Loss of tolerance to dietary proteins: From mouse models to human model diseases.

The critical importance of the immunoregulatory mechanisms, which prevent adverse responses to dietary proteins is demonstrated by the consequences of their failure in two common but distinct human pathological conditions, food allergy and celiac disease. The mechanisms of tolerance to dietary proteins have been extensively studied in mouse models but the extent to which the results in mice can be extrapolated to humans remains unclear. Here, after summarizing the mechanisms known to control oral tolerance in mouse models, we discuss how the monogenic immune disorders associated with food allergy on the one hand, and celiac disease, on the other hand, represent model diseases to gain insight into the key immunoregulatory pathways that control immune responses to food antigens in humans. The spectrum of monogenic disorders, in which the dysfunction of a single gene, is strongly associated with TH2-mediated food allergy suggests an important overlap between the mechanisms that regulate TH2 and IgE responses to food antigens in humans and mice. In contrast, celiac disease provides a unique example of the link between autoimmunity and loss of tolerance to a food antigen.

Elucidating the non-genetic risk factors for celiac disease: an umbrella review of meta-analyses.

The breadth and validity of the associations of nongenetic risk factors with celiac disease (CeD) are elusive in the literature. We aimed to evaluate which of these associations have strong epidemiological credibility and assessed presence and extent of potential literature biases. We systematically searched PubMed until April 2024 for systematic reviews and meta-analyses of studies examining associations between putative risk factors and CeD. Each association was categorized in five evidence grades (convincing, highly suggestive, suggestive, weak, and not statistically significant) based on broadly used criteria for evaluating quality of evidence in observational studies. Five eligible publications were included, describing 15 meta-analytic associations on seven nongenetic risk factors, three of which were nominally significant ( P  < 0.05). None of the associations received a strοng or highly suggestive evidence. One meta-analytic association received suggestive evidence, namely any infections during childhood and adulthood for a higher risk of CeD (OR, 1.37; 95% CI, 1.2-1.56; P =3.77 × 10 -6 ). Two meta-analyses reported weak evidence, pertaining to current smoking for a lower risk of CeD (OR, 0.52; 95% CI, 0.32-0.84; P =7.84 × 10 -3 ) and use of antibiotics for a higher risk (OR, 1.2; 95% CI, 1.04-1.38; P 14.8 × 10 -3 ). The rest of the meta-analyses did not report statistically significant results, and pertained to breastfeeding, time of gluten introduction, rotavirus vaccination, and cesarean section. No association of nongenetic risk factors for CeD received high levels of evidence. The evidence was suggestive for the association of any infections during childhood and adulthood with higher risk of CeD. More and prospective future research is warranted.

Early diet and the risk of coeliac disease. An update 2024 position paper by the ESPGHAN special interest group on coeliac disease.

This position paper by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Special Interest Group on Coeliac Disease (SIG-CD) presents an update to the 2016 recommendations concerning early diet and the risk of coeliac disease (CD). This update adheres to the policy that mandates reviewing guidelines every 5 years, particularly when new data emerge. The 2024 statements and recommendations are essentially similar to the 2016 recommendations. Breastfeeding, whether any amount, exclusive, or of any duration, does not reduce the risk of developing CD. Introducing gluten into an infant's diet at any time between completed 4 months (≥17 weeks) and 12 months of age does not affect the cumulative incidence of CD, although earlier introduction may lead to earlier seroconversion and CD. In observational studies involving cohorts with a known risk for CD, consuming a high amount of gluten compared to a low amount during weaning and in the subsequent childhood years-specifically the first 2-3 years, and even up to 5 years in some studies-was associated with an increased risk for CD. However, the specific optimal amounts of gluten consumption remain undetermined due to insufficient evidence on safe thresholds, and the impact of restricting gluten in the diet of healthy children of unknown risk for CD is unknown. Thus, any recommendation on the gluten amount is currently unjustifiable for the general population and infants with known HLA risk types. There is no specific guidance on the type of gluten-containing foods to be introduced at weaning.

Risk of Gluten Cross-Contamination Due to Food Handling Practices: A Mini-Review.

Celiac disease (CD) is an autoimmune disease triggered by the ingestion of gluten in genetically predisposed individuals, affecting 1.4% of the world population. CD induces an inflammatory reaction that compromises small intestine villi, leading to nutrient malabsorption, and gastro and extraintestinal manifestations. Although other treatment approaches are being studied, adherence to a gluten-free diet (GFD) is the only effective intervention to date. Despite this, about 50% of patients experience persistent inflammation, often associated with unintentional gluten ingestion through contaminated food. There are regulations for labeling gluten-free foods which specify a limit of 20 mg/kg (20 ppm). The risks of gluten cross-contamination above that level are present throughout the whole food production chain, emphasizing the need for caution. This review explores studies that tested different procedures regarding the shared production of gluten-containing and gluten-free food, including the use of shared equipment and utensils. A literature review covering PubMed, Scielo, Web of Science, VHL and Scopus identified five relevant studies. The results indicate that shared environments and equipment may not significantly increase gluten cross-contamination if appropriate protocols are followed. Simultaneous cooking of gluten-containing and gluten-free pizzas in shared ovens has demonstrated a low risk of contamination. In general, shared kitchen utensils and equipment (spoon, ladle, colander, knife, fryer, toaster) in controlled experiments did not lead to significant contamination of samples. On the other hand, cooking gluten-free and gluten-containing pasta in shared water resulted in gluten levels above the established limit of 20 ppm. However, rinsing the pasta under running water for a few seconds was enough to reduce the gluten content of the samples to less than 20 ppm.

Cumulative incidence of type 1 diabetes in two cohorts of children with different national gluten recommendations in infancy.

AIMS: Between 1985 and 1996, Sweden experienced an "epidemic" of celiac disease with a fourfold increase in incidence in young children. Timing and amount of gluten introduced during infancy have been thought to explain this "epidemic". We aimed to study whether the cumulative incidence of type 1 diabetes differs between children born during the "epidemic" compared to children born after. METHODS: This is a national register study in Sweden comparing the cumulative incidence of type 1 diabetes in two birth cohorts of 240 844 children 0-17 years old born 1992-1993, during the "epidemic", and 179 530 children born 1997-1998, after the "epidemic". Children diagnosed with type 1 diabetes were identified using three national registers. RESULTS: The cumulative incidence of type 1 diabetes by the age of 17 was statistically significantly higher in those born after the "epidemic" 0.77% than in those born during the "epidemic" 0.68% (p < 0.001). CONCLUSION: The incidence of type 1 diabetes is higher in those born after the epidemic compared to those born during the epidemic, which does not support the hypothesis that gluten introduction increases the incidence of T1D. Changes in gluten introduction did not halt the increased incidence of type 1 diabetes in Sweden.

Bridging science and accessibility: a tactile journey from gluten through to coeliac disease.

As part of the Monash Sensory Science Exhibition, our team guided participants through a multisensory journey unraveling coeliac disease development and pathology. Through tactile and sensory exhibits, we showed how benign dietary gluten can be transformed into a harmful entity for the 1 in 70 Australians with this illness. In contrast to the common misconception of coeliac disease as a food allergy, our exhibits revealed its closer association with autoimmune diseases such as type 1 diabetes, involving genetic susceptibility linked to specific human leukocyte antigens, crucial antigen-specific T- and B-cell responses and autoantibody production. Tactile models underscored the severe consequences of the proinflammatory immune response to gluten on patient health and quality of life. This educational event affirmed to us the value and importance of fostering inclusivity in science education.

Associations of dietary patterns between age 9 and 24 months with risk of celiac disease autoimmunity and celiac disease among children at increased risk.

BACKGROUND: Higher gluten intake in childhood is associated with increased incidence of celiac disease autoimmunity (CDA) and celiac disease. It remains to be studied whether different dietary patterns independent of gluten intake contribute to the incidence. OBJECTIVES: This study aimed to explore associations of dietary patterns by age 2 y with risk of CDA and celiac disease in genetically susceptible children. METHODS: Data was used from 6726 participants at genetic risk of type 1 diabetes and celiac disease enrolled in the observational cohort, The Environmental Determinants of Diabetes in the Young (TEDDY) study. Children were annually screened for tissue transglutaminase autoantibodies (tTGAs) from age 2 y. Principal component analysis extracted dietary patterns, based on intake of 27 food groups assessed by 3-d food records at age 9 to 24 mo. The primary outcome was CDA (i.e., persistently tTGA-positive in at least 2 consecutive samples), and the secondary outcome was celiac disease. During follow-up to mean age 11.0 (standard deviation 3.6) y, 1296 (19.3%) children developed CDA, and 529 (7.9%) were diagnosed with celiac disease. Associations of adherence to dietary patterns (per 5-unit increase) with the study outcomes were estimated by Cox regression models adjusted for risk factors including gluten intake. RESULTS: At age 9 mo, a dietary pattern higher in the food groups vegetable fats and milk was associated with reduced risk of CDA (hazard ratio [HR]: 0.88; 95% confidence interval [CI]: 0.79, 0.98; P = 0.02). At 24 mo, a dietary pattern higher in the food groups wheat, vegetable fats, and juices, and lower in milk, meat, and oats at age 24 mo was associated with increased risk of CDA (HR: 1.18; 95% CI: 1.05, 1.33; P < 0.001) and celiac disease (HR: 1.24; 95% CI: 1.03, 1.50; P = 0.03). CONCLUSIONS: Dietary patterns in early childhood are associated with risk of CDA and celiac disease in genetically predisposed children, independent of gluten intake.

Early environmental risk factors and coeliac disease in adolescents: a population-based cohort study in Denmark.

OBJECTIVES: Our aim was to investigate the association between early environmental factors and the development of coeliac disease (CeD) in adolescents, recruited from a cohort nested in the Danish National Birth Cohort (DNBC). DESIGN: The study was designed as a prospective cohort study, nested in DNBC PARTICIPANTS: The Glutenfunen cohort comprises 1266 participants, nested in DNBC. All participants were screened for CeD, and in total, 28 cases of biopsy proven CeD were identified. Data about breastfeeding, timing of introduction to solid food in infancy, use of antibiotics, infections and symptoms were parentally reported prospectively at 6 months and 18 months, respectively. We estimated ORs and 95% CIs of CeD in adolescents using logistic regression analysis. RESULTS: Viral croup reported at 18 months of age was associated with CeD in adolescents with an OR of 3.2 (95% CI: 1.2 to 8.7). Furthermore, otitis media also reported at 18 months of age was linked with CeD with an OR of 3.2 (95% CI: 1.5 to 7.3). We were not able to find any statistical associations between CeD and breastfeeding, frequency of infections, parentally reported use of antibiotic and timing of solid foods. CONCLUSION: In this study, we present an overview of the relationship between early environmental factors and occurrence of CeD in adolescents. Our findings, despite limitations due to a limited number of cases of CeD, suggest a role of viral infections in the pathogenesis of CeD.

Relationship between gluten availability and celiac disease prevalence: A geo-epidemiologic systematic review.

Celiac disease is a global disease requiring genetic susceptibility and gluten exposure to trigger immune-mediated enteropathy. The effect of the degree of gluten-containing grain availability on celiac disease prevalence is unknown. Our objective was to compare country-based gluten availability to celiac prevalence using a systematic literature review. We searched MEDLINE, Embase, Cochrane, and Scopus until May 2021. We included population-based serum screening with confirmatory testing (second serological study or small intestine biopsy) and excluded specific, high-risk, or referral populations. We determined country-specific gluten availability using the United Nations food balance for wheat, barley, and rye. Human leukocyte antigen (HLA) frequencies were obtained from allelefrequencies.net. The primary outcome was association between gluten-containing grain availability and celiac disease prevalence. Generalized linear mixed models method with Poisson's link was used for analysis. We identified 5641 articles and included 120 studies on 427 146 subjects from 41 countries. Celiac disease prevalence was 0-3.1%, median 0.75% (interquartile range 0.35, 1.22). Median wheat supply was 246 g/capita/day (interquartile range 214.8, 360.7). The risk ratio (RR) for wheat availability on celiac disease was 1.002 (95% confidence interval [CI]: 1.0001, 1.004, P = 0.036). A protective association was seen with barley, RR 0.973 (95% CI: 0.956, 0.99, P = 0.003), and rye, RR 0.989 (95% CI: 0.982, 0.997, P = 0.006). The RR for gross domestic product on celiac disease prevalence was 1.009 (95% CI: 1.005, 1.014, P < 0.001). The RR for HLA-DQ2 was 0.982 (95% CI: 0.979, 0.986, P < 0.001), and that for HLA-DQ8 was 0.957 (95% CI: 0.950, 0.964, P < 0.001). In this geo-epidemiologic study, gluten-containing grain availability showed mixed associations with celiac disease prevalence.

Intravenous route for folate supplementation in a patient with celiac disease treated by pemetrexed-based chemotherapy for non-small-cell lung cancer.

INTRODUCTION: Oral folic acid supplementation is essential for patients treated with pemetrexed, to prevent the risk of severe hematologic toxicity. In case of intestinal absorption disorder, no recommendations exist for intravenous folic acid supplementation. CASE REPORT: We describe a 74-year-old patient with multimetastatic non-small-cell lung adenocarcinoma, receiving first-line chemotherapy with carboplatin AUC5, pemetrexed 500 mg/m2 and pembrolizumab 200 mg intravenously every 3 weeks. The patient presented neglected celiac disease, resulting in malabsorption syndrome with iron and folic acid deficiency. The question was how to administer folic acid supplementation during the pemetrexed-based chemotherapy. MANAGEMENT AND OUTCOMES: Intravenous injection of 200 mg levoleucovorin on day 1 of cycle 1 of pemetrexed-based chemotherapy was administered and well tolerated. During the second cycle, the levoleucovorin perfusion was not renewed by omission. The patient was hospitalized for 7 days because of febrile aplasia. Piperacillin-tazobactam was started, and then switched to amoxicillin-clavulanate plus ciprofloxacin. After this episode of post-chemotherapy febrile aplasia, it was decided to systematically supplement the patient with intravenous levoleucovorin, with blood folate concentration monitoring at each cycle. At 16 months after start of treatment, the patient was in complete remission, indicating that the immune-chemotherapy was effective, with no further febrile neutropenia. DISCUSSION/CONCLUSION: This case report highlights intravenous levoleucovorin supplementation as an alternative to oral folic acid if needed during pemetrexed-antifolate-based chemotherapy.

Estado nutricional integral de niños y adolescentes con enfermedad celíaca / Comprehensive nutritional status of children and adolescents with celiac disease

Introducción: La enfermedad celíaca (EC) es una enteropatía autoinmune desencadenada por la ingestión de gluten, en personas con predisposición genética. Su prevalencia está aumentando y el impacto nutricional de la enfermedad y de su tratamiento es objeto de numerosas publicaciones. Objetivo: analizar el estado nutricional integral de los pacientes con EC, atendidos en el Centro de Atención Nutricional Infantil Antímano CANIA, entre 1996 y 2016. Materiales y Métodos: investigación descriptiva, retrospectiva y transeccional. Las variables estudiadas: edad, sexo, diagnóstico nutricional integral, (indicadores antropométricos, de maduración ósea, dietéticos y bioquímicos) y cumplimiento de dieta sin gluten. Resultados: Se evaluaron 55 pacientes con EC, entre 2 y 7 años (58,2 %) con predominio de sexo femenino. El diagnóstico nutricional más frecuente fue la desnutrición en un 56,4 %, un 16,4 % presentó talla baja. El retardo en la maduración ósea se presentó en 33,3 %, y mostró asociación significativa con la desnutrición. El déficit de hierro sérico e hipocalcemia se registraron en 24,4 % y 18,8 % de los pacientes. El cumplimiento de la dieta sin gluten fue reportado en el 78,2 % de los casos. La dieta tuvo una tendencia al déficit de energía, macro y micronutrientes, especialmente grasas y calcio, independiente de su cumplimiento. Conclusión: los resultados evidenciaron que los pacientes son vulnerables desde el punto de vista nutricional. La dieta mostró déficit de energía, macronutrientes y calcio. La mayoría presentó algún grado de desnutrición. La atención nutricional debe ser ofrecida a esta población, desde el mismo momento en que se realiza el diagnóstico independiente de la edad(AU)

ackground: Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten, in people with a genetic predisposition. Its prevalence is increasing and the nutritional impact of the disease and its treatment is the subject of numerous publications. Objective: to analyze the comprehensive nutritional status of patients with CD, treated at the Centro de Atención Nutricional Infantil Antímano CANIA, between 1996 and 2016. Methods: descriptive, retrospective and transectional research. The variables studied: age, sex, comprehensive nutritional diagnosis (anthropometric, bone maturation, dietary and biochemical indicators) and compliance with a gluten- free diet. Results: 55 patients with CD were evaluated, the majority between 2 and 7 years (58.2%) with a predominance of females. The most frequent nutritional diagnosis was malnutrition in 56.4%, 16.4% had short stature. The delay in bone maturation occurred in 33.3%, and showed a significant association with malnutrition. Serum iron deficiency and hypocalcemia were recorded in 24.4% and 18.8% of patients. Compliance with the gluten-free diet was reported in 78.2% of cases. The diet had a tendency towards a deficit of energy, macro and micronutrients, especially fats and calcium, regardless of compliance. Conclusion: the results showed that patients are vulnerable from a nutritional point of view. The diet showed a deficit of energy, macronutrients and calcium. The majority presented some degree of malnutrition. Nutritional care must be offered to this population, from the moment the diagnosis is made, regardless of age(AU)

Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis, Diagnosis and Therapy.

Type 2 transglutaminase (TG2) is the main autoantigen in coeliac disease (CD), a widespread inflammatory enteropathy caused by the ingestion of gluten-containing cereals in genetically predisposed individuals. As a consequence, serum antibodies to TG2 represent a very useful marker in CD diagnosis. However, TG2 is also an important player in CD pathogenesis, for its ability to deamidate some Gln residues of gluten peptides, which become more immunogenic in CD intestinal mucosa. Given the importance of TG2 enzymatic activities in CD, several studies have sought to discover specific and potent inhibitors that could be employed in new therapeutical approaches for CD, as alternatives to a lifelong gluten-free diet. In this review, we summarise all the aspects regarding TG2 involvement in CD, including its enzymatic reactions in pathogenesis, the role of anti-TG2 antibodies in disease management, and the exploration of recent strategies to reduce deamidation or to use transamidation to detoxify gluten.

Review article: Epidemiology of coeliac disease.

Coeliac disease is an immune-mediated disease caused by ingestion of gluten in genetically susceptible individuals. Coeliac disease has been thought to affect mainly people of European origin but subsequently many studies revealed that it affects people living in North America, Oceania, South America, Asia as well as Africa. The global pooled seroprevalence and prevalence of biopsy-confirmed coeliac disease are 1.4% and 0.7% respectively. The pooled incidence rates in women and men are 17.4 (95% CI: 13.7-21.1) and 7.8 (95% CI: 6.3-9.2) per 100 000 person-years respectively. The systematic reviews, based on many population-based data, suggest that both the prevalence and the incidence of coeliac disease has increased over past three decades, which may be attributable not only to an increase in the detection rate (improvement in diagnostic tests, simplification of diagnostic criteria and increase in awareness about the disease) but also because of modernisation and globalisation related changes in the dietary practices including increase in the use of convenience food and dietary gluten. In addition to genetic factors, while there are many environmental risk factors, including age at the first introduction of gluten, breastfeeding, caesarean section, exposure to antibiotics and gut microbiome; the amount of gluten ingestion during early part of life, however, has been shown to increase the risk of coeliac disease, and this is relevant from the point of view of primary prevention. In this review, we have reviewed and summarised the literature, up till year 2021, related to the global and continent-wise epidemiology and risk factors associated with coeliac disease.

Pro-Inflammatory Nutrient: Focus on Gliadin and Celiac Disease.

Ingested food can cause tissue inflammation through different mechanisms [...].

Sources of dietary gluten in the first 2 years of life and associations with celiac disease autoimmunity and celiac disease in Swedish genetically predisposed children: The Environmental Determinants of Diabetes in the Young (TEDDY) study.

BACKGROUND: High gluten intake is associated with increased risk of celiac disease (CD) in children at genetic risk. OBJECTIVES: We aimed to investigate if different dietary gluten sources up to age 2 y confer different risks of celiac disease autoimmunity (CDA) and CD in children at genetic risk. METHODS: Three-day food records were collected at ages 6, 9, 12, 18, and 24 mo from 2088 Swedish genetically at-risk children participating in a 15-y follow-up cohort study on type 1 diabetes and CD. Screening for CD was performed with tissue transglutaminase autoantibodies (tTGA). The primary outcome was CDA, defined as persistent tTGA positivity. The secondary outcome was CD, defined as having a biopsy specimen showing Marsh score ≥ 2 or an averaged tTGA level ≥ 100 Units. Cox regression adjusted for total gluten intake estimated HRs with 95% CIs for daily intake of gluten sources. RESULTS: During follow-up, 487 (23.3%) children developed CDA and 242 (11.6%) developed CD. Daily intake of ≤158 g porridge at age 9 mo was associated with increased risk of CDA (HR: 1.53; 95% CI: 1.05, 2.23; P = 0.026) compared with no intake. A high daily bread intake (>18.3 g) at age 12 mo was associated with increased risk of both CDA (HR: 1.47; 95% CI: 1.05, 2.05; P = 0.023) and CD (HR: 1.79; 95% CI: 1.10, 2.91; P = 0.019) compared with no intake. At age 18 mo, milk cereal drink was associated with an increased risk of CD (HR: 1.16; 95% CI: 1.00, 1.33; P = 0.047) per 200-g/d increased intake. No association was found for other gluten sources up to age 24 mo and risk of CDA or CD. CONCLUSIONS: High daily intakes of bread at age 12 mo and of milk cereal drink during the second year of life are associated with increased risk of both CDA and CD in genetically at-risk children.

Cesarean section is not associated with increased risk of celiac disease in the offspring: a meta-analysis.

OBJECTIVE: Epidemiologic findings are inconsistent concerning the association between cesarean section (C-section) and celiac disease in offspring. METHODS: We performed a systematic literature search of PubMed and Embase databases until July 2021. A meta-analysis was performed for each outcome in which a summary odds ratio (OR) was calculated while taking heterogeneity into account. RESULTS: A total of 11 observational were identified for the literature review. We found that C-section was not associated with an increase in the risk of CD (OR = 1.03, 95% CI, 0.95-1.12; p = .501). In subgroup analyses, the association remained insignificant for both infants born after elective C-section (OR 1.05; 0.95-1.16; p = .329) and emergency C-section (OR 1.06; 1-1.13; p = .051). CONCLUSIONS: Our results indicate that C-section is not associated with CD in offspring.

Review on pediatric coeliac disease from a clinical perspective.

Coeliac disease is an immune-mediated condition characterized by chronic inflammation of the small bowel with villous atrophy driven by gluten ingestion in genetically predisposed individuals. It occurs frequently in both children and adults, affecting 1-4% of the population. The disease is associated with both gastrointestinal and extra-intestinal symptoms related to malabsorption and/or immune activation, and autoantibodies to tissue transglutaminase. Removal of gluten from the diet results in resolution of symptoms and enteropathy in the majority of patients. A good diagnostic work-up is important to avoid unnecessary restrictive diets in children. In this review on pediatric coeliac disease, we address epidemiology including predisposing environmental factors and possible preventive strategies, as well as the clinical presentation, diagnosis and follow-up. What is Known: •Primary prevention of coeliac disease is not possible; however, secondary prevention by targeting high-risk groups is recommended. •The diagnosis is safe without duodenal biopsies if specific conditions are met, also in asymptomatic children. What is New: •HLA-DQ typing is not routinely required for the diagnosis, whereas it can rule out coeliac disease if HLA-DQ2 and HLA-DQ8 are absent. •Follow-up could be improved by a more rational use of (laboratory) tests, increased intention to dietary compliance and quality of life.

Iron Deficiency in Celiac Disease: Prevalence, Health Impact, and Clinical Management.

Iron is an essential nutrient to life and is required for erythropoiesis, oxidative, metabolism, and enzymatic activities. It is a cofactor for mitochondrial respiratory chain enzymes, the citric acid cycle, and DNA synthesis, and it promotes the growth of immune system cells. Thus, iron deficiency (ID) leads to deleterious effects on the overall health of individuals, causing significant morbidity. Iron deficiency anemia (IDA) is the most recognized type of anemia in patients with celiac disease (CD) and may be present in over half of patients at the time of diagnosis. Folate and vitamin B12 malabsorption, nutritional deficiencies, inflammation, blood loss, development of refractory CD, and concomitant Heliobacter pylori infection are other causes of anemia in such patients. The decision to replenish iron stores and the route of administration (oral or intravenous) are controversial due, in part, to questions surrounding the optimal formulation and route of administration. This paper provides an algorithm based on the severity of symptoms; its impact on the health-related quality of life (HRQL); the tolerance and efficiency of oral iron; and other factors that predict a poor response to oral iron, such as the severity of histological damage, poor adherence to GFD, and blood loss due to mucosal lesions.

Ranking of immunodominant epitopes in celiac disease: Identification of reliable parameters for the safety assessment of innovative food proteins.

A ranking of gluten T-cell epitopes triggering celiac disease (CD) for its potential application in the safety assessment of innovative food proteins is developed. This ranking takes into account clinical relevance and information derived from key steps involved in the CD pathogenic pathway: enzymatic digestion, epitope binding to HLA-DQ receptors of the antigen-presenting cells and activation of pro-inflammatory CD4 T-cells, which recognizes the HLA-DQ-epitope complex and initiates the inflammatory response. In silico chymotrypsin digestion was the most discriminatory tool for the ranking of gluten T-cell epitopes among all digestive enzymes studied, classifying 81% and 60% of epitopes binding HLA-DQ2.5 and HLA-DQ8 molecules, respectively, with a high risk. A positive relationship between the number of prolines and the risk of gluten T-cell epitopes was identified. HLA-binding data analysis revealed the additional role played by the flanking regions of the 9-mer epitopes whereas the integration of T-cell activation data into the ranking strategy was incomplete because it was difficult to combine results from different studies. The overall ranking proposed in decreasing order of immunological relevance was: α-gliadins > ω-gliadins > hordeins > γ-gliadins âˆ¼ avenins âˆ¼ secalins > glutenins. This novel approach can be considered as a first step to reshape the risk assessment strategy of innovative proteins and their potential to trigger CD.