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Key Points Patients with coeliac disease demonstrate concurrent autoimmune diseases more frequently (∼5%) than healthy individuals, and patients with autoimmune diseases often have coeliac disease, particularly those with diabetes or thyroid disease Screening for coeliac disease in patients with autoimmune disease should be done regularly by evaluating serum antibodies (serological testing), although negative serology results do not entirely exclude coeliac disease HLA typing offers a good negative predictive value, but only a modest positive predictive value Gastroduodenoscopy whilst on gluten-containing diet is required for final diagnosis in adults, whereas HLA typing is part of the recent diagnostic work-up in children (many can be diagnosed without endoscopy) Extensive genetic overlap exists between coeliac disease and other autoimmune diseases and current genetic risk profiling does not enable a precise prediction of disease development Many autoimmune diseases are known to occur alongside coeliac disease and, in some instances, patients see improvements in both if coeliac disease is diagnosed and treated. Shared genetic traits have been identified between coeliac disease and many of these forms of autoimmunity. In this Review, an overview is presented of the genetic and immunological features of coeliac disease, its overlap with other autoimmune diseases and implications for screening strategies. Coeliac disease is a treatable, gluten-induced disease that often occurs concurrently with other autoimmune diseases. In genetic studies since 2007, a partial genetic overlap between these diseases has been revealed and further insights into the pathophysiology of coeliac disease and autoimmunity have been gained. However, genetic screening is not sensitive and specific enough to accurately predict disease development. The current method to diagnose individuals with coeliac disease is serological testing for the presence of autoantibodies whilst the patient is on a regular, gluten-containing diet, followed by gastroduodenoscopy with duodenal biopsy. Serological test results can also predict the probability of coeliac disease development, even if asymptomatic. In patients with autoimmune diseases known to occur alongside coeliac disease (particularly type 1 diabetes mellitus or thyroid disorders), disease screening—and subsequent treatment if coeliac disease is detected—could have beneficial effects on progression or potential complications of both diseases, owing to the effectiveness of gluten-free dietary interventions in coeliac disease. However, whether diagnosis of coeliac disease and subsequent dietary treatment can prevent autoimmune diseases is debated. In this Review, the genetic and immunological features of coeliac disease, overlap with other autoimmune diseases and implications for current screening strategies will be discussed.

In a phase 2 proof-of-concept trial, patients with celiac disease controlled on a gluten-free diet were assigned to one of three dose levels of ZED1227 (a selective transglutaminase 2 inhibitor) or placebo. Patients were challenged with 3 g of gluten daily for 6 weeks. Comparison of duodenal-biopsy samples between baseline and 6 weeks showed that ZED1227 attenuated gluten-induced mucosal damage.

Crypt hyperplasia is a key feature of celiac disease (CeD) and several other small intestinal inflammatory conditions. Analysis of the gut epithelial crypt zone by mass spectrometry-based tissue proteomics revealed a strong IFN-[gamma] signal in active CeD. This signal, hallmarked by increased expression of MHC molecules, was paralleled by diminished expression of proteins associated with fatty acid metabolism. Crypt hyperplasia and the same proteomic changes were observed in WT mice administered IFN-[gamma]. In mice with conditional KO of the IFN-[gamma] receptor in gut epithelial cells, these signature morphological and proteomic changes were not induced with IFN-[gamma] administration. IFN- [gamma] was thus a driver of crypt hyperplasia in CeD by acting directly on crypt epithelial cells. The results are relevant to other enteropathies with involvement of IFN-[gamma].

Introduction Since the publication of the first European Society for the Study of Coeliac Disease (ESsCD) guidelines in 2019, significant advancements have emerged in the diagnosis of coeliac disease (CeD) in adults. These 2025 guidelines incorporate new evidence to refine diagnostic strategies, aiming for improved accuracy of testing, and enhance overall quality of clinical care. Methods A multidisciplinary panel of experts revised the ESsCD guidelines using the AGREE II instrument (Appraisal of Guidelines for Research and Evaluation II) and the GRADE methodology (The Grading of Recommendations Assessment, Development, and Evaluation). Clinical questions were structured using the PICO format, and statements and recommendations were finalised through a Delphi consensus process. Literature quality was assessed using AMSTAR‐2 and QUADAS‐2 tools. Results The updated guidelines are presented in two parts. Part 1 focuses on adult CeD diagnosis, introducing major changes such as a conditional no‐biopsy approach for selected adults with high‐titre IgA anti‐TG2 serology (≥ 10 × ULN). Regarding serology, the use of validated high‐performance ELISAs displaying a high diagnostic accuracy is emphasised, while routine use of IgA anti‐Endomysium serology is no longer recommended for confirmation. Revised duodenal biopsy protocols now mandate at least four samples from the second part of the duodenum, with bulb biopsies conditionally included. The guidelines provide structured approaches for diagnosing potential CeD, seronegative villous atrophy, and CeD in individuals already on a gluten‐free diet. HLA‐DQ2/DQ8 typing is recommended for diagnostic clarification in select cases. Conclusions The updated 2025 ESsCD guidelines provide a comprehensive framework for the diagnosis of CeD in adults. By integrating evolving diagnostic strategies, minimising over‐testing, and patient‐centred care approaches, they aim to optimise patient outcomes, quality of life and use of diagnostic resources at the same time. Infographic. This infographic summarizes the diagnostic approach to CeD in adults, including initial serological testing, histological confirmation, criteria for a no‐biopsy diagnosis, seronegative CeD, potential CeD, and the role of gluten challenge. Source: Authors' own creation (based on current clinical guidelines).

IgA antibodies directed against tissue transglutaminase 2 (TG2) are used as a serological marker of celiac disease. Ludvig M. Sollid and his colleagues provide an unbiased and thorough characterization of the mucosal antibody response directly from the effector compartment. They report that TG2-specific plasma cells are expanded in the duodenal mucosa of individuals with celiac disease. Antibodies cloned from these cells are of high affinity, show a restricted repertoire and minimal somatic hypermutation, and do not inhibit TG2 enzymatic activity. Celiac disease is an immune-mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) 1 are generated in response to the exogenous antigen gluten 2 in individuals who express human leukocyte antigen HLA-DQ2 or HLA-DQ8 (ref. 3 ). We assessed in a comprehensive and nonbiased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire of ex vivo –isolated intestinal antibody-secreting cells (ASCs). We found that TG2-specific plasma cells are markedly expanded within the duodenal mucosa in individuals with active celiac disease. TG2-specific antibodies were of high affinity yet showed little adaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts 4 , the TG2-specific ASCs had not recently proliferated and were not short-lived ex vivo . Altogether, these observations demonstrate that there is a germline repertoire with high affinity for TG2 that may favor massive generation of autoreactive B cells. TG2-specific antibodies did not block enzymatic activity and served as substrates for TG2-mediated crosslinking when expressed as IgD or IgM but not as IgA1 or IgG1. This could result in preferential recruitment of plasma cells from naive IgD- and IgM-expressing B cells, thus possibly explaining why the antibody response to TG2 bears signs of a primary immune response despite the disease chronicity.

Gut mucosal barrier injury is common following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and associated with poor clinical outcomes. Diet is critical for microbial diversity, but whether nutritional support affects microbiota and outcome after allo-HSCT is unknown. We present a secondary analysis of a randomized controlled nutritional intervention trial during allo-HSCT. We investigated if the intervention influenced gut microbiota, short-chain fatty acids (SCFAs), and markers of gut barrier functions, and if these parameters were associated with clinical outcomes. Fecal specimens were available from 47 recipients, and subjected to 16S rRNA gene sequencing. We found no significant differences between the intervention group and controls in investigated parameters. We observed a major depletion of microbiota, SCFAs, and altered markers of gut barrier function from baseline to 3 weeks post-transplant. One-year mortality was significantly higher in patients with lower diversity at 3 weeks post-HSCT, but not related to diversity at baseline. The relative abundance of Blautia genus at 3 weeks was higher in survivors. Fecal propionic acid was associated with survival. Markers of gut barrier functions were less strongly associated with clinical outcomes. Possibly, other strategies than dietary intervention are needed to prevent negative effects of gut microbiota and clinical outcomes after allo-HSCT. ClinicalTrials.gov (NCT01181076).

Introduction Since the publication of the first European Society for the Study of Coeliac Disease (ESsCD) guidelines in 2019, substantial advances have been made in understanding the management and complex disease courses of coeliac disease (CeD) in adults. These 2025 updated guidelines aim to integrate new evidence, refine management strategies, and promote a personalised and multidisciplinary approach to care. Methods The ESsCD convened a multidisciplinary panel of experts to revise the 2019 guidelines using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) framework. Evidence was appraised and graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Statements and recommendations were draughted within working groups and finalised through a structured Delphi consensus process. Results The updated guidelines are presented in two parts. Part 1, which has already been published, addresses the diagnostic approach to CeD in adults, whereas Part 2 focuses on disease management, structured follow‐up, and the evaluation and treatment of persistent symptoms despite a gluten‐free diet or refractory disease. New or expanded sections include guidance on the safe inclusion of oats, use of low‐FODMAP diets in patients with persistent symptoms, management of exocrine pancreatic insufficiency, recognition of functional asplenia and related vaccination recommendations, and stratified bone‐health screening. The guidelines also discuss nutritional and psychosocial support, digital models of care, and structured transition from paediatric to adult services. Updated therapeutic strategies for refractory CeD are provided, including immunosuppressive and novel pharmacologic options. Conclusions These updated guidelines offer a comprehensive, evidence‐based framework for the management and follow‐up of adults with CeD. By integrating recent scientific advances with pragmatic, patient‐centred recommendations, they seek to optimise clinical outcomes, quality of life, and long‐term health in individuals with CeD.

Tetramers of MHC-peptide complexes are used for detection and characterization of antigen-specific T cell responses, but they require knowledge about both antigenic peptide and the MHC restriction element. The successful application of these reagents in human diseases involving CD4⁺ T cells is limited. Celiac disease, an intestinal inflammation driven by mucosal CD4⁺ T cells recognizing wheat gluten peptides in the context of disease-associated HLA-DQ molecules, is an ideal model to test the potential clinical use of these reagents. We investigated whether gluten-specific T cells can be detected in the peripheral blood of celiac disease patients using DQ2 tetramers. Nine DQ2⁺ patients and six control individuals on a gluten-free diet were recruited to the study. Participants consumed 160 g of gluten-containing bread daily for 3 days. After bread-challenge, gluten-specific T cells were detectable in the peripheral blood of celiac patients but not controls both directly by tetramer staining and indirectly by enzyme-linked immunospot. These T cells expressed the β₇ integrin indicative of gut-homing properties. Most of the cells had a memory phenotype, but many other phenotypic markers showed a heterogeneous pattern. Tetramer staining of gluten-specific T cells has the potential to be used for diagnosis of celiac disease.

Celiac disease is an auto-immune disease in which an immune response to dietary gluten leads to inflammation and subsequent atrophy of small intestinal villi, causing severe bowel discomfort and malabsorption of nutrients. The major instigating factor for the immune response in celiac disease is the activation of gluten-specific CD4+ T cells expressing T cell receptors that recognize gluten peptides presented in the context of HLA-DQ2 and DQ8. Here we provide an in-depth characterization of 28 gluten-specific T cell clones. We assess their transcriptional and epigenetic response to T cell receptor stimulation and link this to genetic factors associated with celiac disease. Gluten-specific T cells have a distinct transcriptional profile that mostly resembles that of Th1 cells but also express cytokines characteristic of other types of T-helper cells. This transcriptional response appears not to be regulated by changes in chromatin state, but rather by early upregulation of transcription factors and non-coding RNAs that likely orchestrate the subsequent activation of genes that play a role in immune pathways. Finally, integration of chromatin and transcription factor binding profiles suggest that genes activated by T cell receptor stimulation of gluten‑specific T cells may be impacted by genetic variation at several genetic loci associated with celiac disease.

Celiac disease is associated with HLA-DQ2 and, to a lesser extent, HLA-DQ8. Type 1 diabetes is associated with the same DQ molecules in the opposite order and with possible involvement of trans-encoded DQ heterodimers. T cells that are reactive with gluten peptides deamidated by transglutaminase 2 and invariably restricted by DQ2 or DQ8 can be isolated from celiac lesions. We used intestinal T cells from celiac patients to map DQ2 and DQ8 epitopes within 2 representative gluten proteins, alpha-gliadin AJ133612 and gamma-gliadin M36999. For alpha-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of 2 separate regions. For gamma-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of the same region. Some gamma-gliadin peptides were recognized by T cells in the context of DQ2 or DQ8 when bound in exactly the same registers, but with different requirements for deamidation; deamidation at peptide position 4 (P4) was important for DQ2-restricted T cells, whereas deamidation at P1 and/or P9 was important for DQ8-restricted T cells. Peptides combining the DQ2 and DQ8 signatures could be presented by DQ2, DQ8, and trans-encoded DQ heterodimers. Our findings shed light on the basis for the HLA associations in celiac disease and type 1 diabetes.