candida albicans gut colonization aggravates immune diseases in mice.”

The authors colonized the guts of the study animals and measured changes in contact hypersensitivity and immunoreactive arthritis. Their observations correspond to what we see in our patients:

“C. albicans gut colonization increased the incidence of allergic diarrhea, which was accompanied by gut hyperpermeability, as well as increased infiltration of inflammatory cells in the colon. Contact hypersensitivity was also exacerbated by C. albicans gut colonization, as demonstrated by increased swelling, myeloperoxidase activity, and proinflammatory cytokines in ear auricles. Furthermore, C. albicans gut colonization promoted limb joint inflammation in collagen-induced arthritis, in an animal model of rheumatoid arthritis.”

These results add to the large body of evidence for the key importance of immune regulation by microbes in the gut and the far-reaching impact of disruptions of the intestinal microbial ecology. The authors’ concluding comments apply to other gut pathogens as well:

“These findings suggest that C. albicans gut colonization in mice aggravates inflammation in allergic and autoimmune diseases, not only in the gut but also in the extra-gut tissues and underscores the necessity of investigating the pathogenic role of C. albicans gut colonization in immune diseases in humans.“

The most reliable way to investigate the microbial environment in the gut (now being used for pioneering studies of the human microbiome as well as for examination in clinical practices like ours) is DNA analysis.

The role of autoimmunity and brain inflammation in disorders of learning, behavior and autism

Posted on by
1

There is a large and growing body of evidence for the role of brain inflammation due to immune dysregulation in disorders of learning, behavior and autism. A study recently published in the journal Biological Psychiatry shows how the microglia (immune cells in the brain) are activated and increased in the prefrontal cortex in autism:

“In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been reported. However, it is unknown whether microglial somal volume or density are altered in the cortex and whether any alteration is associated with age or other potential covariates.”

The authors used advanced immunochemistry and nuclear imaging techniques to compare microglial activation and volume in autistic and normal brains. Their conclusion:

“Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients.”

Autoimmune activity may manifest through a variety of autoantibodies to neural tissues in autistic spectrum disorders, epilepsy, Landau-Kleffner Syndrome (infantile acquired aphasia), etc. An earlier paper in Biological Psychiatry documents abnormal immune markers in the serum in association with these disorders:

“Brain derived neurotrophic factor (BDNF) elevation in newborn sera predicts intellectual/social developmental abnormalities. Other autoantibodies (AAs) to endothelial cells (ECs) and myelin basic protein (MBP) are also elevated in some children. We tested relationships between BDNF, BDNF AAs, and other AAs in children with these disorders.“

The authors measured these immune ‘attack molecules’ in measured in children with autism, childhood disintegrative disorder (CDD), pervasive developmental delay-not otherwise specified (PDD-nos), acquired epilepsy, Landau-Kleffner syndrome (LKS); healthy children (HC), and children with non-neurological illnesses (NNI). The data showed significant elevations. Their conclusion:

“Children with developmental disorders and epilepsy have higher AAs to several neural antigens compared to controls. The presence of both BDNF AAs and elevated BDNF levels in some children with autism and CDD suggests a previously unrecognized interaction between the immune system and BDNF.”

Immune dysregulation can manifest on a spectrum of developmental dysfunction from very mild development and learning disorders to full-blown autism. A recent paper in the same journal presents the evidence for immune dysfunction in healthy siblings of autistic kids:

“Endophenotypes are simple biological aspects of a disease that can be observed in unaffected relatives…an “autism endophenotype” justifies the observation that a mild reduction in ideational fluency and nonverbal generativity might be observed in healthy, unaffected relatives of children with autism…we examined whether the “autism endophenotype” would extend its effects on the immune system.“

The authors tested multiple immune parameters in autistic kids and their siblings in comparison to healthy ‘controls’ without a family history for autism and came to this conclusion:

“Results of this pilot study indicate that a complex immune dysfunction is present both in autistic children and in their non-autistic siblings and show the presence of an “autism endophenotype” that expands its effects on immunologic functions.”

An early paper published in Pediatric Neurology provides evidence of neuroinflammation in the cerebrospinal fluid in autism:

“In order to find evidence for neuroinflammation, we compared levels of sensitive indicators of immune activation: quinolinic acid, neopterin, and biopterin, as well as multiple cytokines and cytokine receptors, in cerebrospinal fluid and serum from children with autism, to control subjects with other neurologic disorders.”

Neopterin and biopterin are easily measured in the urine. What did the data show?

“In cerebrospinal fluid from 12 children with autism, quinolinic acid and neopterin were decreased, and biopterin was elevated, compared with control subjects.”

Subsequent research published in the same journal revealed the role of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in cases of autism that became worse:

“Recent reports implicating elevated cytokines in the central nervous system in a small number of patients studied with autism have reported clinical regression.”

The authors’ measurements of TNF-α in the serum and CSF of autistic children resulted in data that painted this picture:

“Elevation of cerebrospinal fluid levels of tumor necrosis factor-alpha was significantly higher than concurrent serum levels in all of the patients studied. The ratio of the cerebrospinal fluid levels to serum levels averaged 53.7:1…This observation may offer a unique insight into central nervous system inflammatory mechanisms that may contribute to the onset of autism and may serve as a potential clinical marker.”

Research just published in the journal Brain, Behavior, and Immunity reports the role of other pro-inflammatory cytokines in worsening cases of autistic spectrum disorder.

“A potential role for immune dysfunction has been suggested in Autism spectrum disorders (ASD). To test this hypothesis, we investigated evidence of differential cytokine release in plasma samples obtained from 2 to 5 year-old children with ASD compared with age-matched typically developing (TD) children and children with developmental disabilities other than autism.”

The data painted an unmistakable and compelling picture:

“Observations indicate significant increases in plasma levels of a number of cytokines, including IL-1β, IL-6, IL-8 and IL-12p40 in the ASD group compared with TD controls. Moreover, when the ASD group was separated based on the onset of symptoms, it was noted that the increased cytokine levels were predominantly in ASD children who had a regressive form of ASD. In addition, increasing cytokine levels were associated with more impaired communication and aberrant behaviors.“

Their conclusion is important for every clinician and parent to bear in mind:

“In conclusion, using larger number of participants than previous studies, we report significantly shifted cytokine profiles in ASD. These findings suggest that ongoing inflammatory responses may be linked to disturbances in behavior and require confirmation in larger replication studies. The characterization of immunological parameters in ASD has important implications for diagnosis, and should be considered when designing therapeutic strategies to treat core symptoms and behavioral impairments of ASD.”

We can also be informed by a fascinating study published in Biological Psychiatry confirming that behavioral abnormalities are associated with autoimmune attack on hormones in the brain and periphery. The authors set out to resolve the biological mechanism involved in aggressive behavior:

“Altered stress response is characteristic for subjects with abnormal aggressive and antisocial behavior…We hypothesized that autoantibodies (autoAbs) directed against several stress-related neurohormones may exist in aggressive subjects.”

Assays for antibodies revealed a definite pattern for both conduct disorder and prisoners groups leading the authors to conclude:

“High levels of ACTH-reactive autoAbs as well as altered levels of oxytocin- and vasopressin-reactive autoAbs found in aggressive subjects may interfere with the neuroendocrine mechanisms of stress and motivated behavior. Our data suggest a new biological mechanism of human aggressive behavior that involves autoAbs directed against several stress-related neurohormones.”

We can also appreciate the evidence presented the Journal of Neuroimmunology that autism is characterized by a deficit in the ability to dampen autoimmune attack on the brain by the cytokine transforming growth factor beta-1 (TGFβ1):

“Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. There is evidence of both immune dysregulation and autoimmune phenomena in autism. We examined the regulatory cytokine transforming growth factor beta-1 (TGFβ1) because of its role in controlling immune responses.”

The authors compared plasma levels of active TGFβ1 were in 75 children with ASD to 68 controls, finding that they were significantly lower in the ASD group. Moreover…

“…there were significant correlations between psychological measures and TGFβ1 levels, such that lower TGFβ1 levels were associated with lower adaptive behaviors and worse behavioral symptoms. The data suggest that immune responses in autism may be inappropriately regulated due to reductions in TGFβ1.”

Their findings likely apply to a range of developmental, learning and behavioral disorders:

“Such immune dysregulation may predispose to the development of possible autoimmune responses and/or adverse neuroimmune interactions during critical windows in development.“

Along these lines, a paper published in Biological Psychiatry describes the impaired immune tolerance due to deficiencies in regulatory T cells, another critical immune regulating factor in children with Tourette Syndrome. The authors state:

“Since regulatory T (T reg) cells play a major role in preventing autoimmunity, we hypothesized that a defect in T reg cells may be present in children with Tourette syndrome (TS).”

They analyzed the peripheral blood of TS kids compared to matched control subjects on multiple occasions to determine the numbers of CD4+CD25+CD69− T reg cells. The results were clear:

“A significant decrease in T reg cells was observed in patients with moderate to severe TS symptoms compared with healthy age-matched control children. A decrease in T reg cell number was also noted during symptom exacerbations in five out of six patients.”

Their conclusion affirms the role of autoimmunity in Tourette syndrome:

“These data support our hypothesis that at least some TS patients may have a decreased capacity to inhibit autoreactive lymphocytes through a deficit in T reg cells. Interactions of host T cell immunity and microbial factors may also contribute to the pathogenesis of TS.”

Early evidence for the role of autoimmunity in autism was presented in the journal Neuroscience Letters. The authors state:

“It is well established that increased neopterin levels are associated with activation of the cellular immune system and that reduced biopterins are essential for neurotransmitter synthesis. It has been suggested that some autistic children may be suffering from an autoimmune disorder.”

They measured these pterins in the urine of pre-school autistic children, their siblings and age-matched control children and found:

“Both urinary neopterin and biopterin were raised in the autistic children compared to controls and the siblings showed intermediate values. This supports the possible involvement of cell-mediated immunity in the aetiology of autism.”

The finding for the non-autistic siblings shows again that brain autoimmunity can manifest on a wide spectrum.

Yet more evidence for autoimmune dysfunction in both kids with autism and their siblings was offered in a study published in the Journal of Neuroimmunology on antibrain antibodies:

“Serum autoantibodies to human brain, identified by ELISA and Western immunoblotting, were evaluated in 29 children with autism spectrum disorder (22 with autistic disorder), 9 non-autistic siblings and 13 controls.”

The authors sum up the abnormalities found by concluding:

“Results suggest that children with autistic disorder and their siblings exhibit differences compared to controls in autoimmune reactivity to specific epitopes located in distinct brain regions.”

No discussion of autoimmunity and the brain would be complete without considering the role of the gut, the site of 60-80% of all the immune system tissue in the body. A paper published in the Journal of Clinical Immunology describes the corresponding autoimmune intestinal inflammation in children with autism.

“A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced pro-inflammatory cytokine production is present in these ASD children.”

The authors performed duodenal biopsies and measured CD3+ lymphocytes in the colonic mucosa for the presence of the pro-inflammatory cytokines TNF-α, IL-2, IL-4, IFN-γ and the anti-inflammatory IL-10. Again we see a clear expression of autoimmunity:

“Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls. In the duodenum…epithelial TNF-α+ cells in ASD children [were] significantly greater compared with noninflamed controls but not coeliac disease controls…IL-10+ cells were fewer in ASD children than in noninflamed controls. In the colon,TNF-α+ and CD3+IFN-γ+ were more frequent in ASD children than in noninflamed controls.”

Note the similar findings for ASD and celiac disease. In striking accordance with with the authors found:

“There was a significantly greater proportion of TNF-α+ cells in colonic mucosa in those ASD children who had no dietary exclusion compared with those on a gluten and/or casein free diet. There is a consistent profile of lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities.”

It would be a shame for any clinician or parent to be unaware of their conclusion:

“The data provide further evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and immunomodulatory therapies.“

Regarding the link between autoimmune inflammation in the gut and brain it’s important to remember that the classical IgE-mediated food allergy diagnosed by skin prick is not usually the concern. Two papers published the Annals of Allergy, Asthma & Immunology illustrate the point. In IgE and non-IgE food allergy the authors note that:

“Food allergy (FA) is characterized by an abnormal immunologic reactivity to food proteins. The gastro-intestinal tract serves not only a nutritive function but also is a major immunologic organ. Although previously thought to be triggered primarily by an IgE-mediated mechanism of injury, considerable evidence now suggests that non-IgE mechanisms may also be involved in the pathogenesis of FA.”

The authors gathered extensive data on a range of disorders including attention-deficit-hyperactivity disorder and behavioral disorders, and correlated them with immunologic deviations to Th1 or Th2 mechanisms of FA. Their conclusion is crucial knowledge for anyone treating food allergy mediated disorders:

“The results of this review allow the construction of a central, unifying hypothesis for a new classification of FA as follows: the clinical manifestations of FA, expressed in affected target organs, may be the result of immunologic injury mediated by interaction of food antigens with contiguous elements of mucosal associated lymphoid tissue. These appear to be modulated by relative imbalances of the Th1/Th2 paradigm, which may be the ultimate determinant governing the expression of FA as IgE-mediated, non-IgE-mediated, or mixed forms of IgE/non-IgE mechanisms of FA.”

This is critically important because Th1 and Th2 imbalances require different interventions; it also offers a partial explanation of why antibody tests for food allergy are not reliable. The recent post on why autoimmune and allergic diseases are on the rise is of interest in this context. We also see in the same issue of Annals of Allergy, Asthma & Immunology a paper on the link between non-IgE-mediated food allergies and the inflamed lymphoid intestinal tissue that was described above in the report on mucosal immune activation and autism. Here the authors conclude:

“These studies suggest that abnormalities in Th1 function may not only play a role in some patients with non—IgE-mediated FA in whom decreased Th1 function is seen, but also in patients with celiac disease in whom an increased Th1 function is seen. The studies also suggest that lymphonodular hyperplasia may be a hallmark histologic lesion in patients with non—IgE-mediated FA.”

What does lymphonodular hyperplasia feel like? Sometimes nothing more than a little bloating. All of this helps us to appreciate the significance of neurologic disorders with gluten sensitivity. This was explored in a paper published in the journal Pediatrics more than six years ago:

“During the past 2 decades, celiac disease (CD) has been recognized as a multisystem autoimmune disorder. A growing body of distinct neurologic conditions such as cerebellar ataxia, epilepsy, myoclonic ataxia, chronic neuropathies, and dementia have been reported, mainly in middle-aged adults. There still are insufficient data on the association of CD with various neurologic disorders in children, adolescents, and young adults, including more common and “soft” neurologic conditions, such as headache, learning disorders, attention-deficit/hyperactivity disorder (ADHD), and tic disorders. The aim of the present study is to look for a broader spectrum of neurologic disorders in CD patients, most of them children or young adults.”

The authors found that kids with CD were far more likely to develop neurologic disorders than the control subjects, including hypotonia, developmental delay, learning disorders and ADHD, headache, and cerebellar ataxia. Thus their conclusion:

“This study suggests that the variability of neurologic disorders that occur in CD is broader than previously reported and includes “softer” and more common neurologic disorders, such as chronic headache, developmental delay, hypotonia, and learning disorders or ADHD.”

Research published in the journal Nutritional Neuroscience clarifies one of the mechanisms behind autoimmune reaction to nervous system antigens in autism:

“We assessed the reactivity of sera from 50 autism patients and 50 healthy controls to specific peptides from gliadin and the cerebellum. A significant percentage of autism patients showed elevations in antibodies against gliadin and cerebellar peptides simultaneously.“

The authors employed detailed antigen-antibody probes with confirmation by sophisticated DOT-immunoblot and inhibition studies to reach their conclusion:

“We conclude that a subgroup of patients with autism produce antibodies against Purkinje cells [a type of brain cell] and gliadin peptides, which may be responsible for some of the neurological symptoms in autism. “

Gliadin is the immunoreactive antigen contained in gluten.

Mention should also be made of the ability of infections to sometimes trigger an autoimmune disorder as discussed in a study published in the Journal of Child Psychology and Psychiatry on PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections).

“…(PANDAS) is a recently recognized syndrome in which pre-adolescent children have abrupt onsets of tics and/or obsessive-compulsive symptoms, a recurring and remitting course of illness temporally related to streptococcal infections, and associated neurologic findings including adventitious movements, hyperactivity and emotional lability.

The authors undertook a search for clinical and laboratory evidence and found consistent clinical findings have been described in a large case series, including magnetic resonance imaging that shows inflammatory changes in the basal ganglia, along with anti-basal ganglia antibodies have been found in some acute cases that were similar to those against streptococcal antigens. They note in their conclusion:

“PANDAS…has stimulated new research endeavors into the possible links between bacterial pathogens, autoimmune reactions, and neuropsychiatric symptoms.”

Why are autoimmune and allergic diseases on the rise?

Posted on by
1

An interesting paper just published in PLoS (Public Library of Science) clarifies one of the mechanisms that account for the recent increase in autoimmune disorders. The authors set out to investigate the possibility of an induced dysregulation of the immune system:

“Repeated immunization with antigen causes systemic autoimmunity… Overstimulation of CD4+ T cells led to the development of autoantibody-inducing CD4+ T (aiCD4+ T) cell[s]…[which became] antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen cross-presentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE).”

This essentially means that overexposure to a potential antigen (increased amounts of gluten in hybridized wheat, higher environmental levels of mercury, etc.) can result in sensitization of the immune system with cross-reaction to our own tissues (autoimmune disease). The authors clearly state their conclusion drawn from the evidence:

“Systemic autoimmunity appears to be the inevitable consequence of over-stimulating the host’s immune ‘system’ by repeated immunization with antigen, to the levels that surpass system’s self-organized criticality.”

Vitamin D for mold allergies

Posted on by
Reply

Mold allergies are a vexing problem for many whose immune system is compromised, especially when exposure at home or work is unavoidable. Research just published in The Journal of Clinical Investigation provides welcome evidence that Vitamin D substantially reduces the allergic response to mold and promotes tolerance.

“The development of Th2 responses, as in asthma and allergic bronchopulmonary aspergillosis (ABPA), is driven by both genetic and environmental factors. Mechanistically, inhaled allergens are presented by lung DCs [dendritic cells] to naive T cells, which leads to induction of allergen-specific Th2 cells…In patients with ABPA, immunological responses to a variety of A. fumigatus [mold] antigens result in a heightened Th2 response and an elevated IgE level.”

To determine what determines a Th2 allergic response as opposed to Treg (regulatory T cell) tolerance the authors compared a groups of cystic fibrosis patients suffering from ABPA and and another group without it by measuring several key immune factors. Their findings have great practical significance:

“Furthermore, we discovered that ABPA correlated with vitamin D deficiency, and supplementation with vitamin D potentiated Treg-mediated regulation of Th2 reactivity…Patients with ABPA had significantly lower 25-OH vitamin D (the major circulating form of vitamin D3) levels compared with non-ABPA controls, and the mean level was significantly below the recommended level of 30 ng/ml in CF.”

Any doctor who is diligently testing their patients for Vitamin D insufficiency knows that suboptimal levels are surprisingly common. Could this have something to do with relative malnutrition, time of year or geographic location? The authors’ data says “no”:

“Notably, there was no significant difference in BMI or vitamin A and E levels between ABPA and non-ABPA patients, suggesting that the relative vitamin D deficiency was not associated with relative malnutrition… To exclude potential environmental/geographical differences in our cohort, we used geographical information systems (GIS) mapping to determine whether there was geographical clustering of ABPA patients versus non-ABPA patients; however, this analysis did not identify significant clustering… Finally, there was no significant difference in terms of month of accrual in the study between the ABPA or non-ABPA cohort… Taken together, these findings strongly suggest that the relative 25-OH vitamin D deficiency observed in ABPA patients was not a surrogate marker of another variable…”

This research adds to the immense body of evidence regarding the importance of Vitamin D for immune regulati0n and the treatment of allergies and autoimmune diseases (along with a host of other conditions). How can you reliably know your Vitamin D status? Ask your doctor for a 25-hydroxy vitamin D blood test, and look for a level closer to the middle of the typical lab’s reference range rather than toward the bottom.

This is how metals and chemicals can provoke autoimmune disease

Posted on by
2

This review published in the International Archives of Allergy and Immunology gives a good description of how certain chemicals and metal ions can interact with proteins in our body to become recognizable to white blood cells, triggering inflammatory allergic or autoimmune disease. Key point: it doesn’t have to be enough of a chemical or metal like mercury to cause a toxic (metabolically poisonous) effect—in a susceptible individual a relatively small amount of something in our food, environment or vaccine can set in motion a chronic disease. What makes a person susceptible? Various factors are evaluated in the functional medicine model.

Have cow’s milk allergy? Goat and sheep allergies are possible

Posted on by
1

If you have confirmed an allergy to cow’s milk it is not guaranteed that you can tolerate goat and sheep milk. As this recent study published in the journal Current Opinion in Allergy and Clinical Immunology notes, this may apply mainly to IgE-mediated (acute hypersensitivity) milk allergy. When in doubt, the elimination-provocation test is the immunological gold standard (the foods in question are eliminated from your diet and re-introduced later while observing carefully for symptoms).