Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease | Science

 Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an a virulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD."



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Uncovering the effects of cooking, digestion on gluten and wheat allergens in pasta -- ScienceDaily

 "In the lab, the researchers cooked store-bought pasta and simulated how the body would digest it. They found that while some gluten proteins persisted throughout the cooking and digestion process, other allergenic non-gluten proteins are lost during boiling as they almost completely leak into the cooking water. This suggests that for people with particular types of wheat allergies unrelated to celiac disease, eating pasta might cause a weaker reaction than wheat products that are baked, the researchers say. Their findings also contribute to understanding the chemistry of gluten digestion."



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Food-derived opioid peptides frim casein and gliadin inhibit cysteine uptake with redox and epigenetic consequences

Dietary interventions like gluten-free and casein-free diets have been
reported to improve intestinal, autoimmune and neurological symptoms in
patients with a variety of conditions; however, the underlying mechanism
of benefit for such diets remains unclear. Epigenetic programming,
including CpG methylation and histone modifications, occurring during
early postnatal development can influence the risk of disease in later
life, and such programming may be modulated by nutritional factors such
as milk and wheat, especially during the transition from a solely
milk-based diet to one that includes other forms of nutrition. The
hydrolytic digestion of casein (a major milk protein) and gliadin (a
wheat-derived protein) releases peptides with opioid activity, and in
the present study, we demonstrate that these food-derived proline-rich
opioid peptides modulate cysteine uptake in cultured human neuronal and
gastrointestinal (GI) epithelial cells via activation of opioid
receptors. Decreases in cysteine uptake were associated with changes in
the intracellular antioxidant glutathione and the methyl donor S-adenosylmethionine.
Bovine and human casein-derived opioid peptides increased genome-wide
DNA methylation in the transcription start site region with a potency
order similar to their inhibition of cysteine uptake. Altered expression
of genes involved in redox and methylation homeostasis was also
observed. These results illustrate the potential of milk- and
wheat-derived peptides to exert antioxidant and epigenetic changes that
may be particularly important during the postnatal transition from
placental to GI nutrition. Differences between peptides derived from
human and bovine milk may contribute to developmental differences
between breastfed and formula-fed infants. Restricted antioxidant
capacity, caused by wheat- and milk-derived opioid peptides, may
predispose susceptible individuals to inflammation and systemic
oxidation, partly explaining the benefits of gluten-free or casein-free
diets.

Food-derived opioid peptides (from gliadin and casein) inhibit cysteine uptake with redox and epigenetic consequences.

Dietary interventions like gluten-free and casein-free diets have been
reported to improve intestinal, autoimmune and neurological symptoms in
patients with a variety of conditions; however, the underlying mechanism
of benefit for such diets remains unclear. Epigenetic programming,
including CpG methylation and histone modifications, occurring during
early postnatal development can influence the risk of disease in later
life, and such programming may be modulated by nutritional factors such
as milk and wheat, especially during the transition from a solely
milk-based diet to one that includes other forms of nutrition. The
hydrolytic digestion of casein (a major milk protein) and gliadin (a
wheat-derived protein) releases peptides with opioid activity, and in
the present study, we demonstrate that these food-derived proline-rich
opioid peptides modulate cysteine uptake in cultured human neuronal and
gastrointestinal (GI) epithelial cells via activation of opioid
receptors. Decreases in cysteine uptake were associated with changes in
the intracellular antioxidant glutathione and the methyl donor
S-adenosylmethionine. Bovine and human casein-derived opioid peptides
increased genome-wide DNA methylation in the transcription start site
region with a potency order similar to their inhibition of cysteine
uptake. Altered expression of genes involved in redox and methylation
homeostasis was also observed. These results illustrate the potential of
milk- and wheat-derived peptides to exert antioxidant and epigenetic
changes that may be particularly important during the postnatal
transition from placental to GI nutrition. Differences between peptides
derived from human and bovine milk may contribute to developmental
differences between breastfed and formula-fed infants. Restricted
antioxidant capacity, caused by wheat- and milk-derived opioid peptides,
may predispose susceptible individuals to inflammation and systemic
oxidation, partly explaining the benefits of gluten-free or casein-free
diets.

Related articles

• Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder. (polygenicpathways.blogspot.com)

PLOS ONE: Markers of Celiac Disease and Gluten Sensitivity in Children with Autism

Gastrointestinal symptoms are a common feature in children with autism, drawing attention to a potential association with celiac disease or gluten sensitivity. However, studies to date regarding the immune response to gluten in autism and its association with celiac disease have been inconsistent. The aim of this study was to assess immune reactivity to gluten in pediatric patients diagnosed with autism according to strict criteria and to evaluate the potential link between autism and celiac disease.

Methods

Study participants included children (with or without gastrointestinal symptoms) diagnosed with autism according to both the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview, Revised (ADI-R) (n = 37), their unaffected siblings (n = 27), and age-matched healthy controls (n = 76). Serum specimens were tested for antibodies to native gliadin, deamidated gliadin, and transglutaminase 2 (TG2). Affected children were genotyped for celiac disease associated HLA-DQ2 and -DQ8 alleles.

Results

Children with autism had significantly higher levels of IgG antibody to gliadin compared with unrelated healthy controls (p<0.01). The IgG levels were also higher compared to the unaffected siblings, but did not reach statistical significance. The IgG anti-gliadin antibody response was significantly greater in the autistic children with gastrointestinal symptoms in comparison to those without them (p<0.01). There was no difference in IgA response to gliadin across groups. The levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between patients and controls. An association between increased anti-gliadin antibody and presence of HLA-DQ2 and/or -DQ8 was not observed.

Conclusions

A subset of children with autism displays increased immune reactivity to gluten, the mechanism of which appears to be distinct from that in celiac disease. The increased anti-gliadin antibody response and its association with GI symptoms points to a potential mechanism involving immunologic and/or intestinal permeability abnormalities in affected children.

PLOS ONE: Markers of Celiac Disease and Gluten Sensitivity in Children with Autism

Gastrointestinal symptoms are a common feature in children with autism, drawing attention to a potential association with celiac disease or gluten sensitivity. However, studies to date regarding the immune response to gluten in autism and its association with celiac disease have been inconsistent. The aim of this study was to assess immune reactivity to gluten in pediatric patients diagnosed with autism according to strict criteria and to evaluate the potential link between autism and celiac disease.

Methods

Study participants included children (with or without gastrointestinal symptoms) diagnosed with autism according to both the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview, Revised (ADI-R) (n = 37), their unaffected siblings (n = 27), and age-matched healthy controls (n = 76). Serum specimens were tested for antibodies to native gliadin, deamidated gliadin, and transglutaminase 2 (TG2). Affected children were genotyped for celiac disease associated HLA-DQ2 and -DQ8 alleles.

Results

Children with autism had significantly higher levels of IgG antibody to gliadin compared with unrelated healthy controls (p<0.01). The IgG levels were also higher compared to the unaffected siblings, but did not reach statistical significance. The IgG anti-gliadin antibody response was significantly greater in the autistic children with gastrointestinal symptoms in comparison to those without them (p<0.01). There was no difference in IgA response to gliadin across groups. The levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between patients and controls. An association between increased anti-gliadin antibody and presence of HLA-DQ2 and/or -DQ8 was not observed.

Conclusions

A subset of children with autism displays increased immune reactivity to gluten, the mechanism of which appears to be distinct from that in celiac disease. The increased anti-gliadin antibody response and its association with GI symptoms points to a potential mechanism involving immunologic and/or intestinal permeability abnormalities in affected children.

Elevated gliadin antibody levels in individuals with schizophrenia.

We aimed to replicate, in a larger sample and in a different geographical location, the previously reported elevation of anti-gliadin IgG antibodies in schizophrenia. Methods. A total of 950 adults with schizophrenia (severity assessed by PANSS) and 1000 healthy controls were recruited in the Munich metropolitan area. Anti-gliadin IgG antibodies were analyzed with ELISA. χ(2)-tests and logistic regression were used to analyze the association of schizophrenia with elevated anti-gliadin IgG. A multivariable general linear model was used to compare anti-gliadin IgG levels between patients and controls. Results. The odds ratio of having elevated anti-gliadin IgG antibodies in the schizophrenia group was 2.13 (95% CI 1.57 to 2.91, p < 0.0001). Mean anti-gliadin IgG levels were higher in schizophrenia patients (0.81 ± 0.79 vs. 0.52 ± 0.56, t = 9.529, df = 1,697, p < 0.0001) and the difference persisted after adjusting for potential confounders. Conclusions. Our study, limited by its cross sectional design, confirmed an association between anti-gliadin IgG antibodies and schizophrenia. Replication in longitudinal studies, clinical trials of gluten free diet and mechanistic investigation could lead to novel treatment targets, preventive and therapeutic considerations in schizophrenia.

Antibody Repertoire Profiling Using Bacterial Display Identifies Reactivity Signatures of Celiac Disease - Analytical Chemistry (ACS Publications)

A general strategy to identify serum antibody specificities associated with a given disease state and peptide reagents for their detection was developed using bacterial display peptide libraries and multiparameter flow cytometry (MPFC). Using sera from patients with celiac disease (CD) (n = 45) or healthy subjects (n = 40), bacterial display libraries were screened for peptides that react specifically with antibodies from CD patients and not with those from healthy patients. The libraries were screened for peptides that simultaneously cross-react with CD patient antibodies present in two separate patient groups labeled with spectrally distinct fluorophores but do not react with unlabeled non-CD antibodies, thus affording a quantitative separation. A panel of six unique peptide sequences yielded 85% sensitivity and 91% specificity (AUC = 0.91) on a set of 60 samples not used for discovery, using leave-one-out cross-validation. Individual peptides were dissimilar with known CD-specific antigens tissue transglutaminase (tTG) and deamidated gliadin, and the classifier accuracy was independent of anti-tTG antibody titer. These results demonstrate that bacterial display/MPFC provides a highly effective tool for the unbiased discovery of disease-associated antibody specificities and peptide reagents for their detection that may have broad utility for diagnostic development.

Anti-Gluten Immune Response following Toxoplasma gondii Infection in Mice

Gluten sensitivity may affect disease pathogenesis in a subset of individuals who have schizophrenia, bipolar disorder or autism. Exposure to Toxoplasma gondii is a known risk factor for the development of schizophrenia, presumably through a direct pathological effect of the parasite on brain and behavior. A co-association of antibodies to wheat gluten and to T. gondii in individuals with schizophrenia was recently uncovered, suggesting a coordinated gastrointestinal means by which T. gondii and dietary gluten might generate an immune response. Here, we evaluated the connection between these infectious- and food-based antigens in mouse models. BALB/c mice receiving a standard wheat-based rodent chow were infected with T. gondii via intraperitoneal, peroral and prenatal exposure methods. Significant increases in the levels of anti-gluten IgG were documented in all infected mice and in offspring from chronically infected dams compared to uninfected controls (repetitive measures ANOVAs, two-tailed t-tests, all p≤0.00001). Activation of the complement system accompanied this immune response (p≤0.002-0.00001). Perorally-infected females showed higher levels of anti-gluten IgG than males (p≤0.009) indicating that T. gondii-generated gastrointestinal infection led to a significant anti-gluten immune response in a sex-dependent manner. These findings support a gastrointestinal basis by which two risk factors for schizophrenia, T. gondii infection and sensitivity to dietary gluten, might be connected to produce the immune activation that is becoming an increasingly recognized pathology of psychiatric disorders.

Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia.

Immune system factors including complement pathway activation are increasingly linked to the etiology and pathophysiology of schizophrenia. Complement protein, C1q, binds to and helps to clear immune complexes composed of immunoglobulins coupled to antigens. The antigenic stimuli for C1q activation in schizophrenia are not known. Food sensitivities characterized by elevated IgG antibodies to bovine milk caseins and wheat glutens have been reported in individuals with schizophrenia. Here, we examined the extent to which these food products might comprise the antigen component of complement C1q immune complexes in individuals with recent onset schizophrenia (n=38), non-recent onset schizophrenia (n=61) and non-psychiatric controls (n=63). C1q seropositivity was significantly associated with both schizophrenia groups (recent onset, odds ratio (OR)=8.02, p≤0.008; non-recent onset, OR=3.15, p≤0.03) compared to controls (logistic regression models corrected for age, sex, race and smoking status). Casein- and/or gluten-IgG binding to C1q was significantly elevated in the non-recent onset group compared to controls (OR=4.36, p≤0.01). Significant amounts of C1q-casein/gluten-related immune complexes and C1q correlations with a marker for gastrointestinal inflammation in non-recent onset schizophrenia suggests a heightened rate of food antigens in the systemic circulation, perhaps via a disease-associated altered intestinal permeability. In individuals who are in the early stages of disease onset, C1q activation may reflect the formation of immune complexes with non-casein- or non-gluten-related antigens, the presence of C1q autoantibodies, and/or a dissociated state of immune complex components. In conclusion, complement activation may be a useful biomarker to diagnose schizophrenia early during the course of the disease. Future prospective studies should evaluate the impacts of casein- and gluten-free diets on C1q activation in schizophrenia.

Our Genes Are Not Yet Ready For So Many Wheat-Based Products

According to an expert in digestive disorders, the current rise in dietary problems related to gluten could be due to over reliance on wheat-based products.Sanders explains that up to 6% of the world's population could be sensitive to gluten, making it the second leading gluten-related disorder after celiac disease.

Maternal antibodies to gluten linked to schizophrenia risk in children

Babies born to women with sensitivity to gluten appear to be at increased risk for certain psychiatric disorders later in life, according to research by scientists at Karolinska Institutet in Sweden and Johns Hopkins Children's Center in Baltimore.

Gluten-free Bipolar Disorder | Channel N

The controversial link between sensitivities to foods including milk casein, wheat, and gluten, and effects on psychiatric disorders such as schizophrenia and bipolar disorder.

Association of attention-deficit/hyperactivity disorder and celiac disease: a brief report.

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In this study, 10/67 ADHD patients also had celiac disease, and these patients benefited from a gluten free diet

Celiac disease vaccine shows promising results in Phase I trial

This is a vaccine against gluten, which has also been implicated in a number of other diseases, including autism, bipolar disorder. multiple sclerosis and schizophrenia . Perhaps the vaccine could have a wider use than in coeliac disease.

Markers of gluten sensitivity and celiac disease i... [Bipolar Disord. 2011] - PubMed result

Gliadin antibodies are found in schizophrenia, and as now shown, also in Bipolar disorder: How they might interfere with pathological pathways is shown in this article: 
In some patients,  where this is applicable, a gluten free diet may provide symptom relief.



Risk factors: Bipolar disorder : 

Evidence for gliadin antibodies and gluten as causative agents in schizophrenia. : Nature Precedings

Antibodies to gliadin, a component of gluten, have frequently been reported in schizophrenia. Highly immunogenic B cell epitopes along its length are homologous to numerous proteins relevant to schizophrenia, including members of the DISC1 interactome, glutamate, dopamine and neuregulin signaling networks, and plasticity or myelination pathways. Antibodies to gliadin may cross react with these key proteins, as has already been observed with synapsin 1 and calreticulin. Gliadin may thus be a causative agent in schizophrenia, under certain genetic and immunological conditions, producing its effects via antibody mediated knockdown of multiple proteins relevant to the disease process. Because of such homology, an autoimmune response may be sustained by the human antigens that resemble gliadin itself, a scenario supported by many reports of immune activation both in the brain and in lymphocytes in schizophrenia. Gluten free diets and removal of such antibodies may be of therapeutic benefit in certain cases of schizophrenia. Gluten schizophrenia Pubmed

Search Amazon.com for gluten free diets

Novel immune response to gluten in individuals with schizophrenia

Gluten antibodies are also elevated in schizophrenia , supporting reported links between celiac disease and schizophrenia

Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia.

This study reported the presence of increased antibodies to gliadin in patients with recent onset psychosis. Gliadin is present in wheat and other cereals and is involved in gluten formation

Related articles

• A Comprehensive List of Gluten Free Foods (brighthub.com)
• Celiac Disease (celiacdiseaseinfoblog.com)

Gluten posts