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.

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.

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.

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.

Apolipoprotein A4 Defines the Villus-Crypt Border in Duodenal Specimens for Celiac Disease Morphometry.

Histological evaluation of the small intestinal mucosa is the cornerstone of celiac disease diagnostics and an important outcome in scientific studies. Gluten-dependent injury can be evaluated either with quantitative morphometry or grouped classifications. A drawback of mucosal readings is the subjective assessment of the border where the crypt epithelium changes to the differentiated villus epithelium. We studied potential immunohistochemical markers for the detection of the villus-crypt border: apolipoprotein A4 (APOA4), Ki-67, glucose transporter 2, keratin 20, cytochrome P450 3A4 and intestinal fatty-acid binding protein. Among these, villus-specific APOA4 was chosen as the best candidate for further studies. Hematoxylin-eosin (H&E)- and APOA4 stained duodenal biopsy specimens from 74 adult patients were evaluated by five observers to determine the villus-to-crypt ratio (VH : CrD). APOA4 delineated the villus to crypt epithelium transition clearly, and the correlation coefficient of VH : CrD values between APOA4 and H&E was excellent (r=0.962). The VH : CrD values were lower in APOA4 staining (p<0.001) and a conversion factor of 0.2 in VH : CrD measurements was observed to make the two methods comparable to each other. In the intraobserver analysis, the doubled standard deviations, representing the error ranges, were 0.528 for H&E and 0.388 for APOA4 staining, and the ICCs were 0.980 and 0.971, respectively. In the interobserver analysis, the average error ranges were 1.017 for H&E and 0.847 for APOA4 staining, and the ICCs were better for APOA4 than for H&E staining in all analyses. In conclusion, the reliability and reproducibility of morphometrical VH : CrD readings are improved with the use of APOA4 staining.

Enteropathy-Associated T cell Lymphoma.

PURPOSE OF REVIEW: Enteropathy-associated T cell lymphoma (EATL) is a rare subtype of mature T cell lymphoma. The available literature about this rare type T cell lymphoma is relatively limited. This article provides a summary and review of the available literature addressing this entity in terms of risk factors, pathogenesis, diagnostic, and therapeutic options. RECENT FINDINGS: EATL has two distinct subtypes. Type I EATL, now known as EATL, is closely, but not exclusively linked to celiac disease (CD), and it is primarily a disease of Northern European origin. It accounts for < 5% of peripheral T cell lymphoma (PTCL). Risk factors for EATL include advanced age, male sex, and most importantly, genetic susceptibility in the form of HLA-DQ2 homozygosity. The pathogenesis of EATL is closely related to celiac disease as it shares common pathogenic features with refractory celiac disease. The gold standard of diagnosis is histological diagnosis. EATL carries an aggressive course and a poor prognosis. Treatment of EATL includes surgery, induction chemotherapy, and consolidation in first complete remission and autologous stem cell transplant. The role of targeted and biologic therapies in newly diagnosed EATL patients along with relapsed, refractory cases is evolving and discussed in this review. EATL is an aggressive peripheral T cell lymphoma with poor overall treatment outcome using currently available therapy options. Clinical trials are considered the best approach for treatment of EATL. Early diagnosis and early referral to specialized centers would be the best way to deal with such patients. Development of new prognostic models and early surgical intervention are warranted. Prevention is where all the efforts should be spent, by counseling patients with CD regarding the importance of adherence to gluten-free diet and development of periodic surveillance programs in celiac disease patients for early detection of pre-lymphoma lesions.

Cellular and molecular bases of refractory celiac disease.

Refractory celiac disease (RCD) encompasses biologically heterogeneous disorders that develop in a small proportion (0.3%) of individuals with celiac disease that are associated with high morbidity. Two broad categories are currently recognized, type I (RCD I) and type II (RCD II), based on immunophenotypic and molecular features of the intraepithelial lymphocytes (IELs). RCD I is characterized by a polyclonal expansion of IELs displaying a normal immunophenotype, while RCD II represents a clonal proliferation of immunophenotypically "aberrant" IELs, and is considered a low-grade lymphoproliferative disorder. The pathogenesis of RCD I has not been clarified, but limited studies suggest multifactorial etiology. On the other hand, recent immunologic, molecular and immunophenotypic analyses have proposed lineage-negative innate IELs to be the cell of origin of a proportion of RCD II cases. Furthermore, sequencing studies have identified frequent, recurrent, activating mutations in members of the JAK-STAT pathway in RCD II. This finding, in conjunction with prior in vitro experimental observations, suggests roles of deregulated cytokine signaling in disease pathogenesis. In this review, we describe current understanding of environmental, immune and genetic factors associated with the development of RCD and briefly discuss diagnostic and therapeutic considerations.

Circulating CD103+ γδ and CD8+ T cells are clonally shared with tissue-resident intraepithelial lymphocytes in celiac disease.

Gut intraepithelial γδ and CD8+ αß T lymphocytes have been connected to celiac disease (CeD) pathogenesis. Based on the previous observation that activated (CD38+), gut-homing (CD103+) γδ and CD8+ αß T cells increase in blood upon oral gluten challenge, we wanted to shed light on the pathogenic involvement of these T cells by examining the clonal relationship between cells of blood and gut during gluten exposure. Of 20 gluten-challenged CeD patients, 8 and 10 had increase in (CD38+CD103+) γδ and CD8+ αß T cells, respectively, while 16 had increase in gluten-specific CD4+ T cells. We obtained γδ and αß TCR sequences of >2500 single cells from blood and gut of 5 patients, before and during challenge. We observed extensive sharing between blood and gut γδ and CD8+ αß T-cell clonotypes even prior to gluten challenge. In subjects with challenge-induced surge of γδ and/or CD8+ αß T cells, as larger populations of cells analyzed, we observed more expanded clonotypes and clonal sharing, yet no discernible TCR similarities between expanded and/or shared clonotypes. Thus, CD4+ T cells appear to drive expansion of clonally diverse γδ or CD8+ αß T-cell clonotypes that may not be specific for the gluten antigen.

Prevalence of celiac disease in low and high risk population in Asia-Pacific region: a systematic review and meta-analysis.

This systematic review and meta-analysis study was conducted to estimate the pooled prevalence of CD in low and high risk groups in this region. Following keywords were searched in the Medline, PubMed, Scopus, Web of Science and Cochrane database according to the MeSH terms; celiac disease, prevalence, high risk population and Asian-Pacific region. Prevalence studies published from January 1991 to March 2018 were selected. Prevalence of CD with 95% confidence interval (CI) was calculated using STATA software, version 14. The pooled sero-prevalence of CD among low risk group in Asia-Pacific region was 1.2% (95% CI 0.8-1.7%) in 96,099 individuals based on positive anti-tissue transglutaminase (anti-t-TG Ab) and/or anti-endomysial antibodies (EMA). The pooled prevalence of biopsy proven CD in Asia-Pacific among high and low risk groups was 4.3% (95% CI 3.3-5.5%) and 0.61% (95% CI 0.4-0.8%) in 10,719 and 70,344 subjects, respectively. In addition, the pooled sero-prevalence and prevalence of CD in general population was significantly higher in children compared with adults and it was significantly greater in female vs. male (P < 0.05). Our results suggest high risk individuals of CD are key group that should be specifically targeted for prevention and control measures, and screening may prove to have an optimal cost-benefit ratio.

Celiac disease can be predicted by high levels of tissue transglutaminase antibodies in children and adolescents with type 1 diabetes.

OBJECTIVES: Children with type 1 diabetes (T1D) are not included in guidelines regarding diagnosis criteria for celiac disease (CD) without a diagnostic biopsy, due to lack of data. We explored whether tissue transglutaminase antibodies (anti-tTG) that were ≥ 10 times the upper limit of normal (10× ULN) predicted CD in T1D. METHODS: Data from the Swedish prospective Better Diabetes Diagnosis study was used, and 2035 children and adolescents with T1D diagnosed between 2005-2010 were included. Of these, 32 had been diagnosed with CD before T1D. The children without CD were repeatedly screened for CD using anti-tTG antibodies of immunoglobulin type A. In addition, their human leukocyte antigen (HLA) were genotyped. All children with positive anti-tTG were advised to undergo biopsy. Biopsies were performed on 119 children and graded using the Marsh-Oberhüber classification. RESULTS: All of the 60 children with anti-tTG ≥10x ULN had CD verified by biopsies. The degree of mucosal damage correlated with anti-tTG levels. Among 2003 screened children, 6.9% had positive anti-tTG and 5.6% were confirmed CD. The overall CD prevalence, when including the 32 children with CD before T1D, was 7.0% (145/2035). All but one of the children diagnosed with CD had HLA-DQ2 and/or DQ8. CONCLUSIONS: As all screened children and adolescents with T1D with tissue transglutaminase antibodies above 10 times the positive value 10x ULN had CD, we propose that the guidelines for diagnosing CD in screened children, when biopsies can be omitted, should also apply to children and adolescents with T1D as a noninvasive method.

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.

Review article: exposure to microbes and risk of coeliac disease.

BACKGROUND: Coeliac disease is an immune-mediated intestinal disease characterised by lifelong intolerance to dietary gluten in genetically predisposed individuals. Microbial factors including infections or bacterial microbiota have long been suspected to be involved in the aetiology, but the scientific literature on the topic is scattered and heterogeneous. AIMS: To review human observational studies on microbes and coeliac disease METHODS: We identified 135 publications judged relevant. Most studies were cross-sectional, and prone to reverse causation and other biases. Only a few were prospective. Cohort studies and longitudinal studies that have sampled biological specimens before disease onset are emphasised in the review. RESULTS: Infections during early childhood were associated with an increased risk of subsequent coeliac disease in nine studies , whereas maternal infections during pregnancy did not show a clear association. For the most frequently studied microbial factors, some evidence for an association was found, including Helicobacter pylori (four out of 16 studies), adenovirus (two out of nine studies) and enterovirus (two out of six studies). Rotavirus infections have been associated with disease development, and rotavirus vaccination may reduce the risk. Among the many studies of gut microbiota, most were cross-sectional and, therefore, potentially influenced by reverse causation. Only two smaller prospective case-control studies with sampling before disease onset were identified; they reported inconsistent findings regarding the faecal microbiome. CONCLUSIONS: Several microbes are potentially linked to coeliac disease. As microbial factors are amenable to interventions, larger prospective studies are still warranted.

Effects of In Vivo Gluten Challenge on PBMC Gene Expression Profiles in Diet Treated Celiac Disease.

The pathological mechanisms that lead to the onset and reactivation of celiac disease (CD) remain largely unknown. While gluten free diet (GFD) improves the intestinal damage and associated clinical symptoms in majority of cases, it falls short of providing full recovery. Additionally, late or misdiagnosis is also common as CD presents with a wide range of symptoms. Clear understanding of CD pathogenesis is thus critical to address both diagnostic and treatment concerns. We aimed to study the molecular impact of short gluten exposure in GFD treated CD patients, as well as identify biological pathways that remain altered constitutively in CD regardless of treatment. Using RNAseq profiling of PBMC samples collected from treated CD patients and gluten challenged patient and healthy controls, we explored the peripheral transcriptome in CD patients following a short gluten exposure. Short gluten exposure of just three days was enough to alter the genome-wide PBMC transcriptome of patients. Pathway analysis revealed gluten-induced upregulation of mainly immune response related pathways, both innate and adaptive, in CD patients. We evaluated the perturbation of biological pathways in sample-specific manner. Compared to gluten exposed healthy controls, pathways related to tight junction, olfactory transduction, metabolism of unsaturated fatty acids (such as arachidonic acid), metabolism of amino acids (such as cysteine and glutamate), and microbial infection were constitutively altered in CD patients regardless of treatment, while GFD treatment appears to mostly normalize immune response pathways to "healthy" state. Upstream regulator prediction analysis using differentially expressed genes identified constitutively activated regulators relatively proximal to previously reported CD associated loci, particularly SMARCA4 on 19p13.2 and CSF2 on 5q31. We also found constitutively upregulated genes in CD that are in CD associated genetic loci such as MEF2BNB-MEF2B (BORCS8-MEF2B) on 19p13.11 and CSTB on 21q22.3. RNAseq revealed strong effects of short oral gluten challenge on whole PBMC fraction and constitutively altered pathways in CD PBMC suggesting important factors other than gluten in CD pathogenesis.

Prevalence of celiac disease in Iranian patients with type 1 diabetes: A systematic review and meta-analysis.

Patients with type 1 diabetes mellitus (T1DM) are at high risk for celiac disease (CD) due to the common genetic background and interaction between environmental and immunological factors. The purpose of this systematic review and meta-analysis was to estimate the prevalence of CD among Iranian patients with type 1 diabetes. The search for articles was conducted using the following keywords: "celiac disease," "celiac," "coeliac disease," "diabetes," "Iran," and all other possible combinations of these terms. The following databases were searched from inception to June 2019: Scientific Information Database (SID), MagIran, Web of Science, PubMed, and Scopus. Meta-analysis was performed using the random-effects models, and the heterogeneity of results across the studies was assessed using the Cochran's Q test and quantified by the I2 statistic. Data analysis was performed by Stata version 14. A total of 14 papers were included in the meta-analysis, involving 2030 Iranian patients with T1DM. The pooled prevalence of CD in patients with T1DM was 5% (95% CI 3-7). The prevalence of CD in Tehran (4%; 95% CI 1-6) was lower than in other provinces of the country (6%; 95% CI 4-8). Meta-regression analysis showed that, with increasing sample size, the prevalence of  CD was significantly reduced (p = 0.018).Given the adverse effects of CD , such as osteoporosis and malignancy (especially lymphoma), patients with T1DM must be screened for CD .

Celiac disease: histology-differential diagnosis-complications. A practical approach.

Celiac disease is a multi-factorial chronic inflammatory intestinal disease, characterized by malabsorption resulting from mucosal injury after ingestion of wheat gluten or related rye and barley proteins. Inappropriate T-cell-mediated immune response against ingested gluten in genetically predisposed people, leads to characteristic histological lesions, as villous atrophy and intraepithelial lymphocytosis. Nevertheless, celiac disease is a comprehensive diagnosis with clinical, serological and genetic characteristics integrated with histological features. Biopsy of duodenal mucosa remains the gold standard in the diagnosis of celiac disease with the recognition of the spectrum of histological changes and classification of mucosa damage based on updated Corazza-Villanacci system. Appropriate differential diagnosis evaluation and clinical context also for the diagnosis of complications is, moreover, needed for correct histological features interpretation and clinical management.

Gluten Degrading Enzymes for Treatment of Celiac Disease.

Celiac disease (CeD) affects about 1% of most world populations. It presents a wide spectrum of clinical manifestations, ranging from minor symptoms to mild or severe malabsorption, and it may be associated with a wide variety of autoimmune diseases. CeD is triggered and maintained by the ingestion of gluten proteins from wheat and related grains. Gluten peptides that resist gastrointestinal digestion are antigenically presented to gluten specific T cells in the intestinal mucosa via HLA-DQ2 or HLA-DQ8, the necessary genetic predisposition for CeD. To date, there is no effective or approved treatment for CeD other than a strict adherence to a gluten-free diet, which is difficult to maintain in professional or social environments. Moreover, many patients with CeD have active disease despite diet adherence due to a high sensitivity to traces of gluten. Therefore, safe pharmacological treatments that complement the gluten-free diet are urgently needed. Oral enzyme therapy, employing gluten-degrading enzymes, is a promising therapeutic approach. A prerequisite is that such enzymes are active under gastro-duodenal conditions, quickly neutralize the T cell activating gluten peptides and are safe for human consumption. Several enzymes including prolyl endopeptidases, cysteine proteases and subtilisins can cleave the human digestion-resistant gluten peptides in vitro and in vivo. Examples are several prolyl endopeptidases from bacterial sources, subtilisins from Rothia bacteria that are natural oral colonizers and synthetic enzymes with optimized gluten-degrading activities. Without exception, these enzymes must cleave the otherwise unusual glutamine and proline-rich domains characteristic of antigenic gluten peptides. Moreover, they should be stable and active in both the acidic environment of the stomach and under near neutral pH in the duodenum. This review focuses on those enzymes that have been characterized and evaluated for the treatment of CeD, discussing their origin and activities, their clinical evaluation and challenges for therapeutic application. Novel developments include strategies like enteric coating and genetic modification to increase enzyme stability in the digestive tract.

The expression levels of CHI3L1 and IL15Rα correlate with TGM2 in duodenum biopsies of patients with celiac disease.

OBJECTIVE AND DESIGN: Celiac disease (CD) is an intestinal inflammatory disorder of the small intestine. Gliadins are a component of gluten and there are three main types (α, γ, and ω). Recent studies indicate that gliadin peptides are able to activate an innate immune response. IL15 is a major mediator of the innate immune response and is involved in the early alteration of CD mucosa. The chitinase molecules are highly expressed by the innate immune cells during the inflammatory processes. MATERIAL OR SUBJECTS: We analyzed several microarray datasets of PBMCs and duodenum biopsies of CD patients and healthy control subjects (HCs). We verified the modulation CHI3L1 in CD patients and correlated the expression levels to the IL15, IL15Rα, TGM2, IFNγ, and IFNGR1/2. Duodenal biopsy samples belonged to nine active and nine treated children patients (long-term effects of gliadin), and 17 adult CD patients and 10 adults HCs. We also selected 169 samples of PBMCs from 127 CD patients on adherence to a gluten-free diet (GFD) for at least 2 years and 44 HCs. RESULTS: Our analysis showed that CHI3L1 and IL15Rα were significantly upregulated in adult and children's celiac duodenum biopsies. In addition, the two genes were correlated significantly both in children than in adults CD duodenum biopsies. No significant modulation was observed in PBMCs of adult CD patients compared to the HCs. The correlation analysis of the expression levels of CHI3L1 and IL15Rα compared to TGM showed significant values both in adults and in children duodenal biopsies. Furthermore, the IFNγ expression levels were positively correlated with CHI3L1 and IL15Rα. Receiver operating characteristic (ROC) analysis confirmed the diagnostic ability of CHI3L1 and IL15Rα to discriminate CD from HCs. CONCLUSION: Our data suggest a role for CHI3L1 underlying the pathophysiology of CD and represent a starting point aiming to inspire new investigation that proves the possible use of CHI3L1 as a diagnostic factor and therapeutic target.