Suicide and biomarkers of gastrointestinal inflammation

Suicide and gastrointestinal inflammation

Suicide mostly occurs in association with neuropsychiatric disorders characterized by neuroinflammation (brain inflammation). Neuroinflammation often results from perturbations of the brain-gut axis, with pro-inflammatory immune signaling from the gut to the brain. An important study just published in Psychiatry Research offers data showing the connection between biomarkers of gastrointestinal inflammation and recent suicide attempt. The authors were motivated by the intent to validate biomarkers to help assess, treat and prevent suicide attempts.

Most attempting suicide have an illness associated with neuroinflammation

“Psychological autopsy and epidemiological studies indicate that more than 90% of people who die by suicide have a diagnosable psychiatric illness, particularly major depression, bipolar disorder, or schizophrenia…The identification of blood-based markers would provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts.”

It is an urgent clinical need to identify causes that promote dysregulated activation of the immune system against the neuronal antigens.

The GI tract is often the source of immune activation against the brain

Biomarkers of gastrointestinal inflammation are frequently increased in neuropsychiatric disorders.

“Many individuals with schizophrenia and mood disorders have evidence of immune activation suggesting that immune dysregulation may be part of the etiopathology of these disorders. Studies by our group and others indicate that the gastrointestinal tract is often the primary source of this immune activation as evidenced by increased levels of markers of gastrointestinal inflammation in individuals with serious mental illness.”

IBD (inflammatory bowel disease) and celiac disease appear to increase risk for suicide.

“Furthermore, increased rates of suicide and suicide attempts have been found in some populations of individuals with celiac disease or inflammatory bowel diseases.”

But previous studies have focused on a lifetime history rather than attempts, so the authors set out to:

“…examine the association between levels of markers of gastrointestinal inflammation and a recent suicide attempt in individuals with schizophrenia, bipolar disorder or major depressive disorder in comparison with non-psychiatric controls.”

Elevated IL-6

Interleukin-6 (IL-6), a key pro-inflammatory cytokine which can arise from the GI tract, is associated.

“Results from other investigators indicate that inflammation may be associated not only with a proclivity for a psychiatric disorder, but specifically with suicidal behavior. Studies have found an association between a suicide attempt history and the level of cytokines such as IL-6 which are cell signaling molecules involved in the immune response and which can arise from inflammation from many sources, including the gastrointestinal tract”

Gluten and brain inflammation

Neuroinflammation triggered by non-celiac gluten sensitivity is also implicated:

“Gliadin is a component of gluten, found in wheat and related cereals. Antibody response to dietary gliadin is associated with celiac disease, an immune-mediated enteropathy, and with non-celiac wheat sensitivity and is thought to indicate intestinal inflammation and/or intestinal barrier dysfunction. We have found increased levels of antibodies to gliadin in individuals with schizophrenia and with bipolar disorder and in individuals with acute mania during a hospital stay…”

Additionally, loss of tolerance to a commensal yeast may promote neuroinflammation.

“We also have studied the antibody response to yeast mannans represented by antibodies to Saccharomyces cerevisiae (ASCA), a commensal organism present in some foods and in the intestinal tract of many individuals. Elevated ASCA levels are associated with increased intestinal inflammation. We have previously found increased levels of ASCA in individuals with mood disorders.”

Pathogens and loss of immune tolerance

Various pathogens present at low levels can elicit a persistent cross-reaction to self-antigens, including brain antigens, in individuals disposed to loss of immune tolerance.

“An association between elevated antibodies to Toxoplasma gondii, an apicomplexan parasite, and suicide attempts have also been reported. In a recent study, we found that individuals with serious mental illness who had a lifetime history of a suicide attempt had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV); we also found an association between the levels of these antibodies and the number of suicide attempts.”

Significant link found

Association between suicide and markers of GI inflammation

The authors examined data for 282 participants: 90 with schizophrenia, 72 with bipolar disorder, 48 with major depressive disorder, and 72 non-psychiatric controls; who were enrolled in ongoing studies of the role the immune response to infections in individuals with serious psychiatric disorders. Biomarkers measured included IgA antibody to yeast mannan from Saccharomyces cerevisiae (ASCA), IgG antibody to gliadin, IgA antibody to bacterial lipopolysaccharide (LPS) from E. coli O111:B4, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and levels of C-Reactive protein.

“We found a statistically significant difference between the recent attempters and the control group in levels of IgA ASCA; the level in the recent attempt group was significantly higher…We also found that the level of IgG antibodies to gliadin was significantly higher in the recent attempters vs. the control group…We also found that the level of IgA antibodies to bacterial lipopolysaccharide (LPS) was significantly higher in the recent attempters vs. the control group…In terms of CRP, we found that there was a significantly higher level in the past attempter group.”

Predicting risk and protecting patients

These findings offer a valuable opportunity for clinicians to gauge and ameliorate risk of suicide in patients with serious neuropsychiatric disorders.

“The markers of gastrointestinal inflammation are of interest because they can be readily measured in blood samples. In addition, some of the markers studied here may be an attractive target for therapeutic intervention since intestinal inflammation can be modulated by dietary interventions as well as the administration of available prebiotic, probiotic, and antibiotic medications.”

The authors conclude:

“Suicide, for which a previous suicide attempt is the greatest risk factor, is a major cause of death worldwide and is highly prevalent in patients with serious mental illness. Unfortunately, the ability to predict suicide remains limited and no reliable biological markers are available. The identification of blood-based markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.”

For additional categories of importance in evaluating neuropsychiatric risk see The Parents’ Guide to Brain Health.

ALS and gluten sensitivity

JAMA NeurologyALS (amyotrophic lateral sclerosis) is a devastating, lethal autoimmune disease characterized by progressive inflammatory degeneration of motor neurons in the brain cortex, brainstem and ventral (front half) of the spinal cord. Non-celiac gluten sensitivity often entails a neurological target for autoimmune attack in the absence of abdominal symptoms. In a study just published in JAMA Neurology, investigators report an association between some cases of ALS and gluten sensitivity. They state:

Celiac disease is an autoimmune disorder triggered by gluten in genetically predisposed individuals. Gluten sensitivity can cause neurologic manifestations, such as ataxia or neuropathy, with or without gastrointestinal symptoms. Many patients with gluten ataxia produce antibodies toward the newly identified neuronal transglutaminase 6 (TG6). Two case reports described patients initially diagnosed with amyotrophic lateral sclerosis (ALS) and ultimately with celiac disease who improved with a strict gluten-free diet.

To determine whether a gluten-related disorder mimicking ALS might occur in some patients they set out to look for celiac disease–related antibodies and HLA antigen alleles along with TG6 antibodies in patients with ALS compared to healthy individuals. They measured serum levels of total IgA antibodies, IgA antibodies to transglutaminase 2 (TG2) and endomysium, IgA and IgG antibodies to deamidated gliadine peptide, and TG6; and performed HLA antigen genotyping in 150 patients with ALS and 115 healthy volunteers. A striking picture emerged:

All patients and control group participants were seronegative to IgA antibodies to TG2, endomysium, and deamidated gliadine peptide. Twenty-three patients (15.3%) were seropositive to TG6 IgA antibodies as opposed to only 5 controls (4.3%). The patients seropositive for TG6 showed a classic picture of ALS, similar to that of seronegative patients.”

Clinical note

Practitioners should bear in mind the authors’ conclusion:

The data from this study indicate that, in certain cases, an ALS syndrome might be associated with autoimmunity and gluten sensitivity. Although the data are preliminary and need replication, gluten sensitivity is potentially treatable; therefore, this diagnostic challenge should not be overlooked.

Intestinal barrier damage from food additives and pesticides

Autoimmunity ReviewsIntestinal barrier damage from food additives and pesticides/herbicides contributes to autoimmune disease. The intestinal barrier—epithelial cells forming the inner lining of the intestines—is designed for nutrient absorption while protecting the GALT (gut associated lymphoid tissue, the greatest mass of immune system tissue in the body) from compounds that should not gain access. Damage to the tight junctions of the intestinal barrier is a major contributing cause of loss of immune tolerance and autoimmune disease. When the intestinal barrier is breached, the immune system can become sensitized to compounds that either ‘mimic’ the body’s own antigens due to similarity or combine with them to form a hybrid called a hapten. In either case, as the immune system reacts to the compound that has penetrated the intestinal barrier it can cross-react to self-antigens, thus mounting an inflammatory attack on the body’s own tissues. This is how diminished intestinal barrier integrity is contributing to the pandemic of diffuse and blatant autoimmune phenomena.

Food additives promote autoimmunity by damaging the intestinal barrier

In a paper published recently in Autoimmunity Reviews, the authors link industrial food additives to intestinal barrier damage that leads to loss of immune tolerance. They note:

“The incidence of autoimmune diseases is increasing along with the expansion of industrial food processing and food additive consumption…The intestinal epithelial barrier, with its intercellular tight junction, controls the equilibrium between tolerance and immunity to non-self-antigens. As a result, particular attention is being placed on the role of tight junction dysfunction in the pathogenesis of AD [autoimmune disease]. Tight junction leakage is enhanced by many luminal components, commonly used industrial food additives being some of them.”

 Crucial role of the intestinal barrier

The authors offer a review of the intestinal barrier tight junctions that are crucial for the healthy immune system regulation:

“Only a single layer of epithelial cells separates the luminal contents from effector immune cells in the lamina propria and the internal milieu of the body. Breaching this single layer of epithelium can lead to pathological exposure of the highly immunoreactive subepithelium to the vast number of foreign antigens in the lumen. The permeability of the intestinal epithelium depends on the regulation of the mucosal immune system and intercellular tight junction (TJ).”

Integrity and protection of the intestinal barrier depends on a network of key proteins:

Zonulins, occludins, claudins and junctional adhesion molecules are a few examples that modulate movement of fluid, macromolecules and leukocytes from intestinal lumen to the blood stream and vice versa. In addition, these TJ proteins are involved in protecting the epithelial cells of the intestine against colonization by microorganisms. It is now apparent that TJs are dynamic structures that are involved in developmental, physiological and pathological processes. They regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular TJs, controls the equilibrium between tolerance and immunity to non-self antigens…in addition to genetic predisposition and exposure to triggering non-self antigens, the loss of protective function of mucosal barriers that interact with the environment is necessary for autoimmunity to develop.”

Influences on intestinal barrier tight junctions

Clinicians need to constantly bear in mind factors that commonly have an impact on intestinal barrier integrity. Here the authors note some of the very common ones:

“Pathophysiological regulation of tight junctions is influenced by many factors, including: secretory IgA, enzymes, neuropeptides, neurotransmitters, dietary peptides and lectins, yeast, aerobic and anaerobic bacteria, parasites, proinflammatory cytokines, free radicals and regulatory T-cell dysfunction.”

Food additives induce AD

Sequential steps through which industrial food additives induce autoimmune diseases. Commonly used industrial food additives abrogate human epithelial barrier function.

In addition to these ‘classics’, they list seven food additives whose increase in use has paralleled the sharp increase in autoimmune disease:

  1. Sugars: “Glucose is known as an absorption enhancer…found to increase permeability and produce changes in distribution of the main protein of the tight junction in the human cell line Caco-2, indicating intercellular leakage.”
  2. Salt: besides driving TH17-associated proinflammatory cytokines (a ‘key player’ in autoimmune inflammation), “…increased salt consumption is an enhancer of intestinal permeability through the TJ machinery.”
  3. Emulsifiers and surfactants: “… widely used in the bakery, confectionary, dairy, fat and oil, sauces, butter and margarine, ice cream, cream liqueurs, meat, coffee, gum, beverages, chocolate and convenient food industries…Numerous synthetic surfactant food additives have been shown to increase the intestinal permeability through paracellular and/or transcellular mechanisms.” By adversely affecting the hydrophobic intestinal barrier mucus layer, epithelial cell membranes and the transport protein p-glycoprotein, they cause “…destabilization of tight junctions between the GI epithelial cells, thus increasing intestinal leakage.” Note for clinicians prescribing essential fatty acids: “Surface active compounds, like oleic and docosahexaenoic acids, compromised the integrity of the intestinal epithelium and enhanced the paracellular absorption of poorly absorbed hydrophilic substances. In general, fatty acids like EPA, DHA, γLA, capric and lauric acids increase TJ permeability.”
  4. Organic solvents: “Some nutrients like glutamine and polyphenols protect TJ barrier integrity, in contrast, several organic solvents used in the food and beverage industries, like alcohol and its metabolites impair the TJ barriers.”
  5. Gluten: “Evidence exists that intestinal barrier defects have a role in initiating celiac disease. A number of in vitro studies have confirmed the cytotoxicity of gluten’s main antigen, gliadin. Gliadin has agglutinating activity, reduces F-actin content, inhibits cell growth, induces apoptosis, alters redox equilibrium and causes a rearrangement of the cytoskeleton through the zonulin pathway and the loss of TJ competence in the gastrointestinal mucosa…Gliadin causes zonulin release by binding to the CXCR3 receptor in intestinal cells via a MyD88-dependent pathway and subsequent transactivation of EGFR by PAR2, leading to small intestine TJ disassembly.” See more on intestinal barrier damage from gluten in non-celiac gluten sensitivity below.
  6. Microbial transglutaminase (mTG): used to modify the function of proteins in food products. ” There are more than half a dozen ways “…mTG may increase intestinal permeability by cross-linking amino acids or protein.”
  7. Nanoparticles: “Permeation studies showed that nanoparticles opened the tight junctions of monolayer Caco-2 cells and increased paracellular transportation. The signaling mechanism initiating the cascade of disruption of the TJ, was elucidated recently…”

Eat clean natural foods to preserve the intestinal barrier and calm autoimmunity

The bottom line is that there are several mechanisms by which industrial food additives can damage the intestinal barrier and contribute to loss of immune tolerance. The authors conclude:

“The food and beverage industries are constantly changing and transforming our food composition through new food processing technologies. The result is neo-linked, transformed molecules and delivery systems, representing intestinal mucosal load with altered physicochemical and immunogenic properties…Glucose, salt, emulsifiers, organic solvents, gluten, mTG, and nanoparticles are extensively and increasingly used by these industries to improve the qualities of the food (as claimed by manufacturers and some consumers). However, all these food additives increase intestinal permeability by bringing about TJ paracellular transfer. In fact, TJ dysfunction is common in multiple AD [autoimmune disease] and the central part played by the TJ in AD pathogenesis has been extensively described.”

 Glyphosate (Roundup®) promotes celiac disease and gluten intolerance

Interdisciplinary ToxicologyThe herbicide glyphosate (Roundup®) persists in the wheat kernel when used as a ‘dessicant’ to speed harvesting and causes damage to the intestinal barrier as described in an extensive paper published in Interdisciplinary Toxicology. The authors note:

Celiac disease is associated with imbalances in gut bacteria that can be fully explained by the known effects of glyphosate on gut bacteria. Characteristics of celiac disease point to impairment in many cytochrome P450 enzymes, which are involved with detoxifying environmental toxins, activating vitamin D3, catabolizing vitamin A, and maintaining bile acid production and sulfate supplies to the gut. Glyphosate is known to inhibit cytochrome P450 enzymes. Deficiencies in iron, cobalt, molybdenum, copper and other rare metals associated with celiac disease can be attributed to glyphosate’s strong ability to chelate these elements. Deficiencies in tryptophan, tyrosine, methionine and selenomethionine associated with celiac disease match glyphosate’s known depletion of these amino acids.”

Glyphosate causes gut dysbiosis

Disruption of the gut microbial ecology is one mechanism by which the intestinal barrier is compromised leading to loss of tolerance to gluten (and other foods).

“…a broad-spectrum herbicide, considered to be nearly nontoxic to humans…Glyphosate suppresses 5-enolpyruvylshikimic acid-3-phosphate synthase (EPSP synthase), the rate-limiting step in the synthesis of the aromatic amino acids, tryptophan, tyrosine, and phenylalanine, in the shikimate pathway of bacteria, archaea and plants…Humans do not possess this pathway, and therefore we depend upon our ingested food and our gut microbes to provide these essential nutrients. Glyphosate…has been shown to disrupt gut bacteria in animals, preferentially killing beneficial forms and causing an overgrowth of pathogens….celiac disease is associated with a reduced presence in the gut of commensal bacteria such as Lactobacilli and Bifidobacteria, which are known to be preferentially killed by glyphosate, and with an overabundance of C. difficile, which is known to be promoted by glyphosate exposure.”

 Pesticides and herbicides—it’s much worse than it already seems

BioMed Research InternationalWhen the designated active principle (AP) is combined with the other chemicals in a commercial formulation toxicity is greatly increased. Studies done to assess the toxicity of pesticides typically test the main active ingredient, such as glyphosate in Roundup® (hence it’s classification as relatively non-toxic to humans). In practice, however, these primary agents are applied as compound formulations. The authors of a study published in BioMed Research International compared the toxicity of the ‘active ingredients’ of nine major pesticides, herbicides and fungicides with that of the commercial compound formulations actually used in practice. They state:

Pesticides are used throughout the world as mixtures called formulations. They contain adjuvants, which are often kept confidential and are called inerts by the manufacturing companies, plus a declared active principle, which is usually tested alone. We tested the toxicity of 9 pesticides, comparing active principles and their formulations, on three human cell lines (HepG2, HEK293, and JEG3). Glyphosate, isoproturon, fluroxypyr, pirimicarb, imidacloprid, acetamiprid, tebuconazole, epoxiconazole, and prochloraz constitute, respectively, the active principles of 3 major herbicides, 3 insecticides, and 3 fungicides. We measured mitochondrial activities, membrane degradations, and caspases 3/7 activities.”

The results of their investigation are hair-raising:

“Fungicides were the most toxic from concentrations 300–600 times lower than agricultural dilutions, followed by herbicides and then insecticides, with very similar profiles in all cell types…Most importantly, 8 formulations out of 9 were up to one thousand times more toxic than their active principles. Our results challenge the relevance of the acceptable daily intake for pesticides because this norm is calculated from the toxicity of the active principle alone. Chronic tests on pesticides may not reflect relevant environmental exposures if only one ingredient of these mixtures is tested alone.”

Commenting on these principles and the current regulatory practice in general:

“Adjuvants in pesticides are generally declared as inerts, and for this reason they are not tested in long-term regulatory experiments. It is thus very surprising that they amplify up to 1000 times the toxicity of their APs in 100% of the cases where they are indicated to be present by the manufacturer. In fact, the differential toxicity between formulations of pesticides and their APs now appears to be a general feature of pesticides toxicology. As we have seen, the role of adjuvants is to increase AP solubility and to protect it from degradation, increasing its half-life, helping cell penetration, and thus enhancing its pesticidal activity and consequently side effects. They can even add their own toxicity. The definition of adjuvants as “inerts” is thus nonsense; even if the US Environmental Protection Agency has recently changed the appellation for “other ingredients,” pesticide adjuvants should be considered as toxic “active” compounds.”

Regarding Roundup® in particular:

“It is commonly believed that Roundup is among the safest pesticides. This idea is spread by manufacturers, mostly in the reviews they promote, which are often cited in toxicological evaluations of glyphosate-based herbicides. However, Roundup was found in this experiment to be 125 times more toxic than glyphosate. Moreover, despite its reputation, Roundup was by far the most toxic among the herbicides and insecticides tested. This inconsistency between scientific fact and industrial claim may be attributed to huge economic interests, which have been found to falsify health risk assessments and delay health policy decisions.”

Contributing to the vast increase in autoimmunity

There are multiple environmental factors contributing to the widespread increase in both undifferentiated and full-blown autoimmune disorders in clinical practice. Damage to the intestinal barrier is one of the most important. This data highlights the importance of consuming natural, unprocessed, non-toxic organic food for immune system health, with implications for regulatory and public health policy.

Gluten free labeled foods not always gluten free

Journal of Food ProtectionGluten free labeling is, sadly, not a guarantee of safety for those with celiac disease or non-celiac gluten sensitivity as demonstrated in a study recently published in the Journal of Food Protection. The authors state:

“Gluten is the main storage protein in grains and consists of gliadin and glutenin occurring in the same ratio. Persons suffering from intolerances, including celiac disease, must avoid foods containing gluten or products containing wheat, barley, and rye… This study was designed to determine the concentrations of gluten in foods labeled “gluten free” available in the United States.”

Gluten found in diverse products

Many sources of gluten are far from obvious and it may not occur to question whether a product is gluten free.

“Gluten is found not only in all products made with wheat, rye, and barley but also as an ingredient in foods including meat, sausages, soups, and ready-to-eat meals. Due to its physicochemical characteristics, gluten is used in food products to modify both texture, e.g., as a thickener to improve texture and water or fat retention, and form, e.g., to increase the extensibility. Gluten can also be used as an animal protein substitute in meat products to reduce manufacturing costs. Furthermore, gluten and wheat starch are found in some drugs as a filler.”

 Standards for ‘Gluten Free’ labeling

There is a significant difference between gluten free and ‘‘foods specially processed to reduce gluten content’’ or ‘‘very low gluten’’.

“To be labeled ‘‘gluten free,’’ products must contain less than 20 mg/kg gluten, i.e., equivalent to 10 mg/kg gliadin, while foods labeled as ‘‘foods specially processed to reduce gluten content’’ or ‘‘very low gluten’’ must comply with levels between 20 and 100 mg/kg. In October 2013, the U.S. Food and Drug Administration (FDA) issued a final rule to define the term ‘‘gluten free’’ for voluntary use in the labeling of foods. According to the final rule, gluten free means that the food bearing the claim does not contain (i) an ingredient that is a gluten-containing grain (e.g., spelt wheat), (ii) an ingredient that is derived from a gluten-containing grain and has not been processed to remove gluten (e.g., wheat flour), or (iii) an ingredient that is derived from a gluten-containing grain and has been processed to remove gluten (e.g., wheat starch) if the use of that ingredient results in the presence of 20 mg/kg or more gluten in the food, or it means that the food (iv) inherently does not contain gluten, and food with any unavoidable presence of gluten that is below 20 mg/kg gluten can be labeled as gluten free.”


Cross-contamination of products inherently gluten free can occur in production, transportation and storage.

“Cross-contamination of inherently gluten-free foods can occur at all stages of the food chain, including when they are grown, harvested, and/or processed. Comingling of grain in the field can occur because of crop rotation with wheat, barley, or rye if they are grown next to or in rotation with these grains. It is possible that seeds of the gluten-containing grains will linger in the soil and, as a result, some of the gluten-containing grain may be collected during the same harvest with the inherently gluten-free grain. Sharing of storage facilities where relevant, such as in grain elevators, can result in co-mingling of grains. Further, using the same transportation vehicles for moving the grains to the processing site and sharing of processing facilities and equipment within those facilities can also result in cross-contamination. The presence of wheat in oats is a good example of on-farm cross-contamination…If cross-contamination occurs at any stage in the food chain, undeclared glutens can end up in the processed food products…A few small studies have shown that contamination may occur in gluten-free foods or inherently gluten-free grains and their milled fractions, such as oats, millet flour, and sorghum flour. In addition, gluten has been detected in rice-, corn-, oat-, and buckwheat-based foods with or without the gluten-free label. Hence, the aim of the present study was to analyze foods in the U.S. market labeled gluten free for gluten contamination.”

So the authors randomly collected 78 commercially available samples labeled gluten free were from different local markets in Moscow, Idaho and analyzed them for gliadin content by competitive enzyme-linked immunosorbent assay. Their data engenders concern and vigilance for anyone who truly needs to avoid gluten:

Breakfast cereals were the most frequently contaminated

“Based on the gluten levels of samples, 48 of the 78 (61.5%) products contained gluten below the limit of quantification (less than 10 mg/kg gluten). Fourteen of the 78 (17.9%) products contained a detectable amount of gluten ranging from 10.9 to 18.7 mg/kg. Sixteen (20.5%) of the 78 would not be considered gluten free under the proposed FDA rules for gluten-free labeling. Among other parameters, foods labeled gluten free must contain <20 ppm gluten to be labeled gluten free. The gluten contamination frequency was highest in breakfast cereal (62.5%), followed by bread (37.5%), pasta (23.1%), snack food (13.3%), and baking mix (11.1%).”

Rice and corn products are attractive to those avoiding gluten but are not free of treachery:

“Being the most popular ingredients in gluten-free products, rice and corn might be considered to be safer cereal-based foods for CD patients…of the 16 gluten-contaminated samples, the most contaminated gluten-free food samples were made with rice, corn, or mixed grains, including seven rice-based foods, three corn-based foods, and six mixed-grain-based foods. Moreover, all of 6 mixed-grain-based samples included rice flour. According to our data, the most contaminated samples labeled gluten free were made from rice or corn and the levels of contamination were less than 50 mg/kg gluten.”

 Gluten free mislabeling is a world-wide problem

The concern is similar for Europeans and Canadians:

“A few previous studies have examined gluten in gluten- free foods and reported cross-contamination of 14 to 22% in inherently gluten-free foods and 46% in products based on gluten-free wheat starch produced by a deglutination process. According to Valde ́s et al., a study of more than 3,000 gluten-free foods in Europe showed that one third had gluten levels higher than 20 mg/kg, which is above the gluten-free threshold. Another study reported that 5% of 1,583 different products labeled as gluten free contained gluten. In a study of Canadian cereal foods, about 10% of the 77 gluten-free foods were contaminated with gluten.”

Bottom line on gluten free labeling

More rigorous standards of compliance are necessary to ensure the dependability of products labeled or presumed to be gluten free. A product such as rice or corn is being intrinsically gluten free is not sufficient to confirm that it is.

Products made from inherently gluten-free crops that are labeled gluten free but are not tested to be gluten free may be deemed misbranded if the label implies that all inherently gluten-free crops are free of gluten, since these inherently gluten-free grains, such as rice, corn, and buckwheat, can be contaminated with gluten.”

The authors conclude by recommending the measurement of gluten in all grain based products:

“Under the proposed FDA rule for labeling of foods as gluten free, manufacturers who voluntarily choose to label their single-ingredient grain products as gluten free will have to imply to consumers that since all inherently gluten-free grains, such as rice, corn, millet, buckwheat, and sorghum, are gluten free by nature, their products using these grains are gluten free; this does not guarantee, though, that there will be no gluten contamination. …Statements such as ‘‘all millet is gluten free’’ can be misleading and potentially harmful to the consumer with CD who requires a strict gluten-free diet. Therefore, the determination of gluten in all grain-based products, including those made with inherently gluten-free grains or ingredients, is recommended. This study shows that there is no guarantee that products labeled gluten free are in fact gluten free, which could be harmful for patients with CD.”

What should practitioners and patients do?

Avoiding gluten is necessary in cases of celiac disease or non-celiac gluten sensitivity but is not recommended in the absence of objective evidence of intolerance. The clinical manifestations of both can be widely diverse and a high degree of suspicion is warranted, not only with chronic unexplained gastrointestinal complaints but also a wide range of disorders with an autoimmune component. A comprehensive Wheat/Gluten Proteome Reactivity & Autoimmunity™ panel is necessary to avoid false negatives.

When indicated diligence in remaining gluten free is warranted, but it is unrealistic to expect that inadvertent exposure will never occur. Overall case management mandates a treatment plan that includes support for immune tolerance and regulation of inflammation. Additionally, supplementation during times of heightened risk (such as eating meals outside the home) with enzymes that break down gliadin and wholesome natural anti-inflammatory agents can significantly ameliorate the effect of inadvertent exposure.

Eating disorders and the causative role of autoimmunity

PLOS ONEEating disorders are multifactorial; like other psychiatric conditions the causative role of auotimmune neuroinflammation is coming to the fore as evidenced by a study just published in PLoS One (Public Library of Science). The authors note regarding earlier reports relevant to autoimmunity in eating disorders:

“A prior autoimmune disease has recently been shown to increase the risk of mood disorders and schizophrenia. In addition, the risk of both mental disorders increased in a dose response pattern when autoimmune diseases and infections were assessed together. The role of autoimmune processes, such as various pathogens triggering autoantibodies cross-reactive with neuronal antigens (brain-reactive autoantibodies), has also been recognized in the pathogenesis of neuropsychiatric disordersincluding autism spectrum disorders, obsessive-compulsive disorder, tic-disorders, ADHD, post-traumatic stress disorder, and narcolepsy. Furthermore, pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) include anorexia nervosa (AN).”

Research suggests autoimmune processes to be involved in psychiatric disorders. We aimed to address the prevalence and incidence of autoimmune diseases in a large Finnish patient cohort with anorexia nervosa, bulimia nervosa, and binge eating disorder.”


Crohn’s disease and celiac disease have been suggested to act as triggers for the development of eating pathology, and individuals with celiac disease are reported to be at increased risk for eating disorders…To our knowledge, no large scale reports of the co-morbidity of autoimmune diseases and eating disorders have been published. 

So they compared 2342 patients with eating disorders compared to 9368 matched controls from the general population and correlated that with data for 30 autoimmune diseases and found a pertinent association:

“Of patients, 8.9% vs. 5.4% of control individuals had been diagnosed with one or more autoimmune disease. The increase in endocrinological diseases was explained by type 1 diabetes, whereas Crohn’s disease contributed most to the risk of gastroenterological diseases. Higher prevalence of autoimmune diseases among patients with eating disorders was not exclusively due to endocrinological and gastroenterological diseases; when the two categories were excluded, the increase in prevalence was seen in the patients both before the onset of the eating disorder treatment and at the end of the follow-up.”

Shared immunological mechanisms

In other words, the crucial point is that there are shared immunological mechanisms:

“We observed an increased risk for several autoimmune diseases among patients with eating disorders supporting the hypothesis of co-morbidity of these disorders and suggesting that immune-mediated mechanisms could play a role in the development of eating disorders. Importantly, our results were not restricted to the association of T1D with eating disorders as shown in previous studies. Instead, the association was seen for several autoimmune diseases with different genetic backgrounds. Our findings thus suggest that the link between eating disorders and autoimmune diseases is based on shared immunological mechanisms, rather than on the shared genetic background, e.g. the shared HLA risk genotype. In addition, our findings support earlier observations suggesting that autoimmune processes contribute to the onset and maintenance of eating disorders, at least in a subpopulation of patients.”

Chronic inflammation in psychiatric disorders

Chronic inflammation must be assessed in psychiatric disorders:

“Studies indicate that psychiatric disorders co-exist with inflammation, infections and autoimmune diseases, and shared vulnerability underlying many psychiatric disorders suggest that findings from one disorder may be relevant across categories. Pro-inflammatory cytokines and antibodies/autoantibodies against neuronal antigens could induce changes in neurotransmitter and neuroendocrine function, which may subsequently yield psychiatric manifestations. Studies suggest that pro-inflammatory cytokines may have a role in eating disorders.”

Pro-inflammatory cytokines

A key clinical point for clinicians, especially those of us who assess serum cytokines, is the fact that they may be elevated in the brain while remaining normal in the blood:

“It has also been suggested that pro-inflammatory cytokines might be overproduced in specific brain areas and act locally without concomitant increase in serum or immune production. Indeed, the pro-inflammatory cytokines are able to activate HPA axis, the hyperactivity of which in eating disorders has been established.”

Gut-brain axis

Regarding the role of the gut-brain axis and autoimmunity:

“Our findings are supported by the immunological studies performed in patients with eating disorders, where autoantibodies against peptides related to appetite-regulation, stress response, and social-emotional functioning (α-MSH, ACTH, ghrelin, oxytocin, vasopressin) were detected. The postulated role of intestinal microflora contributing to the development of cross-reactive neuronal autoantibodies provides a link between gut and brain…Gut microbiota is an important regulator of the immune system and its alteration has been associated with autoimmune diseases and immune-mediated disorders, such as allergies and T1D. Composition of the microbiota affects gut permeability, and the function of both innate and adaptive immune system including development of regulatory T-cells.”

Sex hormones

Practitioners must also bear in mind that sex hormone dysregulation, as noted earlier here, can contribute to loss of immune tolerance:

“…sex hormones modulate microbiota and the development of autoimmunity, as well as the eating disorders risk. The interplay between gut microbiome, immune regulation, and sex hormones thus provide one potential, complex mechanism underlying eating disorders and explaining the partly shared etiopathogenesis of eating disorders and autoimmune diseases.”

Medscape Medical News quotes the lead author:

“I was surprised about the robust link that we found between autoimmune diseases and eating disorders,” lead author Anu Raevuori, MD, PhD, from the Department of Public Health at the University of Helsinki, Finland.

“On the other hand, my clinical impression is that in many patients with eating disorders, particularly those with long-lasting and persistent symptoms, the disorder appears to have a biological background,” said Dr. Raevuori.

“…other lines of research suggest that some of those eating disorder patients that do not have a diagnosable autoimmune disease might have underlying autoimmunological factors, such as autoantibodies against peptides…related to appetite regulation, stress response, and social-emotional functioning, which could explain their symptoms.”

Anyone involved in case management for patients suffering from eating disorders should consider the authors’ summation:

“In conclusion, we observed the association between eating disorders and several autoimmune diseases with different genetic backgrounds. Our data support the findings from other studies indicating the role of immunological mechanisms at least in a subpopulation of patients with eating disorders. We recommend that clinicians treating patients with eating disorders consider the increased risk of autoimmune diseases and the possible role of autoimmune processes underlying these individuals’ somatic and neuropsychiatric symptoms related to mood disturbances, anxiety and disordered eating.”

Acne, a disorder of dysregulated inflammation

Journal of Clinical and Aesthetic DermatologyAcne vulgaris case management with sustainable, functional methods requires its recognition as a disorder of inflammation associated with loss of immune tolerance for a commensal skin bacteria. A paper published in the Journal of Clinical and Aesthetic Dermatology discusses how elucidating the role of inflammation in the pathology of acne is advancing our understanding:

“The conventional perspective of acne pathogenesis holds that Propionibacterium acnes, which is present on normal skin, colonizes the duct of the sebaceous follicle, causing an innate immune response and the progression from a so-called noninflammatory comedo to an inflammatory papule, pustule, or nodule. However, this viewpoint has come under increasing scrutiny over the last decade, as several lines of evidence have emerged suggesting that inflammation may exist throughout the lifecycle of the acne lesion, perhaps subclinically even before comedo formation. This evidence challenges the current nomenclature of noninflammatory versus inflammatory acne lesions and suggests that the nomenclature is both outdated and incorrect.”

Acne has always been considered an inflammatory disorder in its later stages, but emerging evidence indicates that acnes starts with inflammation.

“There has been little debate about the involvement of inflammation in the later stages of acne, manifested as clinically inflamed papules and pustules. Accumulating histological and immunological evidence, but increasingly also evidence derived from a clinical platform, supports the notion of inflammation as a fundamental process in the early development of acne lesions.”

In this regard…

“…relatively recent studies have suggested that inflammatory events may also occur very early in the development of acne lesions (microcomedones), even before the initial hyperproliferative changes. In these studies, the uninvolved skin from acne patients was found to contain elevated levels of CD3+ and CD4+ T cells in the perifollicular and papillary dermis and increased macrophage numbers similar to those seen in papules.

The role of Propionibacterium acnes

The association of P. acnes with acne vulgaris has been accepted for more than a century, but its central causative role is now being challenged.

“Although several early reports implicated P. acnes as the central causative factor in the development of inflammation in acne vulgaris, numerous observations are inconsistent with this notion. Leyden et al found a much higher density of Propionibacteria among patients with acne vulgaris compared with persons without acne, but failed to show an association between P. acnes density and severity of inflammation. Indeed, in this study, there was a lower density of P. acnes on the foreheads of patients with numerous large papules or pustules with or without nodulocystic lesions, than in individuals with no inflammatory lesions. Similarly, Leeming et al found no significant difference in the proportion of inflamed pilosebaceous units containing P. acnes when biopsied after 1 or 3 days of development, again failing to establish an association between P. acnes density and the development or progression of inflammatory lesions.”

Acne inflammation occurs even without P. acnes

Moreover, acne lesions can occur without the presence of P. acnes:

“Additionally, several independent studies have also shown that comedones are not universally colonized by P. acnes, supporting the argument that the micro-organism is not required for comedogenesis. Lavker et al studied follicular casts (“incipient or potential comedones”) taken from prepuberal children and children aged 9 to 12 years with open and closed comedones. They found no evidence of P. acnes colonization, raising the possibility that early events in comedo formation may occur in the absence of P. acnes. Given that a substantial proportion of comedones have been found to be sterile, it has been suggested that the micro-organisms found in inflammatory lesions are simply an extension of those already colonizing comedones and that their presence is not required for initiation of inflammation in acne…Considered collectively, these findings convincingly demonstrate that only a proportion of acne lesions, whether very early or clinically inflamed, contain micro-organisms. Thus, it appears that P. acnes is not required for the development of inflammation in acne lesions, regardless of the lesion type. That an inflammatory response can occur in the absence of P. acnes suggests that the inflammatory process is being driven via different immunochemical pathways independent of P. acnes. In this regard, accumulating evidence supports a significant role for the sebaceous gland in the development of inflammation in acne lesions.”

Inflammation in acne lesionsAfter reviewing the contribution of proinflammatory agents inclduing the cytokines IL-1 and IL-8, protease-activated receptor-2 (PAR-2), b-defensin-1 and b-defensin-2, peroxisome proliferator activated receptors (PPARs), peptidases and neuropeptides the authors conclude:

“Emerging data indicate that acne vulgaris is a primary inflammatory disease, with histological, immunological, and clinical evidence suggesting that inflammation occurs at all stages of acne lesion development. The immunochemical pathways underlying the initiation and propagation of the inflammation in acne are complex and still being elucidated, but may involve P. acnes. However, given that an inflammatory response can also occur in the absence of P. acnes, in both early and clinically inflammatory lesions, other pathways of inflammation, in addition to those requiring P. acnes for activation or propagation, must exist. These include various inflammatory pathways activated within and around the sebaceous gland, and perhaps other as yet unidentified pathways. Thus, because inflammation is critical to all types of acne lesions and is multifactorial, anti-inflammatory drugs can be expected to exert effects against all lesion stages, albeit via distinct mechanisms of anti-inflammation.”

Interleukin-1 (IL-1) and the NLRP3 inflammasome in Acne

Journal of Investigative DermatologyA study published recently in the Journal of Investigative Dermatology examines key inflammatory pathways in acne and highlights the role of IL-1β:

“Here we reveal a mechanism that regulates inflammatory responses to P. acnes. We show that IL-1β mRNA and the active processed form of IL-1β are abundant in inflammatory acne lesions. Moreover, we identify P. acnes as a trigger of monocyte–macrophage NLRP3-inflammasome activation, IL-1β processing and secretion that is dependent on phagocytosis, lysosomal destabilization, reactive oxygen species, and cellular K+ efflux. In mice, inflammation induced by P. acnes is critically dependent on IL-1β and the NLRP3 inflammasome of myeloid cells. These findings show that the commensal P. acnes—by activating the inflammasome—can trigger an innate immune response in the skin, thus establishing the NLRP3-inflammasome and IL-1β as possible therapeutic targets in acne.”

Key point: P. acnes is a commensal organism in the skin. The decisive factor is whether the immune system mounts an inflammatory reaction or not. This may be analogous to gastrointestinal disorders than ensue from the immune system having lost tolerance for commensal organisms in the gut.

The authors of a commentary in the same journal state:

“Such findings suggest that molecules targeting IL-1β and/or the NLRP3 inflammasome may constitute new treatment possibilities for acne vulgaris.”

Th17/IL-17 inflammatory cascade in acne

Inflammation driven by Th17 white blood cells and the cytokine interleukin-17 (IL-17) is a hallmark of autoimmunity. Evidence for their role in acne suggests that a loss of immune tolerance may be an important factor in developing an inflammatory reaction to P. acnes. Another study published last month also in the Journal of Investigative Dermatology offers details:

“Propionibacterium acnes is a Gram-positive commensal bacterium thought to be involved in the pathogenesis of acne vulgaris. Although the ability of P. acnes in the initiation of pro-inflammatory responses is well documented, little is known about adaptive immune responses to this bacterium. The observation that infiltrating immune cells consist mainly of CD4+ T cells in the perifollicular space of early acne lesions suggests that helper T cells may be involved in immune responses caused by the intra-follicular colonization of P. acnes. A recent report showing that P. acnes can induce IL-17 production by T cells suggests that acne might be a T helper type 17 (Th17)-mediated disease. In line with this, we show in this work that, in addition to IL-17A, both Th1 and Th17 effector cytokines, transcription factors, and chemokine receptors are strongly upregulated in acne lesions.”


“We show that both P. acnes-specific Th17 and Th17/Th1 cells can be found in the peripheral blood of patients suffering from acne and, at lower frequencies, in healthy individuals. We therefore identified P. acnes-responding Th17/Th1 cells as, to our knowledge, a previously unreported CD4+ subpopulation involved in inflammatory acne.”

The implication here is that the Th17/IL-17 inflammatory cascade is upregulated in people with acne by comparison.

The host response to P. acnes is decisive, not simply their presence

Journal of Dermatological ScienceThe authors of a study published in the Journal of Dermatological Science, while elucidating additional inflammatory agents, articulate the key point that Propionibacterium acnes can be present in skin without there being acne lesionsit is the host inflammatory response that determines whether or not they suffer from acne:

“The aim of the present study is to evaluate the importance of the immune response to P. acnes and the bacteriological factor in the pathogenesis of acne.”

To investigate they cultured P. acnes from both subjects with acne lesions and healthy volunteers, and examined the cytokine response of their peripheral blood mononuclear cells (PBMC) when stimulated with the viable P. acnes. Their was a clear difference:

IFN-γ, IL-12p40, and IL-8 mRNA and protein production were significantly increased in PBMC from acne patients compared to that from normal donors. However, different P. acnes species isolated from acne lesions or normal subjects showed no difference in cytokines production from acne patients and normal subjects PBMC.”

In other words, the strain of the P. acnes did not matter at all, only the host inflammatory response. So the authors conclude:

The inflammatory response of acne appears to be attributable to P. acnes-induced host immune response rather than P. acnes strains from normal skin or acne lesions.”

Immune regulating Vitamin A and Vitamin D ameliorate reaction to P. acnes

Journal of Investigative DermatologyAs might be expected for a condition characterized by a dysregulated immune inflammatory responseessentially loss of immune tolerance to P. acnes—with excessive IL-17 activity, the authors of another study published in the Journal of Investigative Dermatology found that Vitamin A and Vitamin D can help calm down the inflammatory reaction:

Acne vulgaris is the most common skin disorder affecting millions of people worldwide and inflammation resulting from the immune response targeting Propionibacterium acnes has a significant role in its pathogenesis. In this study, we have demonstrated that P. acnes is a potent inducer of T helper 17 (Th17) and Th1, but not Th2 responses in human peripheral blood mononuclear cells (PBMCs). P. acnes stimulated expression of key Th17-related genes, including IL-17A, RORα, RORc, IL-17RA, and IL-17RC, and triggered IL-17 secretion from CD4+, but not from CD8+ T cells…Furthermore, we found that the combination of IL-1β, IL-6, and transforming growth factor-β-neutralizing antibodies completely inhibited P. acnes–induced IL-17 production.”

They too found that the host response is decisive:

Importantly, we showed that IL-17-expressing cells were present in skin biopsies from acne patients but not from normal donors.”

And that Vitamin A and Vitamin D, both known to help normalize immune tolerance, can help:

“Finally, vitamin A (all-trans retinoic acid) and vitamin D (1,25-dihydroxyvitamin D3) inhibited P. acnes–induced Th17 differentiation. Together, our data demonstrate that IL-17 is induced by P. acnes and expressed in acne lesions and that both vitamin A and D could be effective tools to modulate Th17-mediated diseases such as acne.

 Acne and the gut-brain axis

Beneficial MicrobesAs with other autoimmune inflammatory disorders the potential role of the gut-brain axis should be considered with acne. The authors of a review article published in the journal Beneficial Microbes articulate the gut-brain-skin theory and several mechanisms by which intestinal dysbiosis and altered gut permeaiblity may contribute.

“Acne vulgaris has long been postulated to feature a gastrointestinal mechanism, dating back 80 years to dermatologists John H. Stokes and Donald M. Pillsbury. They hypothesised that emotional states (e.g. depression and anxiety) could alter normal intestinal microbiota, increase intestinal permeability, and contribute to systemic inflammation. They were also among the first to propose the use of probiotic Lactobacillus acidophilus cultures. In recent years, aspects of this gut-brain-skin theory have been further validated via modern scientific investigations. It is evident that gut microbes and oral probiotics could be linked to the skin, and particularly acne severity, by their ability to influence systemic inflammation, oxidative stress, glycaemic control, tissue lipid content, and even mood. This intricate relationship between gut microbiota and the skin may also be influenced by diet, a current area of intense scrutiny by those who study acne.”

Diet and acne: refined carbohydrates do the most harm

Journal of Drugs in DermatologyClarifying the issue of diet and acne, the authors of a paper published recently in the Journal of Drugs in Dermatology review the evidence and conclude that high glycemic carbohydrates are the main culprit:

“The prevalence of adult acne in the US appears to be increasing over the last few decades. But what’s behind the rise: is it nature or nurture? We are well aware that genetics can strongly influence a patient’s risk of developing acne. However, significant changes in germline genetic variants are unlikely to have occurred over the last 20 years. Consequently, we are forced to examine environmental variables, including diet.”

The authors acknowledge the confusion that had beset the topic of the role of diet in acne:

“The relationship between diet and acne, however, has been historically controversial. In the1930s through the 1960s, patients were regularly counseled regarding their dietary habits, as dietary triggers were thought to play a major role in acne. Following two critically impactful studies dietary restrictions were deemed no longer necessary. The idea that diet affected acne was relegated to myth. In 2007, one of the authors published a review in the JAAD re-implicating certain dietary factors in acne based on emerging evidence. This article concluded that refined carbohydrates and certain dairy products, in particular skim milk, appeared to be associated with acne. Since that review, several studies have been conducted, further elucidating which dietary factors play the largest role when it comes to acne. In this update, we present those studies and confirm our initial suspicion that refined carbohydrates are indeed the main dietary contributors to acne. This article is meant to serve as a follow up to that original JAAD publication, providing an update on the evidence linking diet and acne with a specific focus on carbohydrate intake.”

On extensive review of the evidence the authors conclude:

“Based on the data summarized here, dermatologists should encourage their acne patients to minimize their intake of high glycemic index foods.”

Celiac disease and acne

American Journal of Clinical DermatologyAs might be expected considering the role in acne of a dysregulated immune inflammatory response with loss of tolerance to P. acnes, a study examining isoretinoin use found that acne risk is increased in subjects with celiac disease. The authors were first concerned about the pro-inflammatory effect of isoretinoin in the gut:

Isotretinoin, a vitamin A analogue, can promote a pro-inflammatory milieu in the small intestine in response to dietary antigens. We hypothesized that oral isotretinoin exposure would increase the risk of celiac disease (CD).”

When they examined the data for 26,739 individuals with CD in all 28 pathology departments in Sweden the link with acne emerged:

“Ninety-three individuals with CD (0.35 %) and 378 matched controls (0.28 %) had a prescription of isotretinoin. This corresponded to an odds ratio (OR) of 1.22. Risk estimates were similar in men and women, and when we restricted our data to individuals diagnosed after the start of the Prescribed Drug Registry. Restricting our analyses to individuals diagnosed aged 12–45 years did not influence the risk estimates (OR 1.38). Meanwhile, having a diagnosis of acne was positively associated with CD (OR 1.34).”

Acne and Bee Venom Therapy

Journal of Investigative DermatologyConsidering evidence for the use of bee venom therapy (BVT) in other autoimmune inflammatory disorders, the authors of a study in the Journal of Investigative Dermatology examined its ability to palliate the inflammatory response to P. acnes:

“Melittin is the main component in the venom of the honey bee (Apis mellifera). It has multiple effects including antibacterial, antiviral, and anti-inflammatory activities in various cell types. However, the anti-inflammatory mechanisms of melittin have not been elucidated in Propionibactierium acnes (P. acnes)–induced keratinocyte or inflammatory skin disease animal models. In this study, we examined the effects of melittin on the production of inflammatory cytokines in heat-killed P. acnes–induced HaCaT cells. Heat-killed P. acnes–treated keratinocytes increased the expression of pro-inflammatory cytokines and Toll-like receptor 2. However, melittin treatment significantly suppressed the expression of these cytokines through regulation of the NF-κB and MAPK signaling pathways. Subsequently, the living P. acnes (1 × 107CFU) were intradermally injected into the ear of mice. Living P. acnes–injected ears showed cutaneous erythema, swelling, and granulomatous response at 24 hours after injection. However, melittin-treated ears showed markedly reduced swelling and granulomatous responses compared with ears injected with only living P. acnes. These results demonstrate the feasibility of applying melittin for the prevention of inflammatory skin diseases induced by P. acnes.”

Acne and lauric acid in coconut oil—stronger than benzoyl peroxide

Coconut oil is thought to be beneficial for the skin. Lauric acid has known antimicrobial properties and accounts for about half the fatty acids in coconut oil. Authors of a study in Effects of epicutaneous application of lauric acidthe same journal investigated its use against P. acnes:

“The strong bactericidal properties of lauric acid (C12:0), a middle chain-free fatty acid commonly found in natural products, have been shown in a number of studies…This study evaluated the antimicrobial property of lauric acid against P. acnes both in vitro and in vivo. Incubation of the skin bacteria P. acnes, Staphylococcus aureus (S. aureus), and Staphylococcus epidermidis (S. epidermidis) with lauric acid yielded minimal inhibitory concentration (MIC) values against the bacterial growth over 15 times lower than those of benzoyl peroxide (BPO). The lower MIC values of lauric acid indicate stronger antimicrobial properties than that of BPO. The detected values of half maximal effective concentration (EC50) of lauric acid on P. acnes, S. aureus, and S. epidermidis growth indicate that P. acnes is the most sensitive to lauric acid among these bacteria. In addition, lauric acid did not induce cytotoxicity to human sebocytes. Notably, both intradermal injection and epicutaneous application of lauric acid effectively decreased the number of P. acnes colonized with mouse ears, thereby relieving P. acnes-induced ear swelling and granulomatous inflammation. The obtained data highlight the potential of using lauric acid as an alternative treatment for antibiotic therapy of acne vulgaris…In conclusion, we demonstrated the antimicrobial property of lauric acid against P. acnes in vitro and its therapeutic effects on P. acnes-induced inflammation in vivo using the ICR mouse ear model. The obtained data highlight the potential of using lauric acid as an alternative treatment option to the antibiotic therapy of acne vulgaris.”

Clinical note: Although the last two papers describe palliative measure, the main point is that case management of acne must address the underlying causes that contribute to the dysregulated inflammatory response to P. acnes, similar to management of any other disorder characterized by the loss of immune tolerance.

Neuropsychiatric illness in non-celiac gluten sensitivity

Gastroenterology Research and PracticeNeuropsychiatric illness can result from neuroinflammation due to a variety of causes. Recent studies offer more evidence that depression and other neuropsychiatric disorders can be a manifestation of non-celiac gluten sensitivity. A paper published in Gastroenterology Research and Practice explores the pathophysiologic mechanisms by which gluten sensitivity can present as a variety of neuropsychiatric conditions in the absence of celiac disease. The authors note:

“…emerging scientific literature has noted a link between gluten ingestion and symptomatology from nearly every organ system, often in the absence of classic histological findings of CD on intestinal biopsy…It has been hypothesized for quite some time that gluten sensitivity may also impair central nervous system functioning. In 1996, Hadjivassiliou et al. found a significant difference in the prevalence of patients with positive antigliadin antibodies amongst those with neurological symptoms of unknown cause (57%) compared to a control group of healthy patients (12%). Amid the 57% who did have positive antibody titres, the majority did not demonstrate histological evidence diagnostic of celiac disease. In a 2010 article published in Lancet Neurology, Hadjivassiliou and colleagues published additional support for the link between gluten sensitivity and neurological manifestations, including ataxia, neuropathy, encephalopathy, epilepsy, myopathy, and myelopathy. Similar results continue to be reported in the medical literature and give credence to the association between gluten sensitivity and neurological symptoms in the absence of celiac disease.”

They present an illustrative case of a 23-year-old woman with a longstanding history of auditory and visual hallucinations that completely resolved by avoiding gluten, and would recur when provoked by a gluten exposure. The authors state:

“There have been multiple reports linking celiac disease and/or gluten sensitivity with mental health manifestations including isolated psychosis and full blown schizophrenia. As in our case history, these cases report complete symptom resolution with removal of gluten. There is also evidence of frequent gluten sensitivity (but not celiac disease) in schizophrenic patients. Furthermore, similar reports are published dealing with various other neurological manifestations in response to gluten exposure including “idiopathic” ataxia and neuropathies, epilepsy, mood swings, and autism. In addition to neuropsychiatric phenomena, there are reports of other organ system involvement including reversible cardiomyopathy, resolved primary infertility, uveitis, and osteoporosis in relation to the gluten exposure in celiac disease.”

Regarding causation in autoimmunity or sensitivity related illness (SRI), the authors discuss a topic of premiere clinical importance: toxicant induced loss of tolerance (TILT):

“This mechanism of disease has recently been described and discussed in the scientific literature, whereby accumulated toxic insults often resulting from adverse chemical exposures lead to hypersensitivity and impaired tolerance of the immune system (known as toxicant induced loss of tolerance or “TILT”). With growing attention in the medical literature to the escalating problem of toxicant exposure and bioaccumulation within contemporary society, this mechanism of illness has become compelling indeed. Notable groups such as the World Health Organization and the Centers for Disease Control have recently drawn attention to the reality of ubiquitous toxicant exposures and the chemical erosion of human health associated with toxicant accrual within the human body.”

Sensitivity related illness- a causative pathway to multimorbidityAs for TILT in gluten-induced neuropsychiatric disease:

After the bioaccumulation of a toxicant burden and the consequent immune dysregulation, seemingly insignificant environmental triggers can lead to the release of proinflammatory cytokines, antibodies, chemokines, and interleukins and produce a variety of symptoms, including neuropsychiatric issues, in the affected patient. Gluten is one such common trigger, and is hypothesized to be the culprit in the above case report. With the ability of SRI to induce multisystem manifestations and with its increasing and widespread prevalence, this mechanism of disease is the preferred explanation of the authors for gluten-induced neuropsychiatric disease…This mechanism also explains the apparently inexplicable onset of gluten sensitivity in patients who were previously well and fully tolerant of gluten and accounts for the reversal of gluten sensitivity in some patients who are successful in eliminating their toxicant burden.”

Commenting in conclusion on their case presentation:

“The individual in the presented case demonstrates a clear sensitivity to gluten with remission of longstanding hallucinations with gluten elimination and relapsing symptoms upon reintroduction of dietary gluten. The scientific literature contains numerous case reports where unexplained symptoms are significantly improved and, at times, completely resolved when similar dietary changes are made. Therefore, when clinicians are faced with physical symptoms that have not been otherwise explained, celiac testing may be warranted. If this is found to be negative, the possibility of NCGS and SRI ought to be considered. Although NCGS cannot be definitively diagnosed at this time based on laboratory investigations, a trial of gluten elimination should be incorporated as part of the clinical assessment and potential management.”

Clinical note: non-celiac gluten sensitivity (NCGS) can now be assessed with the Wheat/Gluten Proteome Reactivity & Autoimmunity panel from Cyrex Laboratories and correlated with their Multiple Autoimmune Reactivity Screen that includes anti-brain antibodies.

The authors summarize their key points:

  1. Gluten ingestion in gluten sensitive individuals can lead to a variety of clinical presentations including psychiatric, neurological, gynecological, and cardiac symptoms.
  2. Dietary elimination of gluten may lead to complete symptom resolution.
  3. Health practitioners are advised to consider gluten elimination in patients with otherwise unexplained symptoms.
  4. Non-celiac gluten sensitivity may be a part of a constellation of symptoms resulting from a toxicant induced loss of tolerance (TILT).

 Depression In Non-Celiac Gluten Sensitivity

Alimentary Pharmacology & TherapeuticsA recent clinical trial investigating depression in non-celiac gluten sensitivity was recently published in Alimentary Pharmacology and Therapeutics that demonstrated depression in the absence of gastrointestinal symptoms. The authors state:

“Current evidence suggests that many patients with self-reported non-coeliac gluten sensitivity (NCGS) retain gastrointestinal symptoms on a gluten-free diet (GFD) but continue to restrict gluten as they report ‘feeling better’.”

So they set out to discriminate between mental and gastrointestinal symptoms in NCGS by a double-blind cross-over study in which their subjects received one of three dietary challenges for 3 days, followed by a minimum 3-day washout before crossing over to the next diet ( the challenge gluten-free food was supplemented with gluten, whey (16 g/day) or not supplemented = placebo. Depression scores as assessed by the Spielberger State Trait Personality Inventory (STPI) stood out in association with gluten exposure:

Gluten ingestion was associated with higher overall STPI state depression scores compared to placebo but not whey. No differences were found for other STPI state indices or for any STPI trait measures. No difference in cortisol secretion was identified between challenges. Gastrointestinal symptoms were induced similarly across all dietary challenges.”

Clinical note: In gluten intolerance there is often cross-reactivity to bovine dairy proteins due to similarities in antigen morphology.

The authors conclude:

Short-term exposure to gluten specifically induced current feelings of depression with no effect on other indices or on emotional disposition. Gluten-specific induction of gastrointestinal symptoms was not identified. Such findings might explain why patients with non-coeliac gluten sensitivity feel better on a gluten-free diet despite the continuation of gastrointestinal symptoms.”

Clinical note: Practitioners should bear in mind that FODMAP (Fermentable Oligo-Di-Monosaccharides and Polyols) intolerance can coexist with non-celiac gluten sensitivity wherein the former produces gastrointestinal symptoms while the latter accounts for depression and other neuropsychiatric illness.

Epilepsy as an autoimmune disorder

JAMA NeurologyEpilepsy should be evaluated in case management for neuroinflammation that reduces neuronal thresholds of excitability, and more evidence that this can be due to autoimmunity was just published in JAMA Neurology. The authors note that…

“Epilepsy is a debilitating condition, often with neither a known etiology nor an effective treatment. Autoimmune mechanisms have been increasingly identified.”

They conducted a study investigating the relationship between epilepsy and common autoimmune diseases by examining data for 2,518,034 subjects showing the relationship between epilepsy and these twelve common autoimmune diseases: type 1 diabetes mellitus, psoriasis, rheumatoid arthritis, Graves disease, Hashimoto thyroiditis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren syndrome, myasthenia gravis, and celiac disease. Considering the brain destabilizing effects of neuroinflammation present in many autoimmune conditions it’s not surprising that their data showed a strong association:

“The risk of epilepsy was significantly heightened among patients with autoimmune diseases (odds ratio, 3.8) and was especially pronounced in children (5.2). Elevated risk was consistently observed across all 12 autoimmune diseases.”

That’s a 380% increase in risk in general and a 520% increase in children. Medscape Medical News quotes lead investigator Kenneth Mandl, MD, MPH, from Intelligent Health Laboratory, Harvard Medical School and Boston Children’s Hospital, Boston, Massachusetts:

“We need to expand our thinking when it comes to clinical management of these conditions.”

The authors conclude:

Epilepsy and autoimmune disease frequently co-occur; patients with either condition should undergo surveillance for the other. The potential role of autoimmunity must be given due consideration in epilepsy so that we are not overlooking a treatable cause.”


Clinical NeurophysiologyConsidering that low progesterone can contribute to loss of immune intolerance, a paper just published in Clinical Neurophysiology discussing the anticonvulsant effects of progesterone and its metabolites is worth noting:

Progesterone is an anticonvulsant neurosteroid. It is reduced by the unidirectional enzyme 5α-reductase to 5α-dihydroprogesterone (DHP) and subsequently reduced by the bidirectional enzyme 3α,5α- hydroxysteroidoxidoreductase to 3α,5α-tetrahydroprogesterone (THP, also called “allopregnanolone”). Progesterone, DHP and THP have protective effects in models of traumatic brain injury, and slows epileptogenesis in kindling models. It is possible that these pregnanes could be anticonvulsant. Since anticonvulsant drugs cannot prevent epileptogenesis, endogenous hormones or their analogues remain attractive potential therapies to improve prognoses after a first seizure…We hypothesize that progesterone, DHP, and THP may alter epileptogenic processes by reducing tonic hyper-excitability.”


Also just published in Clinical Neurophysiology is a study showing that the omega-3 fatty acid DHA (docosahexanoic acid), already known to be critical for brain development and function and a modulator of chronic low grade inflammation, has anticonvulsant properties.

Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (n−3 PUFA), which has previously shown to have anticonvulsant activity rats. The purpose of the present experiment was: (1) to confirm that sub-chronic DHA raises thresholds in the maximal pentylenetetrazole (PTZ) model, and (2) to determine whether that increase is correlated with an increase in serum and brain DHA.”

Maximal pentylenetetrazole (PTZ) is a rat model of seizure activity. Interestingly, their results showed that increases of serum DHA reduced seizures (increased seizure latency) without increasing brain DHA, system a global chronic inflammation modulating effect:

“In the maximal PTZ model, DHA significantly increased seizure latency by approximately 3 fold, as compared to vehicle-injected controls. This increase in seizure latency was associated with an increase in serum unesterified DHA levels. Total brain DHA and brain unesterified DHA, however, were not significantly different between treatment and control groups.”

Hyperexcitable brain syndrome and gluten

Journal of Neurology, Neurosurgery & PsychiatryHyperexcitable brain, with potentially severe consequences, is recognized as among the gluten-related autoiimmune neurological disorders in a paper just published in the Journal of Neurology, Neurosurgery & Psychiatry. The authors state:

Hyperexcitable brain and refractory coeliac disease: a new syndrome Gluten related disorders (GRD) is the newly proposed term to encompass a spectrum of immune mediated diseases triggered by gluten ingestion. Whilst coeliac disease (gluten sensitive enteropathy) remains one of the best characterised GRD, neurological dysfunction is one of the commonest extraintestinal manifestations with a range of presentations such as cerebellar ataxia, neuropathy, sensory ganglionopathy and encephalopathy (headaches and white matter abnormalities). Neurological manifestations can occur with or without enteropathy.”

They documented the clinical and electrophysiological characteristics of this hyperexcitable brain syndrome in a severely afflicted group of seven patients:

“The 7 patients (5 male, 2 female) were identified from a cohort of 540 patients with neurological manifestations of GRD that regularly attend our gluten/neurology clinic. The mean age at onset of the neurological symptoms was 58 years (range 46 to 76). Unlike myoclonic ataxia (eg in the context of opsoclonus myoclonus ataxia syndrome) the myoclonic tremor in these patients was initially focal (face, tongue one arm and/or one leg) but then spread to affect other parts of the body. Epilepsy was a feature in 5 of the patients, 3 of which gave a history of Jacksonian march before progression to generalised seizures. In one patient the neurological presentation was with status epilepticus. All patients had a mild degree of limb ataxia and more prominent gait ataxia. Electrophysiology showed evidence of cortical myoclonus. Four had a phenotype of epilepsia partialis continua and three later developed more widespread jerking. There was clinical, imaging and/or pathological evidence of cerebellar involvement in all cases but this was not the main source of disability by contrast to patients with gluten ataxia, where cerebellar ataxia is the most disabling feature.”

Neuroinflammation due to celiac and non-celiac gluten sensitivity can cause a range of neurological disorders. These cases are notable for their severity and association with refractory celiac disease (CD that fails to heal after gluten is eliminated). They are especially troubling because the damage and hyperexcitable brain symptoms remained after gluten was eliminated:

“All patients adhered to a strict gluten–free diet with elimination of gluten–related antibodies, despite which there was still evidence of enteropathy in keeping with refractory celiac disease (type 1 in 5 and type 2 in 2). One of the 2 patients with type 2 refractory enteropathy died 13 years later from metastatic enteropathy–associated lymphoma. The other died 1 year after the neurological presentation from presumed enteropathy associated lymphoma. Four were treated with mycophenolate and one in addition with rituximab and IV immunoglobulins. Whilst their ataxia improved the myoclonus remained the most disabling feature of their illness with a tendency to spread and affect other parts of the body.”

Clinical note: Practitioners should not underestimate the potential severity of gluten-associated neuroinflammation. We should be alert to the far more common milder manifestations of hyperexcitable brain that can present as sleep disorders, anxiety, attention disorders, sympathetic nervous system hyperarousal syndromes, etc. The authors conclude:

“This syndrome whilst rare, appears to be the commonest neurological manifestation of refractory CD. The clinical manifestations extend from focal reflex jerks to epilepsia partialis continua, covering the whole clinical spectrum of cortical myoclonus. This entity is possibly under–diagnosed and difficult to treat.”

Chronic immune stimulation of autoimmunity can trigger leukemia

There is accumulating evidence that autoimmunity must be considered in the case management for leukemia (AML and CLL) not only in regard to complications but as a causative factor. A paper published recently in the journal Haematologica addresses this concern:

“There is considerable evidence to suggest that there is an increased occurrence of hematologic malignancies in patients with autoimmune diseases compared to the general population, with a further increase in risk after exposure to cytotoxic therapies…an increased awareness of this risk and further investigation into the pathogenetic mechanisms of acute leukemia in autoimmune disease patients are warranted.”

They argue against labeling leukemias that develop in patients with autoimmune diseases who are exposed to cytotoxic agents as ‘therapy-related leukemias’, and review the literature that demonstrates the association of leukemia with autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, and systemic sclerosis. They point out the obvious when they state:

“Tumor cells need to evade the immune system to develop overt disease, thus defects in the immune system are recognized risk factors for cancer development. In turn, patients diagnosed with diseases involving a defective immune system, or those receiving immunosuppressive therapies, are believed to be at high risk of developing acute leukemia.”

Practitioners and frequent readers here will be familiar with the importance of NF-kappaB (nuclear factor kappa beta) and inflammatory cytokines in autoimmune diseases…

“Both specific and non-specific immune responses play a major role in controlling the growth of malignant cells (tumor surveillance). Any disruption of this system by a primary pathological or iatrogenic process will provide the opportunity for abnormal cells to evade surveillance and progress into malignancy. In addition, the interaction between tumor cells and the host microenvironment of stromal cells and inflammatory/immune cells contributes to a complex inflammatory signaling process that enhances tumor progression. For example, NF-kappaB a major player in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, is involved in cancer and leukemia development. Furthermore, chemokines and cytokines produced by inflammatory cells have a powerful pro-tumor activity. Early in the neoplastic process, inflammatory cells facilitate genomic instability, promote angiogenesis and create an attractive environment for tumor growth.”

In their conclusion the authors assert:

“Our focus should be on investigating the molecular defects in the autoimmune diseases, including defects in immunity, DNA repair, and apoptosis in these patients rather than studying only drug mechanisms that lead to leukemogenesis. …Finally, the risk of AML in AD patients warrants more attention, as it provides a model for investigating the role of defective immunological mechanisms in leukemogenesis.”

A study investigating chronic immune stimulation as a trigger for leukemia published in the Journal of Clinical Oncology is also of interest. In this case the authors pay special attention to the role of infections (which we know can trigger autoimmune disorders):

“Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often present with infections…To additionally expand our knowledge on the role of immune stimulation in the causation of AML and MDS, we have conducted a large, population-based study to evaluate the risk of AML and MDS associated with a prior history of a broad range of infections or autoimmune diseases.”

They calculated the odds ratios (ORs) and 95% confidence intervals (CIs) for the association of AML or MDS with infectious and/or autoimmune diseases for 9,219 patients with AML, 1,662 patients with MDS, and 42,878 matched controls and found a strong association:

“Overall, a history of any infectious disease was associated with a significantly increased risk of both AML (OR, 1.3; 95% CI, 1.2 to 1.4) and MDS (OR, 1.3; 95% CI, 1.1 to 1.5). These associations were significant even when we limited infections to those occurring 3 or more years before AML/MDS. A previous history of any autoimmune disease was associated with a 1.7-fold (95% CI, 1.5 to 1.9) increased risk for AML and 2.1-fold (95% CI, 1.7 to 2.6) increased risk for MDS. A large range of conditions were each significantly associated with AML and MDS.”

The associations of autoimmune disease with acute myeloid leukemia and myelodysplastic syndrome were particularly strong. The authors conclude:

“Our novel findings indicate that chronic immune stimulation acts as a trigger for AML/MDS development. The underlying mechanisms may also be due to a common genetic predisposition or an effect of treatment for infections/autoimmune conditions.”

Note that the authors of the first paper presented above caution against attributing causation to a treatment effect.

The authors of a paper published in  the Journal of Czech Physicians (Časopis lékařů českých) include chronic lymphocytic leukemia (CLL) in their comments:

“Evidence has been growing that the pathogenesis of lymphoproliferative disease involves immune processes deregulation. It is believed that antigens or immunological elements can trigger transformation of normal lymphocyte polyclonal population into monoclonal neoplastic disorder – lymphoproliferative disease. Extensive studies point to the link between malignant lymphoma development and autoimmune or inflammatory diseases – namely rheumatoid arthritis, Sjörgen’s syndrome, coeliac disease, systemic lupus erythematosus or thyroiditis.”

They state further…

“Besides various lymphomas, the links to autoimmune/inflammatory diseases have also been described in chronic lymphocytic leukaemia.”

Clinicians should note:

“Regarding clinical medicine, it is necessary to distinguish patients with autoimmune, inflammatory and infectious diseases who are at the increased risk of tumour development. New approaches must be found to lower this risk.”

A paper published recently in Current Opinion in Oncology considers chronic lymphocytic leukemia in particular. The authors observe:

Autoimmune disorders can complicate CLL at any stage and even occur in the preleukemic monoclonal B lymphocytosis. CLL cells can act as antigen-presenting cells, possibly inducing the formation of autoreactive T helper cells (through the production of B-cell activator factor and a proliferation-inducing ligand) and nonfunctional T regulatory cells (via CD27–CD70 interaction). Further, nonmalignant lymphocytes may stimulate via CD154-mediated mechanism both tumor growth and the development of autoimmunity, especially after fludarabine-based regimens of therapy. CLL cells tend to produce monoclonal polyreactive autoantibodies suggesting that autoantigen stimulation via B-cell receptor signaling may affect the natural history of CLL…the pathogenetic intertwining between autoimmunity and malignant transformation indicates the importance of defining whether the occurrence of autoimmunity in CLL might be considered an autonomous prognostic indicator that influences treatment decisions.”

Thus autoimmunity and the development and progression of chronic lymphocytic leukemia can be a two-way street. The authors summarize their findings:

“Simple-refractory and complex autoimmunity are independent indicators of therapy for CLL. Further, epidemiological and biological studies will help clarifying the prognostic and possibly also the pathogenetic significance of simple autoimmunity.”

An interesting paper fresh of the presses in blood (Journal of the American Society of Hematology) examines one of the mechanisms by which autoimmunity may promote chronic lymphocytic leukemia (CLL):

“A polymorphic variant of the phosphatase PTPN22 has been associated with increased risk for multiple autoimmune diseases. The risk allele is thought to function by diminishing antigen-receptor signals responsible for negative selection of autoreactive lymphocytes.”

In other words, PTPN22 suppresses the signals that are supposed to turn off lymphocytes that attack self-tissue. The authors make the fascinating observation:

“We now show that PTPN22 is markedly overexpressed in chronic lymphocytic leukemia (CLL), a common malignancy of autoreactive B lymphocytes. We also show that overexpression of PTPN22 significantly inhibits antigen-induced apoptosis of primary CLL cells by blocking B-cell receptor (BCR) signaling pathways that negatively regulate lymphocyte survival. More importantly, we show that PTPN22 positively regulates the antiapoptotic AKT kinase, which provides a powerful survival signal to antigen-stimulated CLL cells.”

So PTPN22 seems to play a significant role in autoimmunity and the immune dysregulation of chronic lymphocytic leukemia. Of interest from the therapeutic perspective:

“Finally, we show that PTPN22 can be effectively down-regulated by the PKC inhibitors ruboxistaurin and sotrastaurin, resulting in enhanced killing of CLL cells exposed to proapoptotic BCR stimuli.”

If the authors’ conclusion gains wide circulation then perhaps other more benign agents that downregulate PTPN22 may be found:

“Collectively, these data suggest that PTPN22 overexpression represents a protective mechanism that allows autoantigen-activated CLL cells to escape from negative selection and indicate that this mechanism could be exploited for therapeutic purposes by targeting PTPN22 with PKC inhibitors.”

Lastly for this post, a paper published in Clinical Lymphoma Myeloma & Leukemia recognizes an association of non-hematologic autoimmune disorders with chronic lymphocytic leukemia.

Autoimmune phenomena are well known to complicate chronic lymphocytic leukemia (CLL) and occur in 10% to 25% of patients. Hematologic autoimmune complications, particularly autoimmune hemolytic anemia and immune thrombocytopenia, are much more common than nonhematologic complications.”

Not surprising since there is so much action going on in the blood compartment. But…

“We present 6 cases of patients who exhibited uncommon complications of CLL: myasthenia gravis, acquired von Willebrand disease, bullous pemphigoid, and acquired angioedema.”


“In our patients, the activity and recrudescences of these complications were highly associated with CLL remission or progression. More awareness of the association of CLL with these complications could facilitate earlier diagnosis and effective treatment.”

‘Take home’ message: the astute clinician should be aware of autoimmunity as both a possible causative and complicating factor in lymphoproliferative disorders such as leukemia (AML and CLL), lymphoma and myelodysplastic syndrome.