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Introduction Recent patient studies have shown that gluten-free diet is less effective in treating celiac disease than previously believed, and additionally patients remain vulnerable to gluten-induced acute symptoms and systemic cytokine release. Safe and effective pharmacological adjuncts to gluten-free diet are in preclinical and clinical development. Clear understanding of the pathogenesis of celiac disease is critical for drug target identification, establishing efficacy endpoints and to develop non-invasive biomarkers suitable to monitor and potentially diagnose celiac disease. Areas covered The role and clinical effects of CD4+ T cells directed against deamidated gluten in the context of an "adaptive immune paradigm" are reviewed. Alternative hypotheses of gluten toxicity are discussed and contrasted. In the context of recent patient studies, implications of the adaptive immune paradigm for future strategies to prevent, diagnose, and treat celiac disease are outlined. Expert opinion Effective therapeutics for celiac disease are likely to be approved and necessitate a variety of new clinical instruments and tests to stratify patient need, monitor remission, and confirm diagnosis in uncertain cases. Sensitive assessments of CD4+ T cells specific for deamidated gluten are likely to play a central role in clinical management, and to facilitate research and pharmaceutical development.

Released 4 years ago, the Wallace EcoMod application (R package wallace) provided an open-source and interactive platform for modeling species niches and distributions that served as a reproducible toolbox and educational resource. wallace harnesses R package tools documented in the literature and makes them available via a graphical user interface that runs analyses and returns code to document and reproduce them. Since its release, feedback from users and partners helped identify key areas for advancement, leading to the development of wallace 2. Following the vision of growth by community expansion, the core development team engaged with collaborators and undertook a major restructuring of the application to enable: simplified addition of custom modules to expand methodological options, analyses for multiple species in the same session, improved metadata features, new database connections, and saving/loading sessions. wallace 2 features nine new modules and added functionalities that facilitate data acquisition from climate-simulation, botanical and paleontological databases; custom data inputs; model metadata tracking; and citations for R packages used (to promote documentation and give credit to developers). Three of these modules compose a new component for environmental space analyses (e.g., niche overlap). This expansion was paired with outreach to the biogeography and biodiversity communities, including international presentations and workshops that take advantage of the software's extensive guidance text. Additionally, the advances extend accessibility with a cloud-computing implementation and include a suite of comprehensive unit tests. The features in wallace 2 greatly improve its expandability, breadth of analyses, and reproducibility options, including the use of emerging metadata standards. The new architecture serves as an example for other modular software, especially those developed using the rapidly proliferating R package shiny, by showcasing straightforward module ingestion and unit testing. Importantly, wallace 2 sets the stage for future expansions, including those enabling biodiversity estimation and threat assessments for conservation., Ecography, 2023 (3), ISSN:0906-7590, ISSN:1600-0587

Introduction Treated patients with celiac disease (CeD) and nonceliac gluten sensitivity (NCGS) report acute, transient, incompletely understood symptoms after suspected gluten exposure. To determine whether (i) blinded gluten exposure induces symptoms, (ii) subjects accurately identify gluten exposure, and (iii) serum interleukin-2 (IL-2) levels distinguish CeD from NCGS subjects after gluten exposure. Methods Sixty subjects (n = 20 treated, healed CeD; n = 20 treated NCGS; n = 20 controls) were block randomized to a single, double-blind sham (rice flour) or 3-g gluten challenge with 72-hours follow-up. Twelve serial questionnaires (100 mm visual analog scale; pain, bloating, nausea, and fatigue) and 10 serial plasma samples were collected. Mucosal permeability was assessed using both urinary lactulose-13C mannitol ratios and endoscopic mucosal impedance. Results Thirty-five of 40 (83%) subjects with CeD and NCGS reported symptoms with gluten (8 CeD, 9 NCGS) and sham (9 CeD, 9 NCGS) compared with 9 of 20 (45%) controls after gluten (n = 6) and sham (n = 3). There was no significant difference in symptoms among groups. Only 2 of 10 subjects with CeD and 4 of 10 NCGS identified gluten, whereas 8 of 10 subjects with CeD and 5 of 10 NCGS identified sham. A significant plasma IL-2 increase occurred only in subjects with CeD after gluten, peaking at 3 hours and normalizing within 24 hours postchallenge despite no significant intestinal permeability change from baseline. Discussion Symptoms do not reliably indicate gluten exposure in either subjects with CeD or NCGS. IL-2 production indicates a rapid-onset gluten-induced T-cell activation in CeD despite long-standing treatment. The effector site is unknown, given no increased intestinal permeability after gluten.

Progress has been made in understanding coeliac disease, a relatively frequent and underappreciated immune-mediated condition that occurs in genetically predisposed individuals. However, several gaps remain in knowledge related to diagnosis and management. The gluten-free diet, currently the only available management, is not curative or universally effective (some adherent patients have ongoing duodenal injury). Unprecedented numbers of emerging therapies, including some with novel tolerogenic mechanisms, are currently being investigated in clinical trials. In March 2020, the Celiac Disease Foundation and the Society for the Study of Celiac Disease convened a consensus workshop to identify high-yield areas of research that should be prioritized. Workshop participants included leading experts in clinical practice, academia, government and pharmaceutical development, as well as representatives from patient support groups in North America. This Roadmap summarizes key advances in the field of coeliac disease and provides information on important discussions from the consensus approach to address gaps and opportunities related to the pathogenesis, diagnosis and management of coeliac disease. The morbidity of coeliac disease is often underestimated, which has led to an unmet need to improve the management of these patients. Expanded research funding is needed as coeliac disease is a potentially curable disease., Coeliac disease is a serious condition and a model disease that can shed light into the mechanisms that underlie autoimmunity and chronic inflammation. This Roadmap summarizes key advances in coeliac disease and provides recommendations from a consensus workshop to address the gaps and opportunities in the pathogenesis, diagnosis and management of coeliac disease, providing a path forward., Key points Coeliac disease is a common and serious medical condition that is under-recognized among the health-care provider community, government and the public.This Roadmap summarizes consensus recommendations to address gaps and opportunities in pathogenesis, diagnosis and management of coeliac disease.Various animal models are available to translate hypotheses generated from human studies, and progress is being made in the development of physiological coeliac epithelial models based on organoid technology.Coeliac-specific serology is highly reliable for the diagnosis of coeliac disease; however, there is disagreement between experts as to the necessity of intestinal biopsy to confirm the diagnosis.There is increasing need for development of programmes for proper clinical management of coeliac disease, and the number of potential therapeutic targets and clinical trials has grown exponentially over the past 15 years.Increased funding for coeliac disease research is crucial to improve clinical management and facilitate development of therapies for this condition.

Wheat flour is one of the most important food ingredients containing several essential nutrients including proteins. Gluten is one of the major protein components of wheat consisted of glutenin (encoded on chromosome 1) and gliadin (encoded on chromosome 1 and 6) and there are around hundred genes encoding it in wheat. Gluten proteins have the ability of eliciting the pathogenic immune responses and hypersensitivity reactions in susceptible individuals called “gluten-related disorders (GRDs)”, which include celiac disease (CD), wheat allergy (WA), and non-celiac gluten sensitivity (NCGS). Currently removing gluten from the diet is the only effective treatment for mentioned GRDs and studies for the appropriate and alternative therapeutic approaches are ongoing. Accordingly, several genetic studies have focused on breeding wheat with low immunological properties through gene editing methods. The present review considers genetic characteristics of gluten protein components, focusing on their role in the incidence of gluten-related diseases, and genetic modifications conducted to produce wheat with less immunological properties.

Environmental variation within a species’ range can create contrasting selective pressures, leading to divergent selection and novel adaptations. The conservation value of populations inhabiting environmentally marginal areas remains in debate and is closely related to the adaptive potential in changing environments. Strong selection caused by stressful conditions may generate novel adaptations, conferring these populations distinct evolutionary potential and high conservation value under climate change. On the other hand, environmentally marginal populations may be genetically depauperate, with little potential for new adaptations to emerge. Here, we explored the use of ecological niche models (ENMs) linked with common garden experiments to predict and test for genetically determined phenotypic differentiation related to contrasting environmental conditions. To do so, we built an ENM for the alpine plant Silene ciliata in central Spain and conducted common garden experiments, assessing flowering phenology changes and differences in leaf cell resistance to extreme temperatures. The suitability patterns and response curves of the ENM led to the predictions that: (1) the environmentally marginal populations experiencing less snowpack and higher minimum temperatures would have delayed flowering to avoid risks of late-spring frosts and (2) those with higher minimum temperatures and greater potential evapotranspiration would show enhanced cell resistance to high temperatures to deal with physiological stress related to desiccation and heat. The common garden experiments revealed the expected genetically based phenotypic differentiation in flowering phenology. In contrast, they did not show the expected differentiation for cell resistance, but these latter experiments had high variance and hence lower statistical power. The results highlight ENMs as useful tools to identify contrasting putative selective pressures across species ranges. Linking ENMs with common garden experiments provides a theoretically justified and practical way to study adaptive processes, including insights regarding the conservation value of populations inhabiting environmentally marginal areas under ongoing climate change., This work was funded by the projects AdAptA (CGL2012-33528) and EVA (CGL2016-77377-R) of the Spanish Ministry of Science and Innovation. JML was supported by a predoctoral fellowship (BES-2013-064951) and by a short research stay fellowship at the City College of New York (EEBB-I-16-11347) from the Spanish Ministry of Science and Innovation. JML was also supported by the REMEDINAL TE-CM project postdoctoral fellowship (S2018/EMT-4338). CLR was supported by a Juan de la Cierva post-doctoral fellowship (MINECO: FJCI-2015-24712). JMK received support from the City College of New York, the Graduate Center of the City University of New York, a Japan Society for the Promotion of Science Postdoctoral Fellowship for Foreign Researchers, and the Okinawa Institute of Science and Technology Graduate University. The Consejo Superior de Investigaciones Científicas covered open access charges of the publication.

BACKGROUND: Diagnosing coeliac disease (CD) in patients on a gluten-free diet (GFD) is difficult. Ingesting gluten elevates circulating interleukin (IL)-2, IL-8 and IL-10 in CD patients on a GFD. OBJECTIVE: We tested whether cytokine release after gluten ingestion differentiates patients with CD from those with self-reported gluten sensitivity (SR-GS). METHODS: Australian patients with CD (n = 26) and SR-GS (n = 18) on a GFD consumed bread (estimated gluten 6 g). Serum at baseline and at 3 and 4 h was tested for IL-2, IL-8 and IL-10. Separately, Norwegian SR-GS patients (n = 49) had plasma cytokine assessment at baseline and at 2, 4 and 6 h after food bars containing gluten (5.7 g), fructan or placebo in a previous double-blind crossover study. RESULTS: Gluten significantly elevated serum IL-2, IL-8 and IL-10 at 3 and 4 h in patients with CD but not SR-GS. The highest median fold-change from baseline at 4 h was for IL-2 (8.06, IQR: 1.52–24.0; P