Archive for the ‘Autoimmune’ Category

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Why are autoimmune and allergic diseases on the rise?

Friday, September 3rd, 2010

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.”

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Neurological disease with GAD antibodies and gluten sensitivity

Thursday, September 2nd, 2010

GAD (glutamic acid decarboxylase) antibodies are expressed in type 1 (autoimmune) diabetes, adrenal failure (Addison disease), autoimmune thyroid diseases, premature ovarian failure, myasthenia gravis, pernicious anemia, Stiff-man syndrome and a number of other disorders. An informative study recently published in Acta Neurologica Scandinavica documents the link between these conditions and gluten sensitivity. The authors state:

“The high prevalence of gluten sensitivity in patients with stiff-person syndrome (SPS) lead us to investigate the relationship between gluten sensitivity and GAD-antibody-associated diseases.”

They used ELISA assays for GAD antibodies and serological markers of gluten sensitivity that generated compelling data:

“”Six of seven (86%) patients with SPS were positive for anti-GAD…This compared with 9/90 (11%) patients with idiopathic sporadic ataxia…16/40 (40%) patients with gluten ataxia…and 6/10 patients with type 1 diabetes only…”

Note that the serological tests for gluten sensitivity are a blunt instrument—only 40% of confirmed cases of gluten ataxia were recognized. The abundance of false negatives is why the gluten gene sensitivity test is so valuable.

Additionally, the authors found that…

“The titre of anti-GAD reduced following the introduction of a gluten-free diet in patients with SPS who had serological evidence of gluten sensitivity.”

Their conclusion is simply stated:

“These findings suggest a link between gluten sensitivity and GAD antibody-associated diseases.“

This study is especially interesting in connection with earlier research published in the journal Psychiatry. The authors set out to investigate the role of GAD antibodies in schizophrenia and related disorders:

“We hypothesized that GAD antibodies are increased in patients with chronic psychotic disorders. The aim of this pilot study was to compare the level of GAD antibodies in patients with chronic psychotic disorders with normal controls.”

By way of background they note that:

“The role of GABAergic neurotransmission in epilepsy, anxiety disorders, schizophrenia, and premenstrual dysphoric disorder has been a subject of some recent investigations. Absence of structural abnormalities in the brains of most patients with chronic psychotic disorders has always raised suspicion for an alternative pathogenesis and a possible functional disturbance at the neuronal/cellular level. Glutamic acid decarboxylase (GAD)…is involved in the formation of gamma aminobutyric acid (GABA) a central inhibitory neurotransmitter of the nervous system. Antibodies to GAD may impair GABA formation or inhibitory function.“

What did the data show?

“Serum levels of GAD antibodies in 12 patients with chronic psychotic disorders (schizophrenia and schizoaffective disorders) and 10 age-matched healthy control subjects were evaluated… Antibodies to GAD in patients with chronic psychotic disorders have a higher mean than nonpatient control individuals.”

The authors’ conclusion alerts the practitioner to be on the lookout:

“Antibodies to GAD65 are peripherally present in patients with chronic psychotic disorders (schizophrenia/schizoaffective disorders)... The presence of such antibodies also suggests a possible role for autoimmune mechanism in the pathogenesis of these disorders. In summary, from a practicing psychiatrist’s point of view, measurements of antibodies to GAD65 could potentially be used to screen for chronic psychotic disorders and for diabetes mellitus very early on in the disease process.”

GAD (glutamic acid decarboxylase) produces GABA, the most abundant inhibitory (calming) neurotransmitter in the body. Suboptimal levels can manifest as anxiety, insomnia, hyperarousal, panic, feeling overwhelmed, disorganized attention, restlessness, worry, tension, inner excitability, inability to relax, etc.

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Acetyl-L-carnitine protects the brain from alcohol-induced damage

Tuesday, August 31st, 2010

Alcohol in excess is a significant promoter of accelerated neurodegeneration. The authors of a welcome paper recently published in Free Radical Biology and Medicine first elucidate the…

“…cellular and biochemical mechanisms of alcohol-induced oxidative damage in different types of brain cells.”

Interestingly, alcohol administration generated increased levels of reactive oxygen species (‘free radicals’) localized mainly in the astrocytes and microglia (‘housekeeper’ immune cells in the brain). As a result,

“Oxidative damage in glial cells was accompanied by their pronounced activation (astrogliosis) and coincident neuronal loss, suggesting that inflammation in glial cells caused neuronal degeneration.“

In other words, the oxidative stress induced by alcohol resulted in an autoimmune inflammatory attack on brain tissue. But here’s the good news:

“Co-administration of ALC [acetyl-L-carnitine] with alcohol showed a significant reduction in oxidative damage, neuronal loss and a restoration of synaptic neurotransmission in this brain region, suggesting that ALC protects brain cells from ethanol-induced oxidative injury. These findings suggest the potential clinical utility of ALC as a neuroprotective agent that prevents alcohol-induced brain damage and development of neurological disorders.”

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Feeling uncoordinated? Gluten sensitivity and ataxia

Wednesday, August 25th, 2010

A paper published a while back in the prestigious medical journal The Lancet is a useful reminder of a common neurological disorder resulting from gluten sensitivity that manifests as problems with coordination and balance. The authors state:

“Ataxia is the commonest neurological manifestation of coeliac disease. Some individuals with genetic susceptibility to the disease have serological evidence of gluten sensitivity without overt gastrointestinal symptoms or evidence of small-bowel inflammation. The sole manifestation of disease in such patients may be ataxia.”

The authors carried out clinical, neurophysiological, neuroradiological, and neuropathological examinations patients with antibodies to gliadin (the immunoreactive component of gluten):

“28 patients with gluten ataxia were identified. All had gait ataxia and most had limb ataxia….16 patients had no gastrointestinal symptoms…Six patients had evidence of cerebellar atrophy on magnetic-resonance imaging. Necropsy was done on two patients who died; there was lymphocytic infiltration of the cerebellum, damage to the posterior columns of the spinal cord, and sparse infiltration of the peripheral nerves.”

A key point is that most of the patients whose gluten sensitivity caused severe neurological damage had no gastrointestinal symptoms.

The authors conclude:

“Gluten sensitivity is an important cause of apparently idiopathic ataxia and may be progressive. The ataxia is a result of immunological damage to the cerebellum, to the posterior columns of the spinal cord, and to peripheral nerves.“

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Changes in gut flora can ‘turn on’ autoimmune genes

Friday, August 6th, 2010

A fascinating study just published in the journal Cell sheds light on how the genetic susceptibility to autoimmune disease can be activated by changes in gut flora, in this case the interaction of a virus with intestinal bacteria. The authors describe their findings:

“Here we demonstrate that an interaction between a specific virus infection and a mutation in the Crohn’s disease susceptibility gene Atg16L1 induces intestinal pathologies in mice…These pathologies triggered by virus-plus-susceptibility gene interaction were dependent on TNFα and IFNγ [pro-inflammatory cytokines] and were prevented by treatment with broad spectrum antibiotics. Thus, we provide a specific example of how a virus-plus-susceptibility gene interaction can, in combination with additional environmental factors and commensal bacteria, determine the phenotype [functional expression] of hosts carrying common risk alleles [genotype] for inflammatory disease.”

A perspective on this work published in Science Translational Medicine helps us to appreciate the significance of this research:

“…these findings link host genotype and viral infection with a response to chemical challenge, resulting in Crohn’s-like symptoms, a virus–plus–susceptibility gene interaction. However, the story gets even more complicated, because this interaction was shown to depend not only on the host inflammatory cytokines TNF-α and interferon-γ, but also on the gut microbiome…These findings are consistent with other models of IBD that are clearly dependent on the presence of gut bacteria and can be produced in germ-free mice colonized with defined bacterial consortia in the absence of a viral trigger.”

The practical message for the clinician and patient is that genetic susceptibility to an autoimmune disease can be triggered by alterations in the gut flora with compromise of the intestinal barrier (‘leaky gut’):

“These studies suggest that the microbiota is a key component of colitis; in mouse models, colitis develops in the context of abnormal adaptive or innate immune responses that fail to prevent translocation across the epithelial layer and the presentation of gut bacteria to immune cells ['leaky gut'], or result in excess activation of the adaptive immune system [dysregulated immune response].”

As we know, once these genes are ‘turned on’ they can’t be turned off. Autoimmune disease can be managed with the correct functional approach; the term ‘cure’ is not justified:

“A fascinating observation from Cadwell et al. is that susceptibility to colitis induction can be switched from off to on; mice in a colitis-resistant state before infection with the virus become susceptible to injury-induced colitis after viral infection, and, once the colitis-sensitive state is induced, cannot go back to a colitis-resistant state.”

Rational therapy that offers the chance to manage autoimmune disease for a much higher quality of life must address the microflora and their interactions with the human immune system along with other factors that modify the expression of the autoimmune potential:

“All of these diverse findings suggest that it is necessary to take into account multiple facets of the human microbiome when considering complex diseases such as Crohn’s. Polymorphisms in key susceptibility genes in our human genome, such as ATG16L1, may only serve to weaken the first link in the chain that protects the intestinal epithelia from a combination of viral infection, microbial stimulation of inflammation, and other dietary or xenobiotic factors.”

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Bulimia and brain inflammation

Thursday, August 5th, 2010

Bulimia nervosa is another example of a behavioral condition that for thorough assessment, treatment and optimal outcomes should be examined for its neuroinflammatory component. Consider this paper published in the journal Clinical Endocrinology that identifies the brain as the source of the inflammatory cytokine TNF-α (tumor necrosis factor alpha) in individuals suffering with bulimia.

“Tumor necrosis factor-α (TNF-α) is a cytokine with numerous immunological and metabolic activities. In addition, TNF-α can stimulate a variety of physiological, neuroendocrine and behavioural responses of the central nervous system. In experimental animals, TNF-α induces changes in physiological and behavioural parameters which have also been observed in eating disorders.”

They measured plasma concentrations of TNF-α and its receptors, TNF-RI and TNF-RII (which are shed in increased amounts when TNF-α is released) in bulimic individuals compared to normal controls. What did the data show?

“Plasma TNF-α concentrations in BN [bulimia nervosa] were significantly higher than those in N [the normal group]…plasma sTNF-RII concentrations in BN were significantly higher than those in N.”

Hence their conclusion:

“Our present findings suggest that the adipose tissue may not be the immediate source of TNF-α in bulimic patients but the increase in plasma TNF-α in these patients may be derived from the central nervous system sources.”

That means increased brain microglial inflammatory activity. The practical message is that bulimia nervosa should be evaluated with the appropriate objective tests to resolve the brain inflammation component, the foundation of the biological component of treatment for this disorder.

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Beneficial E. coli helps heal ulcerative colitis

Tuesday, August 3rd, 2010

The emerging science of the human microbiome and modulation of the immune system by introducing specific strains of probiotic flora into the gut and other microbial ecosystems is one of the most fascinating and promising developments in medicine. A study published some time back in the journal GUT (An International Journal of Gastroenterology and Hepatology) is among a number of investigations into the benefit of Escherichia coli Nissle 1917 in stimulating the immune system to heal ulcerative colitis:

“We compared the efficacy in maintaining remission of the probiotic preparation Escherichia coli Nissle 1917 and established therapy with mesalazine in patients with ulcerative colitis.”

The authors assigned 327 patients to receive either the Escherichia coli Nissle 1917 or mesalazine and evaluated the outcomes according to clinical, endoscopic  and histologic (tissue microscopic) indices over a twelve month period. Mesalazine is an anti-inflammatory medication administered by suppository that is not without concerns, and a suppressive palliation at best.

“The primary aim of the study was to confirm equivalent efficacy of the two drugs in the prevention of relapses.”

Wouldn’t it be better to stimulate the immune system to express healthier regulation if possible? The data established this notable conclusion:

“The probiotic drug E coli Nissle 1917 shows efficacy and safety in maintaining remission equivalent to the gold standard mesalazine in patients with ulcerative colitis. The effectiveness of probiotic treatment further underlines the pathogenetic significance of the enteric flora.”

This is but one example among many more you’ll be hearing about in this fascinating and promising area of research and clinical application.

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There is a broad range of neurologic disorders in children with gluten sensitivity

Monday, July 26th, 2010

This paper recently published in the journal Pediatrics draws attention to our concern for the non-celiac manifestations of gluten sensitivity, especially the neurological dimension. The authors note importantly that:

“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…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.”

They found a much greater prevalence of neurological disorders in children with CD compared to normal controls: 51.4% to 19.9%, including hypotonia, developmental delay, learning disorders and ADHD, headache, and cerebellar ataxia.

The authors conclude:

“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.”

Bear in mind that we are equally concerned with the neurologic manifestations of gluten sensitivity in the absence of celiac disease.

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Should you take Vitamin D for multiple sclerosis?

Tuesday, July 20th, 2010

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

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

The authors conclude their review by stating:

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

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Gluten sensitivity without celiac disease in the elderly: is there a concern?

Monday, July 19th, 2010

Scandinavian Journal of GastroenterologyOften tests shows anti-gliadin antibodies (AGA; gliadin is the immunoreactive component of gluten) in the absence of celiac disease but with various autoimmune conditions representing the non-celiac manifestations of gluten sensitivity. The authors of a study just published in the Scandinavian Journal of Gastroenterology explore this issue for the elderly.

“…data suggest that AGA positivity [without celiac disease] might be related to distinct disease entities such as allergy and gluten ataxia (loss of muscular coordination with unsteady movements and gait). Our aim here is to explore the clinical relevance of positive AGA in the elderly population.”

The authors correlated positive lab tests for gluten sensitivity with the incidence of depression and rheumatoid arthritis in 2815 individuals aged 52–74 years. What did their data show?

“Rheumatoid arthritis and depression were found significantly more often in AGA-positives than controls. The significance remained even when tTGA-positive and known celiac disease cases were excluded.”

Don’t forget that anti-gliadin antibody tests are not an absolute screen for gluten (or any other food) sensitivity because there are a number of factors that can suppress the expression of antibodies at the time of specimen collection. However, this study shows that if an elderly person is suffering from depression or rheumatoid arthritis the possibility of gluten sensitivity should be investigated.

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