The intestinal tract is constantly exposed to a diverse mixture of luminal antigens, such as those derived from commensals, dietary substances, and potential pathogens. It also serves as a primary route of entry for pathogens. At the forefront of this intestinal defense is a single layer of epithelial cells that forms a critical barrier between the gastrointestinal (GI) lumen and the underlying host tissue. The intestinal intraepithelial T lymphocytes (T-IELs), one of the most abundant lymphocyte populations in the body, play a crucial role in actively surveilling and maintaining the integrity of this barrier by tolerating non-harmful factors such as commensal microbiota and dietary components, promoting epithelial turnover and renewal while also defending against pathogens. This immune balance is maintained through interactions between ligands in the GI microenvironment and receptors on T-IELs. This review provides a detailed examination of the ligands present in the intestinal epithelia and the corresponding receptors expressed on T-IELs, including T cell receptors (TCRs) and non-TCRs, as well as how these ligand-receptor interactions influence T-IEL functions under both steady-state and pathological conditions. By understanding these engagements, we aim to shed light on the mechanisms that govern T-IEL activities within the GI microenvironment. This knowledge may help in developing strategies to target GI ligands and modulate T-IEL receptor expression, offering precise approaches for treating intestinal disorders.

Gluten comprises an intricate network of hundreds of related but distinct proteins, mainly "gliadins" and "glutenins," which play a vital role in determining the rheological properties of wheat dough. However, ingesting gluten can trigger severe conditions in susceptible individuals, including celiac disease, wheat allergy, or non-celiac gluten sensitivity, collectively known as gluten-related disorders. This review provides a panoramic view, delving into the various aspects of gluten-triggered disorders, including symptoms, diagnosis, mechanism, and management. Though a gluten-free diet remains the primary option to manage gluten-related disorders, the emerging microbial and plant biotechnology tools are playing a transformative role in reducing the immunotoxicity of gluten. The enzymatic hydrolysis of gluten and the development of gluten-reduced/free wheat lines using RNAi and CRISPR/Cas technology are laying the foundation for creating safer wheat products. In addition to biotechnological interventions, the emerging artificial intelligence technologies are also bringing about a paradigm shift in the diagnosis and management of gluten-related disorders. Here, we provide a comprehensive overview of the latest developments and the potential these technologies hold for tackling gluten sensitivity.

This study aimed to assess the morphometry of enterocytes as well as the goblet cell-to-enterocyte ratio in different intestinal segments of dogs with chronic enteropathies (CE). Histopathological intestinal samples from 97 dogs were included in the study (19 healthy juveniles, 21 healthy adults, 24 dogs with protein-losing enteropathy (PLE), and 33 CE dogs without PLE). Healthy adult small intestinal enterocytes showed progressively reduced epithelial cell height in the aboral direction, while juvenile dogs showed progressively increased epithelial cell height in the aboral direction. CE dogs had increased epithelial cell height in the duodenum, while PLE dogs had decreased epithelial cell heights compared to healthy adult dogs. Both the CE and PLE dogs showed decreased enterocyte width in the duodenal segment, and the ileal and colonic enterocytes of CE dogs were narrower than those of healthy adult dogs. CE dogs had a lower goblet cell-to-enterocyte ratio in the colon segment compared to healthy dogs. This study provides valuable morphometric information on enterocytes during canine chronic enteropathies, highlighting significant morphological enterocyte alterations, particularly in the small intestine, as well as a reduced goblet cell-to-enterocyte ratio in the colon of CE cases compared to healthy adult dogs.

Non-celiac wheat sensitivity (NCWS) is a clinical entity induced by the ingestion of gluten that leads to intestinal and/or extraintestinal symptoms, and is diagnosed when celiac disease and wheat allergy have been ruled out. In addition to gluten, other grains' components, including amylase trypsin inhibitors (ATIs) and fermentable short-chain carbohydrates (FODMAPs), may trigger symptoms in NCWS subjects. Several studies suggest that, compared with tetraploid and hexaploid modern wheats, ancient diploid wheats species could possess a lower immunogenicity for subjects suffering from NCWS. This review aims to discuss available evidence related to the immunological features of diploid wheats compared to common wheats, and at outlining new dietary opportunities for NCWS subjects.

The Indian Association of Pathologists and Microbiologists (IAPM) and Indian Society of Gastroenterology (ISG) decided to make a joint consensus recommendation for handling, processing, and interpretation of SI biopsies for the diagnosis and management of celiac disease (CD) recognizing the inhomogeneous practice of biopsy sampling, orientation, processing, and interpretation. A modified Delphi process was used to develop this consensus document containing a total of 42 statements and recommendations, which were generated by sharing the document draft, incorporating expert's opinion, followed by three cycles of electronic voting as well as a full-day face-to-face virtual ZOOM meeting and review of supporting literature. Of the 42 statements, 7 statements are on small intestinal (SI) biopsy in suspected patients of CD, site and the number of biopsies; 7 on handling, fixative, orientation, processing, and sectioning in pathology laboratories; 2 on histological orientation; 13 statements on histological interpretation and histological grading; 3 on the assessment of follow-up biopsies; 2 statements on gluten-free diet (GFD)-nonresponsive CD; 4 on challenges in the diagnosis of CD; 2 statements each on pathology reporting protocol and training and infrastructure in this area. The goal of this guideline document is to formulate a uniform protocol agreed upon both by the experienced pathologists and gastroenterologists to standardize the practice, improve the yield of small bowel biopsy interpretation, patients' compliance, overall management in CD, and generate unified data for patient care and research in the related field.

Serological tests for coeliac disease (CD) are important in the clinical diagnosis and monitoring of response to a gluten free diet (GFD). The tests differ in their sensitivity, specificity, and diagnostic accuracy. In this study, tissue transglutaminase (IgA) (tTG-IgA) antibody was compared with the deamidated gliadin peptide (DGP), of both IgG (DGP-IgG) and IgA (DGP-IgA) types, in patients with CD.

This cross-sectional study was conducted over a period of 2 years, between 2016 and 2018, at King Abdulaziz University Hospital in children 18 years of age or younger with biopsy-proven CD. Patients' sera were tested for DGP-IgA, DGP-IgG, and tTG-IgA antibodies using enzyme-linked immunosorbent assay (ELISA). A Pearson correlation coefficient and Cohen's kappa coefficient were performed to analyse the serological tests.

The study included 26 patients with CD, with a median age of 15 years (range, 5-18 years). Seventeen patients (65.4%) were males. The median disease duration was 5 years (range, 3-14 years). Fifteen patients (57.7%) reported good adherence to a GFD. The patients' serological tests showed a mean ± SD tTG-IgA titer of 149.8 ± 75 u/ml, a mean DGP-IgG titer of 62.5 ± 36.5, and a mean DGP-IgA of 32 ± 23.3 μ/ml. We found a significant correlation between tTG-IgA and DGP-IgG (r = 0.69, P < 0.001), tTG-IgA and DGP-IgA (r = 0.67, P < 0.001), and DGP-IgG and DGP-IgA (r = 0.83, P < 0.001). Cohen's kappa coefficient (k) showed substantial agreement between tTG-IgA and DGP-IgG (k = 0.71, P < 0.001) and DGP-IgG and DGP-IgA (k = 0.69, P < 0.001), but moderate agreement between tTG-IgA and DGP-IgA (k = 0.45, P = 0.006).

We found a good correlation between tTG-IgA and DGP-IgG and tTG-IgA and DGP-IgA, and substantial agreement between tTG-IgA and DGP-IgG, but moderate agreement between tTG-IgA and DGP-IgA. These results indicate that DGP-IgG was comparable to tTG-IgA and may be useful as an alternative to tTG-IgA in the diagnosis and follow-up of patients with CD.

Coeliac disease is a common small bowel enteropathy arising in genetically predisposed individuals and caused by ingestion of gluten in the diet. Great advances have been made in understanding the role of the adaptive immune system in response to gluten peptides. Despite detailed knowledge of these adaptive immune mechanisms, the complete series of pathogenic events responsible for development of the tissue lesion remains less certain. This review contributes to the field by discussing additional mechanisms which may also contribute to pathogenesis. These include the production of cytokines such as interleukin-15 by intestinal epithelial cells and local antigen presenting cells as a pivotal event in the disease process. A subset of unconventional T cells called gamma/delta T cells are also persistently expanded in the coeliac disease (CD) small intestinal epithelium and recent analysis has shown that these cells contribute to pathogenic inflammation. Other unconventional T cell subsets may play a local immunoregulatory role and require further study. It has also been suggested that, in addition to activation of pathogenic T helper cells by gluten peptides, other peptides may directly interact with the intestinal mucosa, further contributing to the disease process. We also discuss how myofibroblasts, a major source of tissue transglutaminase and metalloproteases, may play a key role in intestinal tissue remodeling. Contribution of each of these factors to pathogenesis is discussed to enhance our view of this complex disorder and to contribute to a wider understanding of chronic immune-mediated disease.

The purpose of this review is to provide a definitive account of small intestinal mucosal structure and interpretation. The coeliac lesion has been well known, but not well described to date and this review aims to identify the interpretative difficulties which have arisen over time with the histological assessment of coeliac disease. In early coeliac interpretation, there were significant inaccuracies, particularly surrounding intraepithelial lymphocyte counts and the degree of villous flattening which occurred in the tissue. Many of these interpretive pitfalls are still encountered today, increasing the potential for diagnostic errors. These difficulties are mostly due to the fact that stained 2-dimensional sections can never truly represent the 3-dimensional framework of the intestinal tissue under investigation. Therefore, this review offers a critical account occasioned by these 2-dimensional interpretative errors and which, in our opinion, should in general be jettisoned. As a result, we leave a framework regarding the true 3-dimensional knowledge of mucosal structure accrued over the 70-year period of study, and one which is available for future reference.

Coeliac disease (CD) and gluten-related disorders represent an important cornerstone of the daily practice of gastroenterologists, endoscopists and dedicated histopathologists. Despite the knowledge of clinical, serological and histological typical lesions, there are some conditions to consider for differential diagnosis. From the first description of histology of CD, several studies were conducted to define similar findings suggestive for microscopic enteritis. Considering the establishment of early precursor lesions, the imbalance of gut microbiota is another point still requiring a detailed definition. This review assesses the importance of a right overview in case of suspected gluten-related disorders and the several conditions mimicking a similar histology.

Overexpression of interleukin-15 (IL-15) is linked with immunopathology of several autoimmune disorders including celiac disease. Here, we utilized an anti-human IL-15 antibody 04H04 (anti-IL-15) to reverse immunopathogenesis of celiac disease. Anti-IL-15 was administered to six gluten-sensitive rhesus macaques with celiac disease characteristics including gluten-sensitive enteropathy (GSE), and the following celiac-related metrics were evaluated: morphology (villous height/crypt depth ratio) of small intestine, counts of intestinal intraepithelial lymphocytes, IFN-γ-producing CD8+ and CD4+ T cells, plasma levels of anti-gliadin and anti-intestinal tissue transglutaminase IgG antibodies, as well as peripheral effector memory (CD3+CD28-CD95+) T cells. Anti-IL-15 treatment reversed the clinically relevant disease endpoints, intraepithelial lymphocyte counts, and villous height/crypt depth ratios within jejunal biopsies to normal levels (P < 0.001). Additionally, intestinal CD8+ and CD4+ T cell IFN-γ production was reduced (P < 0.05). Extra-intestinally, anti-IL-15 treatment reduced peripheral NK cell counts (P < 0.001), but otherwise, non-NK peripheral lymphocytes including effector memory T cells and serum blood chemistry were unaffected. Overall, providing the beneficial disease-modulatory and immunomodulatory effects observed, anti-IL-15 treatment might be considered as a novel therapy to normalize intestinal lymphocyte function in celiac disease patients with GSE.

Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive 'normal' IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens.

The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected.

The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2-88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion.

Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence.