[Dermatitis herpetiformis and other forms of wheat sensitivity]. / Dermatitis herpetiformis und sonstige Formen der Weizensensitivität.

BACKGROUND: Wheat sensitivity is a collective term for several, especially gastrointestinal, diseases that occur as part of a hypersensitivity reaction after wheat consumption. The symptoms, which are mostly similar to those of irritable bowel syndrome, are often accompanied by skin lesions. In addition to celiac disease and dermatitis herpetiformis, the cutaneous manifestation of celiac disease, wheat sensitivity also includes nonceliac gluten sensitivity (NCGS), allergic nickel contact mucositis, wheat allergy, amylase-trypsin inhibitor intolerance, and fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) intolerance. OBJECTIVES: This review article aims to provide an overview of the clinical, especially dermatological and gastrointestinal features of the different forms of wheat sensitivity. Diagnosis and therapeutic management are also discussed. MATERIALS AND METHODS: A selective literature search was carried out with evaluation of our own clinical data. RESULTS: The skin lesions in dermatitis herpetiformis are very disease-specific. In contrast, wheat allergy often shares signs and symptoms with many other diseases. Other forms of wheat sensitivity cause primarily gastrointestinal abnormalities, but extra-intestinal manifestations can also occur. Their diagnosis is often complex and requires cross-disciplinary collaboration with experts in gastroenterology. The therapy consists of a wheat- or gluten-free diet. CONCLUSIONS: Knowledge of the different and frequently occurring dermatological signs of wheat sensitivity is of great importance, because dermatological manifestations associated with gastrointestinal pathology, intolerance reactions, and allergies appear more and more frequently.

Self-reported nonceliac wheat sensitivity in an outpatient digestive endoscopy center: high frequency but insufficient medical approach.

OBJECTIVE: 'Self-reported wheat sensitivity' (SRWS) is a self-reported condition caused by wheat ingestion in the absence of celiac disease or wheat allergy. The aim of the study was to investigate the frequency and characteristics of SRWS in outpatients referred for digestive endoscopy. METHODS: The study, performed at the University of Palermo, enrolled 496 outpatients. RESULTS: Seven individuals (1.4%) had an already established diagnosis of celiac disease. The questionnaire was administered to the other 489 individuals: 98 subjects (20%) were SRWS, the remaining 391 served as controls (i.e. not-SRWS). SRWS patients were younger (P < 0.001), with a higher percentage of females (P = 0.002) than not-SRWS. 'gastroesophageal reflux disease and ulcer-like dyspepsia' and 'chronic unexplained diarrhea' were more frequently the reasons for the endoscopy study in SRWS than in not-SRWS (P = 0.002, and P = 0.05, respectively). Food allergies/intolerances (P = 0.04), milk allergy/intolerance (P = 0.0001), GERD (P = 0.0001), IBS (0.0001), anxiety (P = 0.005) and depression (P = 0.04) were the previous medical diagnoses reported more frequently in SRWS patients than in not-SRWS. In the SRWS group, 38% of the patients had already undergone previous upper endoscopy and 24% colonoscopy. After these investigations, 58% of SRWS patients received no diagnosis, and the other 42% were informed that they 'were not suffering from celiac disease or wheat allergy'. Finally, 28.6% SRWS patients had followed a gluten-free diet (GFD), and 71.4% of them referred being asymptomatic on GFD. CONCLUSIONS: Our data showed a high frequency of SRWS in outpatients referred to a digestive endoscopy center and a lack of medical accuracy in identifying a possible gluten-related disease. REGISTRATION: The study was registered on Clinicaltrials.gov (registration number: NCT04154137), accessible at: https://clinicaltrials.gov/ct2/show/NCT04154137?term=non+celiac+wheat&draw=2&rank=1.

Manifestaciones bucales de la enfermedad celíaca y alergia al trigo: Reporte de tres casos y revisión literatura / Oral Manifestations of Celiac Disease and Wheat Allergy: Report of Three Cases and Review of Literature

Resumen: La Enfermedad Celíaca (EC) es una enfermedad sistémica inmunomediada, provocada por el gluten y prolaminas relacionadas, en individuos genéticamente susceptibles. Se caracteriza por manifestaciones clínicas dependientes del gluten, anticuerpos específicos de EC, haplotipos HLA DQ2 o DQ8 y enteropatía. La mayoría de los pacientes son asintomáticos o con manifestaciones leves. Afecta principalmente el sistema gastrointestinal causando síntomas y signos como diarrea, dolor abdominal recurrente y distensión abdominal; además manifestaciones extradigestivas. Los pacientes con EC pueden tener manifestaciones bucales que incluyen estomatitis aftosa recurrente (EAR), hipoplasia del esmalte, glositis atrófica, entre otras. El diagnóstico de EC se basa en la historia clínica, serología, endoscopía e histología. Existen otras entidades que deben diferenciarse de la EC, como la sensibilidad al gluten no celíaca y la alergia al trigo. El objetivo de este trabajo es presentar tres pacientes con antecedentes de EAR y otras manifestaciones clínicas asociadas al diagnóstico precoz de EC y alergia alimentaria.

Abastract: Celiac Disease (CD) is an immune-mediated systemic disease, caused by gluten and related prolamins, in genetically susceptible individuals. It is characterized by gluten-dependent clinical manifestations, CD-specific antibodies, HLA DQ2 or DQ8 haplotypes, and enteropathy. Most patients are asymptomatic or with mild manifestations. It mainly affects the gastrointestinal system causing symptoms and signs such as diarrhea, recurrent abdominal pain and abdominal distension; also extradigestive manifestations. Patients with CD may have oral manifestations that include recurrent aphthous stomatitis (RAS), enamel hypoplasia, atrophic glossitis, among others. The diagnosis of CD is based on clinical history, serology, endoscopy and histology. There are other entities that should be differentiated from CD, such as non-celiac gluten sensitivity and wheat allergy. The aim of this study is to present three patients with a history of RAS and other clinical manifestations associated with the early diagnosis of CD and food allergy.

Celiac Disease and Sensitization to Wheat, Rye, and Barley: Should We Be Concerned?

BACKGROUND: Concomitance of celiac disease (CD) and IgE-mediated wheat allergy is described in some case reports. The objective was to evaluate the frequency of sensitization to wheat, rye, barley, and malt in children and adolescents with CD. METHODS: Measurement of serum levels of specific IgE to wheat, rye, barley, and malt (ImmunoCAP; sensitization IgE ≥0.35 kUA/L) in CD patients followed in specialized clinics to verify allergy history, general characteristics, small bowel biopsy characteristics, compliance with gluten-free diet (GFD), and occurrence of symptoms in case of noncompliance. RESULTS: We evaluated 74 patients; the median of age and age at diagnosis of CD were 8.6 years (5.0-12.8) and 3.6 years (1.6-7.0), respectively. Median time of GFD was 3.5 years (1.4-5.8). History of asthma occurred in 17.3% of subjects, allergic rhinitis in 13.5%, and AD in 5.4%. Frequency of sensitization was 4% for wheat, 10.8% for rye, 5.4% for barley, and 2.7% for malt. There was no association between wheat sensitization and age at diagnosis, time of GFD, small bowel biopsy characteristics, allergy history, and gluten consumption. There was no relationship between sensitization to wheat and occurrence of immediate symptoms when not complying with GFD. CONCLUSION: In conclusion, the frequency of sensitization to wheat, rye, barley, and malt in CD patients was 4, 10.8, 5.4, and 2.7%, respectively. Therefore, to ensure that cutaneous and respiratory contact with wheat is safe, we advise patients with CD to investigate their sensitivity to wheat, rye, and barley because not all patients with CD are allergic to these cereals.

Gynecological Disorders in Patients with Non-celiac Wheat Sensitivity.

BACKGROUND: Non-celiac wheat sensitivity (NCWS) most frequently presents clinically with irritable bowel syndrome (IBS)-like symptoms, although many extra-intestinal manifestations have also been attributed to it. No studies to date have evaluated the presence and frequency of gynecological symptoms in NCWS. AIM: To evaluate the frequency of gynecological disorders in patients with NCWS. PATIENTS AND METHODS: Sixty-eight women with NCWS were included in the study. A questionnaire investigating gynecological symptoms and recurrent cystitis was administered, and patients reporting symptoms were then examined by specialists. Three control groups were selected: 52 patients with IBS not related to NCWS, 56 patients with celiac disease (CD), and 71 healthy controls. RESULTS: 59% of the patients with NCWS showed gynecological symptoms, a higher frequency than in healthy controls (P = 0.04), IBS controls (P = 0.01) and CD controls (P = 0.02). Menstrual cycle alterations were more frequent in patients with NCWS than in healthy controls (26.5% vs 11.3%; P = 0.03); the patients with NCWS suffered from recurrent vaginitis (16%) and dyspareunia (6%) significantly more frequently than healthy controls. Twenty-nine percent of patients with NCWS reported recurrent cystitis, a finding higher than in the control groups (vs healthy P = 0.0001, vs IBS P = 0.001, vs CD controls P = 0.04). Microbiological examinations were negative in most of the patients with NCWS and recurrent vaginitis or cystitis. During the 1-year follow-up, 46% of patients with menstrual disorders and 36% with recurrent vaginitis reported resolution of symptoms on a wheat-free diet. CONCLUSIONS: Patients with NCWS showed a significantly higher frequency of gynecological symptoms and recurrent cystitis than patients with IBS.

Aporte de energía, macronutrientes y fibra de alimentos farináceos libres de gluten elaborados a partir de premezclas comerciales / Energy, macronutrients and fiber contribution of gluten free farinaceous products produced from commercial premix

Resumen La dieta libre de gluten (DLG) es el único tratamiento frente a la enfermedad celíaca, la alergia al trigo y la sensibilidad al gluten no celíaca. Se reporta a la DLG como una dieta desbalanceada, escasa en fibra y alta en grasas y carbohidratos. El objetivo del estudio fue evaluar el aporte de energía, de macronutrientes y de fibra de alimentos libres de gluten (bizcochuelos, panes estilo inglés, galletitas dulces y pizzas) elaborados a partir de diferentes premezclas comerciales, disponibles en el mercado local. Además, los resultados fueron comparados con un homólogo comercial elaborado con harina de trigo. Para la determinación de la composición centesimal se aplicó la metodología oficial AOAC 2016. El valor energético se calculó utilizando los factores de Atwater. Los resultados obtenidos para los bizcochuelos fueron: 6,0-8,3 g% de proteína; 9,2-11,3 g% de grasas; 1,5-2,3 g% de fibra dietaria; 40,0-53,1 g% de carbohidratos y 285-339 Kcal% de valor energético. Para los panes: 3,0-6,6 g% de proteína; 3,1-12,7 g% de grasas; 2,7-4,0 g% de fibra dietaria; 36,8-50,1 g% de carbohidratos y 217-290 Kcal% de valor energético. Para las galletitas: 3,5-8,5 g% de proteína; 25,9-31,0 g% de grasas; 0,9-5,9 g% de fibra dietaria; 53,9-60,1 g% de carbohidratos y 483-527 Kcal% de valor energético. Para las pizzas: 7,4-9,3 g% de proteína; 7,3-11,2 g% de grasas; 2,8-8,0 g% de fibra dietaria; 19,1-29,6 g% de carbohidratos y 172-240 Kcal% de valor energético. Los alimentos elaborados con premezclas formuladas únicamente con harina de arroz y féculas contribuyen poco a cubrir el valor diario recomendado de fibra. Los que contienen otras fuentes farináceas (harina de sorgo, trigo sarraceno y teff) reflejan un mayor contenido de fibra. La presencia de harina de arveja, soja y teff refleja un aumento del contenido proteico. Los alimentos estudiados frente a su homólogo comercial con harina de trigo presentan, en general, igual o menor aporte proteico, similar aporte energético y de carbohidratos y un mayor aporte de grasas y fibra dietaria.

Abstract The gluten free diet (GFD) is the only treatment for celiac disease, wheat allergy and non-celiac gluten/wheat sensitivity. GFD is reported as an unbalanced diet, low in fibre and high in fat and carbohydrates. The aim of this study was to evaluate energy, macronutrients and fiber contribution of gluten-free cereal products (pound cake, tin loaf, cookies and pizza) coming from different commercial premixes, available at the local market. Also, the results were compared with a commercial equivalent made with wheat flour. For centesimal composition determination, AOAC Official Method 2016 was applied. The energy was calculated using Atwater factors. The results obtained for pound cake were: 6.0-8.3g% protein; 9.2-11.3g% fat; 1.5-2.3g% dietary fibre; 40.0-53.1g% carbohydrate and 285-339Kcal% energy. For tin loaf: 3.0-6.6g% protein; 3.1-12.7% fat; 2.7-4.0g% dietary fibre; 36.8-50.1g% carbohydrate and 217-290Kcal% energy. For cookies: 3.5-8.5g% protein; 25.9-31.0g% fat; 0.9-5.9g% dietary fibre; 53.9-60.1g% carbohydrate and 483-527Kcal% energy. For pizza: 7.4-9.3g% protein; 7.3-11.2g% fat; 2.8-8.0g% dietary fibre; 19.1-29.6g% carbohydrate and 172-240Kcal% of energy. Products made with premix that only contains rice flour and starches contribute little to meeting recommended daily intake. The ones that contain other farinaceous sources (sorghum flour, buckwheat and teff) show higher dietary fibre content. The presence of pea flour, soybean and teff show an increase of protein content. The analysed products present same or lower protein intake, similar energy and carbohydrate intake and higher fat and dietary fibre intake, compared to their commercial equivalent made with wheat flour.

Minimal Lesions of the Small Intestinal Mucosa: More than Morphology.

Minimal lesions of the small bowel are mucosal changes characterized by an increased number of intraepithelial lymphocytes (with or without crypt hyperplasia) and normal villous architecture. Such changes are associated with a wide spectrum of conditions, ranging from food intolerances to infections, and from drugs to immune diseases, with different clinical profiles and manifestations, which complicates the formulation of a differential diagnosis. Patient history, symptom evaluation, and histopathology are the diagnostic features needed to establish a correct diagnosis. Physicians should assist pathologists in formulating a precise morphological evaluation by taking well-oriented small intestinal biopsies and collecting informative clinical findings that inform histopathology. In this current clinical controversy, the authors provide the reader with an appraisal of the small intestine minimal lesions through a careful analysis of the major conditions (e.g., celiac disease and other non-celiac disorders) responsible for such changes and their differential diagnosis. Also, we acknowledge that some of the diseases detailed in this article may progress from an early minimal lesion to overt mucosal atrophy. Thus, the timing of the diagnosis is of paramount importance.

Correlação entre o autodiagnóstico de alergia alimentar e a presença de IgE específica / Correlation between self-diagnosis of food allergy and presence of specific IgE

Introdução: Nos últimos anos a prevalência de alergia alimentar tem aumentado, contudo, o número de autodiagnósticos errados, também. Essa superestimação dos diagnósticos, frequentemente, culmina em dietas restritivas desnecessárias que podem, muitas vezes, ocasionar mais danos do que benefícios para a saúde. Objetivo: Avaliar a relação entre o autodiagnóstico de alergia alimentar e a presença de IgE específica para o referido alimento. Método: Trata-se de um estudo transversal e observacional que avaliou 100 pacientes que aceitaram participar da pesquisa, com idade entre 18 e 75 anos, por meio de um questionário próprio para investigação do autodiagnóstico de doenças alérgicas e um teste cutâneo de leitura imediata ou prick test para detecção de IgE específica para alimentos que podem induzir a uma reação alérgica. Resultados: Foram aplicados e analisados 100 questionários em voluntários na faixa etária de 18 a 75 anos. Destes, 35 pacientes afirmaram ter alergia alimentar durante a aplicação do questionário. Apenas 10 tiveram resultado positivo ao prick test. A maioria dos resultados positivos no prick test estavam associados ao camarão, ao amendoim e ao caranguejo. Conclusão: O presente estudo evidenciou uma importante superestimação do número de autodiagnósticos de alergias alimentares, sendo o número de pacientes que se autodeclararam alérgicos a alimentos consideravelmente maior do que os resultados positivos no prick test. Constata-se que é necessário mais estudos que possuam em sua metodologia informações pré e pós-testes diagnósticos de alergia alimentar, para uma correta avaliação da proporção de casos.

Introduction: In recent years, the prevalence of food allergy has increased, as well as the number of incorrect self-diagnoses. This overestimation of diagnoses often culminates in unnecessary restrictive diets that may cause more harm than benefits to health. Objective: To evaluate the relationship between self-diagnosis of food allergy and the presence of specific IgE for that food. Method: This is a cross-sectional and observational study that evaluated 100 patients who agreed to participate in the research, aged between 18 and 75 years. A questionnaire was used to investigate the self-diagnosis of allergic diseases, and a skin prick test was used to detect food-specific IgE that may induce an allergic reaction. Results: One hundred questionnaires were administered and analyzed in volunteers aged from 18 to 75 years. Of these, 35 patients claimed to have food allergy during the administration of the questionnaire. Only 10 tested positive on the prick test. Most positive prick test results were associated with shrimp, peanut, and crab. Conclusion: The present study showed an important overestimation of the number of self-diagnosed food allergies, as the number of patients who self-reported being allergic to food was considerably greater than that of positive prick test results. More studies that have in their methods pre- and post-diagnostic information from food allergy tests are needed for a correct assessment of the proportion of cases.

TNF-α, IL-17, and IL-22 production in the rectal mucosa of nonceliac wheat sensitivity patients: role of adaptive immunity.

In recent years, a new gluten- or wheat-related disease has emerged, a condition labeled "nonceliac gluten sensitivity" (NCGS) or "nonceliac wheat sensitivity" (NCWS). NCWS pathogenesis is still uncertain and attributed to very different mechanisms. We aimed to study the different T-lymphocyte subsets in the rectal mucosa of NCWS patients to demonstrate the possible contribution of adaptative immune response. Twelve patients (11 women, 1 man, age range 23-61 yr, median 32 yr) with a definitive diagnosis of NCWS were recruited at random for the present study. They underwent rectal endoscopy with multiple mucosal biopsies at the end of a double-blind placebo-controlled (DBPC) wheat challenge when they reported the reappearance of the symptoms. As controls we included 11 "healthy patients", sex- and age-matched with the patients who underwent colonoscopy evaluation for rectal bleeding due to hemorrhoids. Cells freshly obtained from rectal tissue were stained to detect anti-CD45, anti-CD3, anti-CD4, and anti-CD8. Furthermore, intracellular staining was performed with anti-tumor necrosis factor (TNF)-α, anti-interleukin (IL)-17, and anti-IL-22. Production of TNF-α by CD45+, CD3+, CD4+, and CD8+ cells, as well as of IL-17 by CD4+ cells, was higher in the rectal tissue of NCWS patients than in controls. On the contrary, IL-22 production by CD8+ cells was lower in NCWS patients than in the controls. In NCWS patients diagnosed by DBPC wheat challenge, there is a complex immunological activation, with a significant role for the adaptive response.NEW & NOTEWORTHY Nonceliac wheat sensitivity (NCWS) is a syndrome characterized by symptoms triggered by gluten intake. The pathogenesis is still uncertain. Studies have shown a role for innate immunity. We demonstrated that production of TNF-α by CD45+, CD3+, CD4+, and CD8+ cells and of IL-17 by CD4+ cells is higher in the rectal tissue of NCWS patients than in controls. We clearly demonstrated that in patients with NCWS there is a significant role for the adaptive response.

Pitfalls in the Diagnosis of Coeliac Disease and Gluten-Related Disorders.

The spectrum of gluten-related disorders (GRD) has emerged as a relevant phenomenon possibly impacting on health care procedures and costs worldwide. Current classification of GRD is mainly based on their pathophysiology, and the following categories can be distinguished: immune-mediated disorders that include coeliac disease (CD), dermatitis herpetiformis (DH), and gluten ataxia (GA); allergic reactions such as wheat allergy (WA); and non-coeliac gluten sensitivity (NCGS), a condition characterized by both gastrointestinal and extra-intestinal symptoms subjectively believed to be induced by the ingestion of gluten/wheat that has recently gained popularity. Although CD, DH, and WA are well-defined clinical entities, whose diagnosis is based on specific diagnostic criteria, a diagnosis of NCGS may on the contrary be considered only after the exclusion of other organic disorders. Neither allergic nor autoimmune mechanisms have been found to be involved in NCGS. Mistakes in the diagnosis of GRD are still a relevant clinical problem that may result in overtreatment of patients being unnecessary started on a gluten-free diet and waste of health-care resources. On the basis of our clinical experience and literature, we aim to identify the main pitfalls in the diagnosis of CD and its complications, DH, and WA. We provide a practical methodological approach to guide clinicians on how to recognize and avoid them.

Wheat Consumption Leads to Immune Activation and Symptom Worsening in Patients with Familial Mediterranean Fever: A Pilot Randomized Trial.

We have identified a clinical association between self-reported non-celiac wheat sensitivity (NCWS) and Familial Mediterranean Fever (FMF). Objectives: A) To determine whether a 2-week double-blind placebo-controlled (DBPC) cross-over wheat vs. rice challenge exacerbates the clinical manifestations of FMF; B) to evaluate innate immune responses in NCWS/FMF patients challenged with wheat vs. rice. The study was conducted at the Department of Internal Medicine of the University Hospital of Palermo and the Hospital of Sciacca, Italy. Six female volunteers with FMF/NCWS (mean age 36 ± 6 years) were enrolled, 12 age-matched non-FMF, NCWS females, and 8 sex- and age-matched healthy subjects served as controls. We evaluated: 1. clinical symptoms by the FMF-specific AIDAI (Auto-Inflammatory Diseases Activity Index) score; 2. serum soluble CD14 (sCD14), C-reactive protein (CRP), and serum amyloid A (SSA); 3. circulating CD14+ monocytes expressing interleukin (IL)-1ß and tumor necrosis factor (TNF)-α. The AIDAI score significantly increased in FMF patients during DBPC with wheat, but not with rice (19 ± 6.3 vs. 7 ± 1.6; p = 0.028). sCD14 values did not differ in FMF patients before and after the challenge, but were higher in FMF patients than in healthy controls (median values 11357 vs. 8710 pg/ml; p = 0.002). The percentage of circulating CD14+/IL-1ß+ and of CD14+/TNF-α+ monocytes increased significantly after DBPC with wheat vs. baseline or rice challenge. Self-reported NCWS can hide an FMF diagnosis. Wheat ingestion exacerbated clinical and immunological features of FMF. Future studies performed on consecutive FMF patients recruited in centers for auto-inflammatory diseases will determine the real frequency and relevance of this association.

Many Patients With Irritable Bowel Syndrome Have Atypical Food Allergies Not Associated With Immunoglobulin E.

BACKGROUND & AIMS: Confocal laser endomicroscopy (CLE) is a technique that permits real-time detection and quantification of changes in intestinal tissues and cells, including increases in intraepithelial lymphocytes and fluid extravasation through epithelial leaks. Using CLE analysis of patients with irritable bowel syndrome (IBS), we found that more than half have responses to specific food components. Exclusion of the defined food led to long-term symptom relief. We used the results of CLE to detect reactions to food in a larger patient population and analyzed duodenal biopsy samples and fluid from patients to investigate mechanisms of these reactions. METHODS: In a prospective study, 155 patients with IBS received 4 challenges with each of 4 common food components via the endoscope, followed by CLE, at a tertiary medical center. Classical food allergies were excluded by negative results from immunoglobulin E serology analysis and skin tests for common food antigens. Duodenal biopsy samples and fluid were collected 2 weeks before and immediately after CLE and were analyzed by histology, immunohistochemistry, reverse transcription polymerase chain reaction, and immunoblots. Results from patients who had a response to food during CLE (CLE+) were compared with results from patients who did not have a reaction during CLE (CLE-) or healthy individuals (controls). RESULTS: Of the 108 patients who completed the study, 76 were CLE+ (70%), and 46 of these (61%) reacted to wheat. CLE+ patients had a 4-fold increase in prevalence of atopic disorders compared with controls (P = .001). Numbers of intraepithelial lymphocytes were significantly higher in duodenal biopsy samples from CLE+ vs CLE- patients or controls (P = .001). Expression of claudin-2 increased from crypt to villus tip (P < .001) and was up-regulated in CLE+ patients compared with CLE- patients or controls (P = .023). Levels of occludin were lower in duodenal biopsy samples from CLE+ patients vs controls (P = .022) and were lowest in villus tips (P < .001). Levels of messenger RNAs encoding inflammatory cytokines were unchanged in duodenal tissues after CLE challenge, but eosinophil degranulation increased, and levels of eosinophilic cationic protein were higher in duodenal fluid from CLE+ patients than controls (P = .03). CONCLUSIONS: In a CLE analysis of patients with IBS, we found that more than 50% of patients could have nonclassical food allergy, with immediate disruption of the intestinal barrier upon exposure to food antigens. Duodenal tissues from patients with responses to food components during CLE had immediate increases in expression of claudin-2 and decreases in occludin. CLE+ patients also had increased eosinophil degranulation, indicating an atypical food allergy characterized by eosinophil activation.

Thermal treatment reduces gliadin recognition by IgE, but a subsequent digestion and epithelial crossing permits recovery.

Wheat is one of the most important crops in the world in terms of human nutrition. With regards to health, some individuals exhibit wheat-related disorders such as food allergy to wheat (FAW). In this disorder, gluten is involved, particularly the gliadins which are among the main proteins responsible for FAW. Food processing, as well as digestibility and intestinal transport are key factors to consider since they may affect the allergenic potential of food allergens. Wheat is always consumed after heat processing and this step may impact epitope accessibility by inducing aggregation and may irreversibly destroy conformational epitopes. Our aim was to investigate the effects of heating and digestion on the structure of well-known allergens (total gliadins and α-gliadins) and their capacity to maintain their allergenic potential after crossing an intestinal barrier. The sizes of the processed (heated and heated/digested) proteins were characterized by laser light scattering and chromatographic reverse phase. The IgE-binding capacities of native and processed proteins were checked using a dot blot with sera from wheat allergenic patients. Furthermore, the abilities of these samples to cross the intestinal barrier and to induce mast cell degranulation were investigated by combining two in vitro cellular models, Caco-2 and RBL-SX38. The heat treatment of total gliadins and α-gliadins induced the production of large aggregates that were hardly recognized by IgE of patients in dot-blot. However, after limited pepsin hydrolysis, the epitopes were unmasked, and they were able to bind IgE again. Native proteins (gliadins and α-type) and processed forms were able to cross the Caco-2 cells in small amount. Permeability studies revealed the capacity of α-gliadins to increase paracellular permeability. In the RBL assay, the total native gliadins were able to trigger cell degranulation, but none of their processed forms. However after crossing the CaCo-2 monolayer, processed gliadins recovered their degranulation capacity to a certain extent. Total native gliadins remained the best allergenic form compared to α-type.

Identifying True Celiac Disease and Wheat Allergy in the Era of Fashion Driven Gluten-Free Diets.

BACKGROUND: Diagnosing both celiac disease (CD) and wheat allergy (WA) might be challenging due to the increasingly popular gluten-free diets. OBJECTIVES: This study investigates the value of anti-tissue transglutaminase IgA (tTGIgA) and wheat-specific IgE (WIgE), and identifies clinical and serological features associated with CD and WA. METHOD: Serological markers of autoimmunity and allergy along with medical charts of patients assessed for tTGIgA and WIgE between 2010 and 2016 were evaluated. RESULTS: During the last years, an increasing number of patients have been tested for tTGIgA, while the number of positive results decreased linearly. Among the 2,965 patients included, 128 patients showed at least once a positive tTGIgA. All patients with tTGIgA levels higher than the 12-fold upper normal limit had CD. The ratio of tTGIgA/total IgA did not perform better as a diagnostic test for CD compared to tTGIgA. tTGIgA and anti-nuclear antibodies were significantly associated. WA was only rarely investigated, particularly in adults. However, positive WIgE were found in nearly 50% of the cases. WIgE and tTGIgA values were negatively correlated. CONCLUSIONS: tTGIgA were increasingly tested, while the rate of positive results decreased in recent years, possibly reflecting the impact of current alimentary trends on clinical practice. Associated autoimmune disease was frequently found in CD. High levels of tTGIgA accurately predicted CD diagnosis. WA was rarely investigated and deserves more attention, in particular in children with atopic background. WA does not seem to be associated with CD.

Modulative effect of a new hydrazide derivative on wheat-induced pulmonary inflammation in rats.

NEW FINDINGS: What is the central question of this study? What is the mechanism of wheat-induced pulmonary inflammation and how does a hydrazide derivative modulate it? What is the main finding and its importance? A hydrazide derivative significantly reduced wheat-induced pulmonary inflammation in a rat model mainly by down-regulating inflammatory cell infiltration, pathological lesions in the lungs and the level of pro-inflammatory cytokines, COX-1, COX-2 and T-cell proliferation. ABSTRACT: We investigated the ameliorative anti-inflammatory effect of a previously synthesized hydrazide derivative (N'-(4-methoxybenzylidene)-6-(4-chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazide; MD) as an immunomodulator in a newly developed allergen-induced pulmonary inflammation (AIPI) rat model. Wheat and thresher dust were used as allergens to induce pulmonary inflammation while MD was used to reverse the inflammatory response. Blood and bronchoalveolar lavage fluid (BALF) were collected after killing the rats and inflammatory cells were counted. Histological analysis of lung airways was carried out by haematoxylin and eosin and periodic acid-Schiff staining while the level of total serum IgE, interleukin (IL)-4, IL-5 and cyclooxygenase (COX)-1 in BALF and in vitro T-cell proliferation in spleen were measured through enzyme-linked immunosorbent assay. mRNA expression level of IL-4, IL-5, IL-13, transforming growth factor ß (TGF-ß), interferon-γ, tumour necrosis factor α, COX-1 and COX-2 was evaluated by qRT-PCR. A liver and kidney function test was used to observe any toxic impact of MD. The results indicated that 2 mg of wheat and thresher dust led to higher levels of inflammatory cytokines in the blood, BALF and lung airways of rats. MD potentially down-regulated the inflammatory cell infiltration in BALF and pathological lesions in the lung airways of AIPI rats. MD significantly suppressed the elevated total serum IgE, along with IL-4, IL-5, IL-13, TGF-ß, COX-1 and COX-2 mRNA expression and T-cell proliferation in spleen. In conclusion, MD at 10 mg kg-1 exhibited a significant reduction in all the markers in both wheat- and thresher dust-induced pulmonary inflammation mainly by inhibiting pro-inflammatory cytokine production and T-cell proliferation. The data suggest that inhibition of the T-cell response may be responsible for the modulative effect of MD in an AIPI rat model.

Receitas para teste de provocação oral duplo-cego, controlado por placebo / Recipes for double-blind, placebo-controlled oral food challenge

Introdução: O teste de provocação oral (TPO) é o método mais confiável para verificar a relação entre o consumo de um alimento e o desencadeamento de reações adversas. Dentre as dificuldades na realização do TPO, destaca-se o mascaramento dos alimentos em TPO duplo-cego, controlado por placebo (TPODCCP). Objetivo: O objetivo deste trabalho foi elaborar receitas para uso em TPO-DCCP com leite de vaca, soja, ovo e trigo. Métodos: A elaboração das receitas considerou a necessidade de mascaramento do alimento a ser testado, de modo que a receita real e o placebo fossem indistinguíveis. Foram considerados também a quantidade de alimento a ser testado e o volume final das preparações, bem como a hipoalergenicidade dos demais ingredientes utilizados. Resultados: Foram desenvolvidas cinco receitas para TPO-DCCP, sendo duas para testes com leite de vaca, e as outras para testes com soja, ovo e trigo. As receitas placebo e real ficaram semelhantes em relação às cores, texturas, consistências, sabores e aromas. Conclusão: As receitas aqui apresentadas são de preparo fácil e rápido e atendem à maioria dos critérios exigidos para uso em TPO com alimentos. Há, porém, a necessidade de testá-las em estudos de validação para verificarse a possibilidade de serem usadas em protocolos científicos.

Introduction: Oral food challenge (OFC) is the most reliable method to assess the relationship between food consumption and onset of adverse reactions. Among the difficulties in performing OFC there is the masking of food in double-blind, placebocontrolled OFC (DBPC-OFC). Objective: The objective of this study was to prepare recipes to be used in DBPC-OFC with cow's milk, soy, egg and wheat. Methods: Recipe preparation focused on the need of masking the food to be tested, so that actual and placebo recipes were indistinguishable. Also, the amount of food to be tested and the final volume of preparations were considered, and the hypoallergenicity of other ingredients, as well. Results: Five recipes were developed for DBPC-OFC, two for cow's milk tests and the others for soy, egg and wheat tests. Placebo and actual recipes were similar in color, texture, consistency, taste and flavor. Conclusion: The present recipes are quick and easy to prepare and meet most of the criteria required for use in OFC. However, there is the need to test them in validation studies to assess the possibility of use in scientific protocols.

Duodenal and Rectal Mucosa Inflammation in Patients With Non-celiac Wheat Sensitivity.

BACKGROUND & AIMS: Studies of non-celiac gluten or wheat sensitivity (NCGWS) have increased but there are no biomarkers of this disorder. We aimed to evaluate histologic features of colon and rectal tissues from patients with NCGWS. METHODS: We performed a prospective study of 78 patients (66 female; mean age, 36.4 years) diagnosed with NCGWS by double-blind wheat challenge at 2 tertiary care centers in Italy, from January 2015 through September 2016. Data were also collected from 55 patients wither either celiac disease or self-reported NCGWS but negative results from the wheat-challenge test (non-NCGWS controls). Duodenal and rectal biopsies were collected and analyzed by immunohistochemistry to quantify intra-epithelial CD3+ T cells, lamina propria CD45+ cells, CD4+ and CD8+ T cells, mast cells, and eosinophils and to determine the presence and size of lymphoid nodules in patients with NCGWS vs patients with celiac disease or non-NCGWS controls. RESULTS: Duodenal tissues from patients with NCGWS had significantly higher numbers of intra-epithelial CD3+ T cells, lamina propria CD45+ cells, and eosinophils than duodenal tissues from non-NCGWS controls. Duodenal tissues from patients with NCGWS and dyspepsia had a higher number of lamina propria eosinophils than patients with NCGWS without upper digestive tract symptoms. Rectal mucosa from patients with NCGWS had a larger number of enlarged lymphoid follicles, intra-epithelial CD3+ T cells, lamina propria CD45+ cells, and eosinophils than rectal mucosa from non-NCGWS controls. Duodenal and rectal mucosal tissues from patients with celiac disease had more immunocytes (CD45+ cells, CD3+ cells, and eosinophils) than tissues from patients with NCGWS or non-NCGWS controls. CONCLUSIONS: We identified markers of inflammation, including increased numbers of eosinophils, in duodenal and rectal mucosa from patients with NCGWS. NCGWS might therefore involve inflammation of the entire intestinal tract. Eosinophils could serve as a biomarker for NCGWS and be involved in its pathogenesis. Clinicaltrials.gov: NCT01762579.

Towards reducing the immunogenic potential of wheat flour: omega gliadins encoded by the D genome of hexaploid wheat may also harbor epitopes for the serious food allergy WDEIA.

BACKGROUND: Omega-5 gliadins are a group of highly repetitive gluten proteins in wheat flour encoded on the 1B chromosome of hexaploid wheat. These proteins are the major sensitizing allergens in a severe form of food allergy called wheat-dependent exercise-induced anaphylaxis (WDEIA). The elimination of omega-5 gliadins from wheat flour through biotechnology or breeding approaches could reduce the immunogenic potential and adverse health effects of the flour. RESULTS: A mutant line missing low-molecular weight glutenin subunits encoded at the Glu-B3 locus was selected previously from a doubled haploid population generated from two Korean wheat cultivars. Analysis of flour from the mutant line by 2-dimensional gel electrophoresis coupled with tandem mass spectrometry revealed that the omega-5 gliadins and several gamma gliadins encoded by the closely linked Gli-B1 locus were also missing as a result of a deletion of at least 5.8 Mb of chromosome 1B. Two-dimensional immunoblot analysis of flour proteins using sera from WDEIA patients showed reduced IgE reactivity in the mutant relative to the parental lines due to the absence of the major omega-5 gliadins. However, two minor proteins showed strong reactivity to patient sera in both the parental and the mutant lines and also reacted with a monoclonal antibody against omega-5 gliadin. Analysis of the two minor reactive proteins by mass spectrometry revealed that both proteins correspond to omega-5 gliadin genes encoded on chromosome 1D that were thought previously to be pseudogenes. CONCLUSIONS: While breeding approaches can be used to reduce the levels of the highly immunogenic omega-5 gliadins in wheat flour, these approaches are complicated by the genetic linkage of different classes of gluten protein genes and the finding that omega-5 gliadins may be encoded on more than one chromosome. The work illustrates the importance of detailed knowledge about the genomic regions harboring the major gluten protein genes in individual wheat cultivars for future efforts aimed at reducing the immunogenic potential of wheat flour.

Positivity rates of in vitro inhalant/respiratory and food allergy tests in the northern midwestern United States.

Rates of allergy-test positivity vary by country and by regions within countries. Several studies have looked at allergy test results to determine the most common allergens. Many of these studies have been based on surveys or on studies of small numbers of tests. Positivity rates for allergy tests are poorly defined in the northern midwestern region of the United States. We conducted a study to identify the rates of positive allergy tests for both inhalant/respiratory allergens and food allergens in the upper Midwest. We extracted from our laboratory database the results of all test samples sent for one of eight allergen panels that had been analyzed between Sept. 1, 2014, and Sept. 1, 2015. All testing was performed at The Cleveland Clinic with the Phadia ImmunoCAP system. The percentage of positive tests, the distribution of the most frequently positive tests, and the class of in vitro responses were identified. A total of 148,628 test results for 63 different allergens were identified. Of the 125,190 tests for inhalant/respiratory allergens, the most frequently positive were dog dander (24% of tests), cat dander (23%), dust mites (23% for both Dermatophagoides pteronyssinus and Dermatophagoides farinae), and June grass (21%). Of the 23,438 food tests, the most frequently positive test results were for milk (18%), peanut (17%), wheat (16%), and egg white (15%). Most of the results fell into classes 1 through 3, although there was still a notable number of very high responses (class 5 and 6). These findings suggest that there is wide variability in the positivity of in vitro allergy tests and that the likelihood of a positive result in screening panels can be estimated. Evaluating such rates will help identify the most and least common allergens and will help to cost-effectively refine allergy screening panels.

In extremis diagnosis of celiac disease and concomitant wheat allergy.

Celiac disease (CD) and concomitant wheat allergy are not commonly described in the literature. Both can have almost the same treatment consisting of a gluten-free or wheat-free diet. On the other hand, they are based on totally different pathogenetic mechanisms and can be easily underdiagnosed, particularly CD. We describe a peculiar case of a young female patient affected by wheat allergy whose serological and histological data were not diagnostic for CD. Organ culture system successfully detected specific antibodies for CD in duodenal biopsy supernatant, supporting the diagnosis of CD.