Immune checkpoint inhibitor-associated celiac disease.

BACKGROUND: Rare cases of immune checkpoint inhibitor (ICI)-associated celiac disease (ICI-CeD) have been reported, suggesting that disruption of tolerance mechanisms by ICIs can unmask celiac disease (CeD). This study aims to characterize the clinicopathological and immunophenotypic features of ICI-CeD in comparison to ICI-associated duodenitis (ICI-Duo) and usual CeD. METHODS: A medical and pathological records search between 2015 and 2019 identified eight cases of ICI-CeD, confirmed by tTG-IgA. Nine cases of ICI-Duo, 28 cases of moderate CeD, as well as 5 normal controls were used as comparison groups. Clinical information was collected from the electronic medical records. Immunohistochemistry for CD3, CD8, T-cell receptor gamma/delta (γδ), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) were performed, with quantification of intraepithelial lymphocyte (IEL) subsets in three well-oriented villi. CD68, PD-L1, and PD-1 were assessed as a percentage of lamina propria surface area infiltrated by positive cells. Statistical significance was calculated by the Student's t-test and Fisher's exact test. RESULTS: The eight patients with ICI-CeD (F:M=1:3) and nine patients with ICI-Duo (F:M=5:4) presented similarly with diarrhea (13/17) and abdominal pain (11/17) after a median of 1.6 months on ICI therapy. In patients with ICI-CeD, tTG-IgA ranged from 104 to >300 IU/mL. Histological findings in ICI-CeD and ICI-Duo were similar and included expansion of the lamina propria, active neutrophilic duodenitis, variably increased IELs, and villous blunting. Immunohistochemistry showed that the average number of IELs per 100 enterocytes is comparable between ICI-CeD and ICI-Duo, with increased CD3+ CD8+ T cells compared with normal duodenum but decreased γδ T cells compared with CeD. Average PD-L1 percentage was 9% in ICI-CeD and 18% in ICI-Duo, in comparison to <1% in CeD and normal duodenum; average PD-1 percentage was very low to absent in all cases (<3%). On follow-up, five patients with ICI-CeD improved on a gluten-free diet (GFD) as the sole therapeutic intervention (with down-trending tTG-IgA) while the other three required immunosuppression. All patients who developed ICI-Duo received immunosuppression with variable improvement in symptoms. CONCLUSIONS: ICI-CeD resembles ICI-Duo clinically and histologically but shares the serological features and response to gluten withdrawal with classic CeD. Immunophenotyping of IELs in ICI-CeD and ICI-Duo also shows similar CD3, CD8, γδ T cell subsets, and PD-L1 populations, all of which differed quantitatively from usual CeD. We conclude that ICI-CeD is biologically similar to ICI-Duo and is likely a variant of ICI-Duo, but treatment strategies differ, with ICI-CeD often improving with GFD alone, whereas ICI-Duo requires systemic immunosuppression.

Upper gastrointestinal tract involvement of pediatric inflammatory bowel disease: A pathological review.

Upper gastrointestinal (UGI) tract involvement of inflammatory bowel disease (IBD) is commonly seen in pediatric patients. Upper endoscopy is included in the routine workup of children with suspected IBD to enhance the diagnosis and management of these patients. Currently, childhood IBD is classified into ulcerative colitis (UC), atypical UC, Crohn's disease (CD) and IBD unclassified. Histologic confirmation of UGI tract involvement, in particular the presence of epithelioid (non-caseating) granulomas, is helpful in confirming the diagnosis of IBD and its classification. Herein, we reviewed selected IBD-associated UGI tract manifestations in children. Lymphocytic esophagitis, seen predominantly in CD, is histologically characterized by increased intraepithelial lymphocytes (> 20 in one high-power field) in a background of mucosal injury with absence of granulocytes. Focally enhanced gastritis is a form of gastric inflammation in pediatric IBD marked by a focal lymphohistiocytic pit inflammation with or without granulocytes and plasma cells in a relatively normal background gastric mucosa. Duodenal inflammation seen in children with IBD includes cryptitis, villous flattening, increased intraepithelial lymphocytes, and lamina propria eosinophilia. Finally, epithelioid granulomas not associated with ruptured gland/crypt are a diagnostic feature of CD. The clinicopathologic correlation and differential diagnosis of each microscopic finding are discussed. Clinicians and pathologists should be cognizant of the utility and limitations of these histologic features.

Gastroduodenal Disorders in Patients with CVID Undergoing Immunoglobulin Therapy.

BACKGROUND: Common variable immunodeficiency (CVID) encompasses a heterogeneous group of primary antibody deficiency disorders characterized by recurrent infections, autoimmunity and malignancies. Gastrointestinal manifestations are frequently associated with CVID. OBJECTIVE: In this cross-sectional study, we evaluated gastric and duodenal involvement in a cohort of adult patients with CVID. METHODS: Upper gastrointestinal endoscopy was performed in 58 patients (26 males, mean age 47.8±15.6 years), diagnosed with CVID according to 2014 ESID criteria. Random biopsies were collected from gastric antrum and descending duodenum for the all enrolled subjects. Intraepithelial lymphocytosis in descending duodenum was defined as the presence of 25 lymphocytes per 100 enterocytes. RESULTS: The major histopathological findings that we found were: a) chronic active gastritis (44.8%), Helicobacter pylori-associated (8.6%), b) chronic duodenitis (39.6%) with intraepithelial lymphocytosis (31%) and absence of plasma cells (18.9%) and c) autoimmune atrophic gastritis (5.2%). Three patients (5.2%) presented Intestinal Metaplasia (IM) of the gastric antrum. This finding was associated with H. pylori infection and persisted after the eradication in one patient. IM was associated with autoimmune atrophic gastritis in two cases. Giardia lamblia infection was observed in the duodenum samples from three patients (5.2%). A diagnosis of Gastric adenocarcinoma was made in a 58-year- old woman diagnosed with gastric dysplasia one year earlier. CONCLUSION: In our cohort of CVID patients, gastro-duodenal histopathological findings, including malignancies, are frequent and can affect long-term prognosis. A rigorous endoscopic follow-up is needed in CVID patients irrespective of the gastrointestinal symptoms.

CVID enteropathy is characterized by exceeding low mucosal IgA levels and interferon-driven inflammation possibly related to the presence of a pathobiont.

Common variable immunodeficiency (CVID), the most common symptomatic primary antibody deficiency, is accompanied in some patients by a duodenal inflammation and malabsorption syndrome known as CVID enteropathy (E-CVID).The goal of this study was to investigate the immunological abnormalities in CVID patients that lead to enteropathy as well as the contribution of intestinal microbiota to this process.We found that, in contrast to noE-CVID patients (without enteropathy), E-CVID patients have exceedingly low levels of IgA in duodenal tissues. In addition, using transkingdom network analysis of the duodenal microbiome, we identified Acinetobacter baumannii as a candidate pathobiont in E-CVID. Finally, we found that E-CVID patients exhibit a pronounced activation of immune genes and down-regulation of epithelial lipid metabolism genes. We conclude that in the virtual absence of mucosal IgA, pathobionts such as A. baumannii, may induce inflammation that re-directs intestinal molecular pathways from lipid metabolism to immune processes responsible for enteropathy.

A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity.

BACKGROUND: Alpha-synuclein (αS) is a nerve cell protein associated with Parkinson disease (PD). Accumulation of αS within the enteric nervous system (ENS) and its traffic from the gut to the brain are implicated in the pathogenesis and progression of PD. αS has no known function in humans and the reason for its accumulation within the ENS is unknown. Several recent studies conducted in rodents have linked αS to immune cell activation in the central nervous system. We hypothesized that αS in the ENS might play a role in the innate immune defenses of the human gastrointestinal (GI) tract. METHODS: We immunostained endoscopic biopsies for αS from children with documented gastric and duodenal inflammation and intestinal allograft recipients who contracted norovirus. To determine whether αS exhibited immune-modulatory activity, we examined whether human αS induced leukocyte migration and dendritic cell maturation. FINDINGS: We showed that the expression of αS in the enteric neurites of the upper GI tract of pediatric patients positively correlated with the degree of acute and chronic inflammation in the intestinal wall. In intestinal allograft subjects who were closely monitored for infection, expression of αS was induced during norovirus infection. We also demonstrated that both monomeric and oligomeric αS have potent chemoattractant activity, causing the migration of neutrophils and monocytes dependent on the presence of the integrin subunit, CD11b, and that both forms of αS stimulate dendritic cell maturation. INTERPRETATION: These findings strongly suggest that αS is expressed within the human ENS to direct intestinal inflammation and implicates common GI infections in the pathogenesis of PD.

Fulminant phlegmonitis of the esophagus, stomach, and duodenum due to Bacillus thuringiensis.

We report a case of phlegmonitis of the esophagus, stomach, and duodenum in patient in an immunocompromised state. Culture of gastric juice and blood yielded Bacillus thuringiensis. This case showed that even low-virulence bacilli can cause lethal gastrointestinal phlegmonous gastritis in conditions of immunodeficiency.

Catastrophic gastrointestinal complication of systemic immunosuppression.

We present a case of acute upper gastrointestinal haemorrhage in a patient with systemic vasculitis immunosuppressed on cyclophosphamide and prednisolone. The patient presented with a diffuse haemorrhagic oesophagitis and a non-specific duodenitis. Biopsies taken from the oesophagus and duodenum demonstrated infection with herpes simplex virus (HSV) and cytomegalovirus (CMV) respectively. Viral infection of the upper gastrointestinal tract is a recognised complication of immunosuppression and HSV is one of the most common pathogens. CMV on the other hand most commonly causes a colitis or less commonly oesophagitis. CMV enteritis is rare as is the synchronous infection with two viral agents in an immunocompromised patient having being described in a few case series only. Viral infection of the gastrointestinal tract in immunocompromised patients should be treated with systemic anti-viral medication and consideration to withdrawal of the immunosuppressive therapy if possible and appropriate. The authors highlight the need for a high suspicion of viral infection in immunosuppressed patients presenting with upper gastrointestinal bleeding.

[The clinical significance of evaluation of the inflammatory infiltrate in chronic gastroduodenitis in children].

OBJECTIVE: To establish the diagnostic value of the determination of leukocyte composition of inflammatory infiltrate in chronic gastroduodenite in childhood. PATIENTS AND METHODS: We examined 103 patients aged 8-17 with chronic gastroduodenitis associated with Helicobacter pylori. To detect Hp and Epstein-Barr viral infections we used esophagogastroduodenoscopy, quick urease test, bacterioscopy of gastrobiopsies. We performed the analysis of the cellular composition of the inflammatory infiltrate. RESULTS: It was found that the number of lymphocytes and neutrophils located in the lamina and intraepithelial increases, which is associated with the degree of inflammation. Increased to the maximum was the number of intraepithelial lymphocytes, both in the body, and in the antrum. Intensity of leukocyte infiltration is directly correlated with the increased prevalence of inflammation. Persistence of Epstein-Barr virus (35.9% of patients) is followed by more severe intraepithelial lymphocytic infiltration in the stomach. In 4-6 months after treatment 18 patients with severe gastritis were repeatedly studied for the inflammatory infiltrate. A significant decrease in the number of intraepithelial neutrophils was found. CONCLUSION: Cellular composition of the infiltrate is an objective characteristic of chronic inflammation in the gastric mucosa. Persistence of Epstein-Barr virus is accompanied by an increase in the amount of intraepithelial lymphocytes and neutrophils.

Russell body gastritis/duodenitis: a case series and description of immunoglobulin light chain restriction.

Russell body esophago-gastro-duodenitis is an unusual form of chronic inflammation, with only 22 cases being reported in PubMed. However, the prevalence and clinical significance remain unknown. This report describes the clinico-pathological characteristics of nine cases of Russell body gastritis (RBG) and one case of Russell body duodentitis (RBD), with nonspecific endoscopic appearance. The Mott cells (plasma cells with Russell bodies) showed κ light chain restriction in eight gastritis cases and λ light chain restriction in the duodentitis case, and there were no histological features that suggested lymphoma. Thus, a diagnosis of monoclonal RBG/RBD was made. Helicobacter pylori infection was found in 55.6% of RBG cases and in the RBD case. And, the clinical follow-up evaluations were uneventful. This report is the first study to describe this benign disease entity with monoclonality on a large-scale basis. In addition, the monoclonality of Mott cells cannot be used as evidence of an existing neoplastic lesion, and taken together, these findings may indicate a reactive process.

[Non-celiac gluten sensitivity: a critical review of current evidence]. / Sensibilidad al gluten no celiaca: una revisión crítica de la evidencia actual.

Non-celiac gluten sensitivity (NCGS) is an emerging disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food in non-celiac patients. Its prevalence has been estimated to be six to ten-times higher than that of celiac disease (CD). A gluten-free diet is the most widely recommended therapy, but the causative agent remains unknown and there are no consensus diagnostic criteria. Recent studies on NCGS have included patients with possibly overlooked minor CD and diarrhea-predominant irritable bowel syndrome without self-reported gluten intolerance, but showing a response to a gluten-free diet. Furthermore, FODMAPs (Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols) have recently been postulated as the culprit component for NCGS in wheat, instead of gluten. This review updates evidence on the pathophysiology of NCGS and the efficacy of different dietary interventions in its treatment, stressing the need for proper screening for CD before a diagnosis of NCGS is made.

Testing safety of germinated rye sourdough in a celiac disease model based on the adoptive transfer of prolamin-primed memory T cells into lymphopenic mice.

UNLABELLED: The current treatment for celiac disease is strict gluten-free diet. Technical processing may render gluten-containing foods safe for consumption by celiac patients, but so far in vivo safety testing can only be performed on patients. We modified a celiac disease mouse model to test antigenicity and inflammatory effects of germinated rye sourdough, a food product characterized by extensive prolamin hydrolysis. Lymphopenic Rag1-/- or nude mice were injected with splenic CD4+CD62L-CD44high-memory T cells from gliadin- or secalin-immunized wild-type donor mice. We found that: 1) Rag1-/- recipients challenged with wheat or rye gluten lost more body weight and developed more severe histological duodenitis than mice on gluten-free diet. This correlated with increased secretion of IFNγ, IL-2, and IL-17 by secalin-restimulated splenocytes. 2) In vitro gluten testing using competitive R5 ELISA demonstrated extensive degradation of the gluten R5 epitope in germinated rye sourdough. 3) However, in nude recipients challenged with germinated rye sourdough (vs. native rye sourdough), serum anti-secalin IgG/CD4+ T helper 1-associated IgG2c titers were only reduced, but not eliminated. In addition, there were no reductions in body weight loss, histological duodenitis, or T cell cytokine secretion in Rag1-/- recipients challenged accordingly. IN CONCLUSION: 1) prolamin-primed CD4+CD62L-CD44high-memory T cells induce gluten-sensitive enteropathy in Rag1-/- mice. 2) Hydrolysis of secalins in germinated rye sourdough remains incomplete. Secalin peptides retain B and T cell stimulatory capacity and remain harmful to the intestinal mucosa in this celiac disease model. 3) Current antibody-based prolamin detection methods may fail to detect antigenic gluten fragments in processed cereal food products.

[Cycloferon therapy of chronic gastroduodenitis in children].

The efficiency of immunomodulating therapy with cycloferon in children aged from 10 to 16 years with verified chronic gastroduodenitis was estimated. It was shown that the cycloferon treatment provided reliable increase of T- and B-cellular populations in mucous membranes of the stomach and duodenum, normalization of the number of CD8-lymphocytes, higher titers of IgG antibodies to herpes viruses 1 and 2. It also promoted reduction of inflammation in the mucous membranes along with reduction of the disease clinical signs.

[Mucosal immune response to Helicobacter pylori in children with gastroduodenal diseases and allergy].

In children with chronic gastritis/gastroduodenitis, erosions and ulcer of stomach and duodenum and associated allergic diseases (asthma, allergic rhinitis, atopic dermatitis) CagA, sIgA and IgE antibodies to the H. pylori were determined by ELISA in the supernatants of feces. H. pylori infection was determined according to "Maastricht IV". The frequency and contents of CagA did not differ among the groups we studied. However, in children with positive urease test the contents of CagA was significantly higher (p = 0.03) compared with other children. The highest levels of sIgA were found in the feces supernatants from non-allergic children with CG/CGD and were associated with H. pylori infection. The immune response in children with erosions and ulcer of stomach and duodenum and in children with allergy was presented the sIgE to H. pylori. Also, the negative correlation between the level sIgE to H. pylori and content sIgA was found in children with allergy. Thus, increased IgE indicates not only allergy, but also acts as a protective role in the development of anti-infective immunity.

[Lymphocytic duodenosis: etiological study and clinical presentations]. / Duodenosis linfocítica: estudio etiológico y formas de presentación clínica.

INTRODUCTION: Lymphocytic duodenosis (LD) is a characteristic lesion in the initial phases of celiac disease (CD) but can be associated with many other entities. The aim of this study was to evaluate the prevalence of distinct causes of LD and possible differences in clinical presentation according to etiology. METHODS: A retrospective study was performed that included 194 patients diagnosed with LD (more than 25 intraepithelial lymphocytes per 100 epithelial cells). A preestablished strategy to evaluate the cause of the disease was followed that included celiac serology (antitransglutaminase antibodies), HLA-DQ2/DQ8 genotypes, diagnosis of Helicobacter pylori and small intestinal bacterial overgrowth (SIBO). Diagnosis of CD was established on the basis of clinical and histological response to a gluten-free diet in patients with positive serology or compatible findings on HLA-DQ2 (at least one of the alleles) or -DQ8 (both alleles) study. RESULTS: The most frequent cause of LD was CD (39%), followed by SBBO (22%), H.pylori (14%), CD and SIBO (12%), and other causes (13%). Most of the patients (83%) had a compatible HLA-DQ2 or -DQ8 genotype. In these patients, the most frequent diagnosis was CD (46%), while in the absence of HLA-DQ2/DQ8, the most frequent diagnoses were SIBO (44%) and H. pylori (22%). CD was the most frequent diagnosis in patients referred for dyspepsia, diarrhea and anemia, while H. pylori was the most frequent diagnosis in patients with abdominal pain. CONCLUSIONS: The most common causes of LD in our environment are CD, followed by SIBO and H. pylori infection.

[Evaluation of the effectiveness of immunomodulating therapy in children with chronic gastroduodenitis].

The article assesses the effectiveness of administering immunomodulating drug cycloferon in patients aged 10 to 16 years with chronic gastroduodenitis. It is established that the use of cycloferon in children with virus-associated chronic gastroduodenitis leads to a significant increase in T- and B-lymphocyte populations in mucous membranes of the stomach and duodenum, and contributes to the elimination of viruses. This results in reduced severity and activity of inflammation in the mucous membranes and decreases clinical manifestations of the disease.

[Subpopulations and phagocytic activity of monocytes in chronic gastroduodenitis in children].

There was conducted a study of the phagocytic activity, immunophenotype and peripheral blood monocytes by flow cytometry in children with chronic gastroduodenitis associated with Helicobacter pylori, as well as the association of Helicobacter pylori with fungi of the genus Candida and markers of secondary immune deficiency. The differential changes in the structure of circulating profile of monocytes were revealed, that indicate the pathogenetic significance of these disorders in chronic gastroduodenitis with H. pylori etiology, as well as at association of Helicobacter pylori with fungi of the genus Candida. Violations of the phagocytic activity of monocytes in chronic gastroduodenitis in children are associated with depression of different stages of phagocytosis--capture functions, mobilization, killing, intracellular biocidity. A severe depression in phagocytic activity of monocytes occurs in CGD associated with Hp and fungi of the genus Candida.

Effects of acute and chronic inflammation on proteins involved in duodenal iron absorption in mice: a time-course study.

In order to understand better the molecular mechanisms involved in the pathogenesis of anaemia of inflammation, we carried out a time-course study on the effects of turpentine-induced acute and chronic inflammation on duodenal proteins involved in Fe absorption in mice. Expression levels of these proteins and hepatic hepcidin and serum Fe levels were determined in inflamed mice. In acutely inflamed mice, significantly increased expression of ferritin was the earliest change observed, followed by decreased divalent metal transporter 1 expression in the duodenum and increased hepcidin expression in the liver. Ferroportin expression increased subsequently, despite high levels of hepcidin. Hypoferraemia, which developed at early time periods studied, was followed by increased serum Fe levels at later points. The present results thus show that acute inflammation induced several changes in the expression of proteins involved in duodenal Fe absorption, contributing to the development of hypoferraemia. Resolution of inflammation caused attenuation of many of these effects. Effects in chronically inflamed mice were less consistent. The present results also suggest that inflammation-induced increases in ferritin appeared to override the effects of hepcidin on the expression levels of ferroportin in enterocytes.

[Features of homeostasis in children from industrially developed areas].

The goal of the investigation was to detect and assess the specific features of abnormal biochemical and immunological parameters in children living in the industrially developed areas in order to solve the tasks of early diagnosis and to enhance the efficiency of prevention of the chronic pattern of gastroduodenal diseases. It was found that children with increased contamination of biological media had more active inflammatory reactions with a trend towards the chronic pattern of an inflammatory process, altered antioxidant defense and a more common chronic inflammatory process in the biliary tract, and more significant cytolysis syndrome with gallbladder concentration dysfunction.

[Parodontal and immune status in children with oesophagogastroduodenal pathology].

Findings of examination state of parodontal and local immunity of children with chronic gastroduodenitis and oesephagitis were presented in the article.