Subclass Profile of IgG Antibody Response to Gluten Differentiates Nonceliac Gluten Sensitivity From Celiac Disease.
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ABSTRACT:
SUBMITTER: Uhde M
PROVIDER: S-EPMC7680445 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
Publications
Subclass Profile of IgG Antibody Response to Gluten Differentiates Nonceliac Gluten Sensitivity From Celiac Disease.
Uhde Melanie M Caio Giacomo G De Giorgio Roberto R Green Peter H PH Volta Umberto U Alaedini Armin A
Gastroenterology 20200721 5
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Project description:Background: There is evidence that digestive motor disorders are frequently present in untreated celiac disease (CD) patients. Similarly, non-celiac gluten sensitivity (NCGS) can be associated with gut motor disorders. In both cases, gut dysmotility can improve or be completely reversed with a gluten-free diet (GFD). Methods: A literature search for motility disorders in CD and NCGS patients was carried out using the online databases PubMed, Medline and Cochrane. Results: Esophageal, gastric, small bowel and gallbladder motor disorders are common in both children and adults with CD. Although the clinical consequences of these disorders are not clearly defined, gastric dysfunction could affect drug absorption and metabolism in the thyroid and neurological conditions associated with CD. The impact of a GFD on motility disorders is, however, controversial. No systematic studies are available on NCGS. NCGS frequently overlaps with irritable bowel syndrome (IBS) and similar pathophysiological mechanisms may be hypothesized. Conclusions: Mucosal damage may affect gut motility in untreated CD through perturbation of hormonal and neuro-immunomodulatory regulation. A persistent low-grade mucosal inflammation could explain the cases of persistent motor disorders despite a GFD. Further studies are needed to definitely assess the role of gut motor disorders in NCGS.
| S-EPMC6266734 | biostudies-other
Project description:IntroductionCeliac disease (CD) may be associated with gut microbial dysbiosis. Whether discrete gluten exposure in subjects with well-controlled disease on a gluten-free diet impacts the gut microbiome is unknown and may have implications for understanding disease activity and symptoms. We conducted a prospective study to evaluate the impact of gluten exposure on the gut microbiome in patients with CD and nonceliac gluten sensitivity (NCGS).MethodsSubjects with CD (n = 9) and NCGS (n = 8) previously on a gluten-free diet were administered a 14-day gluten challenge (5 g of gluten per day) and compared with controls (n = 8) on a usual gluten-containing diet. Stool was collected for fecal microbiome analysis using 16S rRNA gene and metagenomic sequencing before, during, and after the gluten challenge. Symptoms were assessed using 2 validated clinical scales.ResultsAmong subjects with CD and NCGS, there were no significant fecal microbial changes in response to gluten challenge. Gut microbiome composition differed among controls, subjects with CD, and subjects with NCGS at baseline, and these differences persisted despite gluten exposure. Gastrointestinal and general health symptoms reported by subjects with CD and NCGS were worst in the middle of gluten challenge and lessened by its end, with no consistent associations with gut microbiome composition.DiscussionPre-existing fecal microbiome diversity was unaffected by gluten challenge in adult subjects with CD and NCGS. These findings suggest that current microbiome status is unrelated to current disease activity and disease severity.
| S-EPMC8691493 | biostudies-literature
Project description:The role of B cells and posttranslational modifications in pathogenesis of organ-specific immune diseases is increasingly envisioned but remains poorly understood, particularly in human disorders. In celiac disease, transglutaminase 2-modified (TG2-modified; deamidated) gluten peptides drive disease-specific T cell and B cell responses, and antibodies to deamidated gluten peptides are excellent diagnostic markers. Here, we substantiate by high-throughput sequencing of IGHV genes that antibodies to a disease-specific, deamidated, and immunodominant B cell epitope of gluten (PLQPEQPFP) have biased and stereotyped usage of IGHV3-23 and IGHV3-15 gene segments with modest somatic mutations. X-ray crystal structures of 2 prototype IGHV3-15/IGKV4-1 and IGHV3-23/IGLV4-69 antibodies reveal peptide interaction mainly via germline-encoded residues. In-depth mutational analysis showed restricted selection and substitution patterns at positions involved in antigen binding. While the IGHV3-15/IGKV4-1 antibody interacts with Glu5 and Gln6, the IGHV3-23/IGLV4-69 antibody interacts with Gln3, Pro4, Pro7, and Phe8 - residues involved in substrate recognition by TG2. Hence, both antibodies, despite different interaction with the epitope, recognize signatures of TG2 processing that facilitates B cell presentation of deamidated gluten peptides to T cells, thereby providing a molecular framework for the generation of these clinically important antibodies. The study provides essential insight into the pathogenic mechanism of celiac disease.
| S-EPMC5621872 | biostudies-literature
Project description:Currently, 1% of the United States population holds a diagnosis for celiac disease (CD), however, a more recently recognized and possibly related condition, "non-celiac gluten sensitivity" (NCGS) has been suggested to affect up to 6% of the United States public. While reliable clinical tests for CD exist, diagnosing individuals affected by NCGS is still complicated by the lack of reliable biomarkers and reliance upon a broad set of intestinal and extra intestinal symptoms possibly provoked by gluten. NCGS has been proposed to exhibit an innate immune response activated by gluten and several other wheat proteins. At present, an enormous food industry has developed to supply gluten-free products (GFP) with GFP sales in 2014 approaching $1 billion, with estimations projecting sales to reach $2 billion in the year 2020. The enormous demand for GFP also reflects a popular misconception among consumers that gluten avoidance is part of a healthy lifestyle choice. Features of NCGS and other gluten related disorders (e.g., irritable bowel syndrome) call for a review of current distinctive diagnostic criteria that distinguish each, and identification of biomarkers selective or specific for NCGS. The aim of this paper is to review our current understanding of NCGS, highlighting the remaining challenges and questions which may improve its diagnosis and treatment.
| S-EPMC5677194 | biostudies-other
Project description:Gluten-related disorders (GRDs) are common chronic enteropathies and increasing evidence suggests an involvement of the gut microbiota. We examined the gut microbiota in Mexican people afflicted with GRDs. Ultra-high-throughput 16S marker sequencing was used to deeply describe the duodenal and fecal microbiota of patients with celiac disease (CD, n = 6), non-celiac gluten sensitivity (NCGS, n = 12), and healthy subjects (n = 12) from our local area. Additionally, we also investigated the changes in gut microbiota after four weeks on a gluten-free diet (GFD) in a subset of patients from whom paired samples were available. Despite a high inter-individual variability, significant differences in various microbial populations were identified. The linear discriminant analysis (LDA) effect size (LEfSe) method revealed that the genus Actinobacillus and the family Ruminococcaceae were higher in the duodenal and fecal microbiota of NCGS patients, respectively, while Novispirillum was higher in the duodenum of CD patients (p < 0.05, LDA score > 3.5). Interestingly, paired samples from NCGS patients showed a significant difference in duodenal Pseudomonas between the baseline period (median: 1.3%; min/max: 0.47⁻6.8%) and the period after four weeks on GFD (14.8%; 2.3⁻38.5%, p < 0.01, Wilcoxon signed-rank test). These results encourage more research on GRDs in México.
| S-EPMC6266755 | biostudies-literature
Project description:The aims of this observational "proof-of-concept" study were to analyze the clinical/psychological characteristics and gut microbiota/mycobiota composition of individuals with suspected non-celiac gluten/wheat sensitivity (NCGS/WS) according to responses to the double-blind-placebo-controlled (DBPC) crossover gluten challenge test. Fifty individuals with suspected NCGS/WS were subjected to the DBPC challenge test; anthropometric measurements, psychometric questionnaires, and fecal samples were collected. Twenty-seven (54%) participants were gluten responsive (NCGS), and 23 were placebo responsive, with an order effect. NCGS individuals displayed a significantly lower risk of eating disorders and a higher mental health score when compared to placebo-responsive participants, confirmed by multiple logistic regression analyses (OR = 0.87; 95% CI 0.76-0.98, p = 0.021, and OR = 1.30; 95% CI 1.06-1.59, p = 0.009, respectively). Principal coordinate analyses based on microbiota composition showed a separation by the DBPC response (p = 0.039). For Bacteroides (p = 0.05) and Parabacteroides (p = 0.007), the frequency of amplicon sequence variants was lower, and that for Blautia (p = 0.009) and Streptococcus (p = 0.004) was higher in NCGS individuals at multiple regression analyses. No difference in the mycobiota composition was detected between the groups. In conclusion, almost half of the individuals with suspected gluten sensitivity reported symptoms with placebo; they showed lower mental health scores, increased risk for eating disorders, and a different gut microbiota composition.
| S-EPMC8070191 | biostudies-literature
Project description:IgG-based monoclonal antibody therapeutics, which are mainly IgG1, IgG2, and IgG4 subclasses or related variants, have dominated the biotherapeutics field for decades. Multiple laboratories have reported that the IgG subclasses possess different molecular characteristics that can affect their developability. For example, IgG1, the most popular IgG subclass for therapeutics, is known to have a characteristic degradation pathway related to its hinge fragility. However, there remains a paucity of studies that systematically evaluate the IgG subclasses on manufacturability and long-term stability. We thus conducted a systematic study of 12 mAbs derived from three sets of unrelated variable regions, each cloned into IgG1, an IgG1 variant with diminished effector functions, IgG2, and a stabilized IgG4 variant with further reduced FcγR interaction, to evaluate the impact of IgG subclass on manufacturability and high concentration stability in a common formulation buffer matrix. Our evaluation included Chinese hamster ovary cell productivity, host cell protein removal efficiency, N-linked glycan structure at the conserved N297 Fc position, solution appearance at high concentration, and aggregate growth, fragmentation, charge variant profile change, and post-translational modification upon thermal stress conditions or long-term storage at refrigerated temperature. Our results elucidated molecular attributes that are common to all IgG subclasses, as well as those that are unique to certain Fc domains, providing new insight into the effects of IgG subclass on antibody manufacturability and stability. These learnings can be used to enable a balanced decision on IgG subclass selection for therapeutic antibodies and aid in acceleration of their product development process.
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Project description:PurposeSpecific antibody deficiency (SAD) involves a deficient response to a polysaccharide vaccine despite having normal immunoglobulin levels. The failure of the polysaccharide response can be observed as a component of various primary antibody deficiencies. However, only a few studies have described the clinical and immunological profiles in SAD and/or other primary immunodeficiencies (PIDs) in adults.MethodsA total of 47 patients who had a clinical history suggestive of antibody deficiency or had already been diagnosed with various antibody deficiencies were enrolled. Polysaccharide responses to 7 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) were measured using the World Health Organization enzyme-linked immunosorbent assay (WHO-ELISA), and postvaccination immunoglobulin G (IgG) titers were compared to clinical and laboratory parameters.ResultsBased on the American Academy of Allergy, Asthma, and Immunology (AAAAI) criteria for the WHO-ELISA, 11 (23.4%) patients were diagnosed as having SAD. Sixteen-three percent of them had combined with other types of PID, such as IgG subclass deficiency and hypogammaglobulinemia. Postvaccination IgG titers for the serotypes 4/9V/18C correlated with IgG2 (P = 0.012, P = 0.001, and P = 0.004) and for 6B/9V/14 with IgG3 (P = 0.003, P = 0.041, and P = 0.036, respectively). The IgG3 subclass levels negatively correlated with forced expiratory volume in 1 second (FEV1, %) and FEV1/forced vital capacity (P < 0.001 and P = 0.001, respectively).ConclusionSAD can be diagnosed in patients with normal IgG levels as well as in those deficient in IgG or the IgG3 subclass, implicating that restricted responses to Streptococcus pneumoniae polysaccharide antigens commonly exist in patients with predominantly antibody deficiency.
| S-EPMC7840874 | biostudies-literature
Project description:Celiac disease (CD) is an autoimmune enteropathy that occurs in genetically susceptible individuals carrying the prerequisite genetic markers HLA DQ2 or DQ8. These genetic markers are present in approximately 30% of the population, and the worldwide prevalence of CD is estimated to be approximately 1%-2%. Currently a gluten-free diet is the only treatment for CD, but novel therapies aimed at gluten modification are underway. This review will discuss gluten-based therapies including wheat alternatives and wheat selection, enzymatic alteration of wheat, oral enzyme supplements, and polymeric binders as exciting new therapies for treatment of CD.
| S-EPMC3788609 | biostudies-other
Project description: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.
| S-EPMC7400306 | biostudies-literature