Georgia Malamut

Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease.

Celiac disease (CD) is an enteropathy resulting from an abnormal immune response to gluten-derived peptides in genetically susceptible individuals. This immune response is initiated by intestinal transport of intact peptide 31-49 (p31-49) and 33-mer gliadin peptides through an unknown mechanism. We show that the transferrin receptor CD71 is responsible for apical to basal retrotranscytosis of gliadin peptides, a process during which p31-49 and 33-mer peptides are protected from degradation. In patients with active CD, CD71 is overexpressed in the intestinal epithelium and colocalizes with immunoglobulin (Ig) A. Intestinal transport of intact p31-49 and 33-mer peptides was blocked by polymeric and secretory IgA (SIgA) and by soluble CD71 receptors, pointing to a role of SIgA–gliadin complexes in this abnormal intestinal transport. This retrotranscytosis of SIgA–gliadin complexes may promote the entry of harmful gliadin peptides into the intestinal mucosa, thereby triggering an immune response and perpetuating intestinal inflammation. Our findings strongly implicate CD71 in the pathogenesis of CD.

Presentation and Long-Term Follow-up of Refractory Celiac Disease: Comparison of Type I With Type II

BACKGROUND & AIMS Refractory celiac disease (RCD) was recently subdivided into 2 subtypes (RCD I and II) based on a normal or abnormal phenotype of intraepithelial lymphocytes (IELs), respectively. It is not clear, however, if these 2 entities differ in their presentation at diagnosis or long-term outcome. We compared the clinical and biological characteristics of RCD I and RCD II at diagnosis, the risk of developing an overt lymphoma, and the predictive factors of survival. METHODS Medical files of 14 patients with RCD I and 43 with RCD II were analyzed retrospectively. Predictive factors of overt lymphoma and survival were studied in univariate and multivariate analyses. RESULTS At diagnosis, malnutrition, ulcerative jejunitis, and lymphocytic gastritis were more common in patients with RCD II than RCD I (P< .05). Overt lymphomas occurred in 2 patients with RCD I and 16 with RCD II. In the univariate analysis, abnormal IEL phenotype and increased age at diagnosis of RCD were predictive factors for overt lymphoma. Abnormal IEL phenotype (P< .01), clonality (P= .01), and overt lymphoma (P= .001) predicted short survival time. Only abnormal IEL phenotype (P= .03) and overt lymphoma (P= .04) were predictive in the multivariate analysis. The 5-year survival rate was 93% in patients with RCD I and 44% with RCD II. CONCLUSIONS RCD II has a much more severe presentation and prognosis than patients with RCD I; <44% of patients with RCD II survive 5 years after diagnosis. Abnormal IEL phenotype is a predictive factor but not a necessary condition for the development of overt lymphoma.

IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease–associated inflammation and lymphomagenesis

Enteropathy-associated T cell lymphoma is a severe complication of celiac disease (CD). One mechanism suggested to underlie its development is chronic exposure of intraepithelial lymphocytes (IELs) to potent antiapoptotic signals initiated by IL-15, a cytokine overexpressed in the enterocytes of individuals with CD. However, the signaling pathway by which IL-15 transmits these antiapoptotic signals has not been firmly established. Here we show that the survival signals delivered by IL-15 to freshly isolated human IELs and to human IEL cell lines derived from CD patients with type II refractory CD (RCDII) - a clinicopathological entity considered an intermediary step between CD and enteropathy-associated T cell lymphoma - depend on the antiapoptotic factors Bcl-2 and/or Bcl-xL. The signals also required IL-15Rbeta, Jak3, and STAT5, but were independent of PI3K, ERK, and STAT3. Consistent with these data, IELs from patients with active CD and RCDII contained increased amounts of Bcl-xL, phospho-Jak3, and phospho-STAT5. Furthermore, incubation of patient duodenal biopsies with a fully humanized human IL-15-specific Ab effectively blocked Jak3 and STAT5 phosphorylation. In addition, treatment with this Ab induced IEL apoptosis and wiped out the massive IEL accumulation in mice overexpressing human IL-15 in their gut epithelium. Together, our results delineate the IL-15-driven survival pathway in human IELs and demonstrate that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII.

The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease.

OBJECTIVES:The enteropathy associated with common variable immunodeficiency (CVID) is poorly characterized, and its possible relationships with well-defined causes of enteropathy, such as celiac sprue (CS), remain debated. We aimed to assess the clinical and histopathological features of the enteropathy associated with CVID.METHODS:The medical files of 50 CVID patients with gastrointestinal symptoms were analyzed retrospectively. Histological, phenotypic, and molecular analysis of intestinal endoscopic specimens was centrally performed.RESULTS:Chronic diarrhea was the most frequent gastrointestinal symptom (92%), and biological evidence of malabsorption was observed in 54% of patients. Chronic gastritis associated or not with pernicious anemia and microscopic colitis were the most frequently observed histopathological features in gastric and colonic mucosa, respectively. Small-bowel biopsies available in 41 patients showed moderate increase in intestinal intraepithelial lymphocytes in 31 patients (75.6%) and villous atrophy in 21 patients (51%). Distinctive features from CS were a profound depletion in plasma cells and follicular lymphoid hyperplasia. Presence of peripheral blood CD8+ hyperlymphocytosis was predictive of intestinal intraepithelial hyperlymphocytosis. Intravenous (i.v.) immunoglobulin (Ig) therapy had no effect on enteropathy-related symptoms. Gluten-free diet improved only two out of 12 patients with villous atrophy, whereas all patients (7/7) responded to steroid therapy.CONCLUSIONS:Several distinctive features differentiate CVID enteropathy from other causes of enteropathy including CS. Replacement i.v. Ig therapy is insufficient to improve gastrointestinal symptoms. Steroids are effective in reducing inflammation and restoring mucosal architecture.

Long‐term follow‐up of 61 coeliac patients diagnosed in childhood: evolution toward latency is possible on a normal diet

Background/Aims: Whether a life-long gluten-free diet (GFD) is necessary in all children with diagnosed coeliac disease (CD) remains debated. To address this question, a retrospective analysis of the clinical and biological status of adult coeliac patients diagnosed in childhood, who remained on a normal diet after gluten challenge and were clinically silent, was carried out. Methods: Patients aged 18–65 years with CD diagnosed in childhood were included. Clinical status, gluten intake, biological parameters of malabsorption, bone mineral density, human leucocyte antigen (HLA) genotype, serological markers of CD, and histological and immunohistochemical parameters in duodenal biopsies were recorded. Results: Sixty-one patients had resumed a normal diet and were asymptomatic. Forty-eight showed different degrees of villous atrophy (silent CD), while 13 had no detectable atrophy (latent CD) on duodenal biopsies. Latent CD patients had significantly less osteopenia/osteoporosis (1/9 (11%) vs 23/33 (70%), p<0.001)), and lower T cell receptor (TCR) αβ+ intraepithelial T cell counts (38±20 vs 55±15, p<0.01) than silent CD patients. The mean age at diagnosis and first GFD was lower in latent than in silent patients (14.4±5 vs 40.1±47 months, p<0.05). Latent patients did not differ significantly from the seven control patients on a long-term GFD, except for a higher frequency of CD-specific serum antibodies. However, two latent patients relapsed clinically and histologically during subsequent follow-up. Conclusions: Long-term latency developed in about 20% of CD patients who remained symptom free after gluten reintroduction. This latency can be transient and thus a regular follow-up is mandatory. In silent patients, the increased risk of osteoporosis substantiates the need for a GFD.

Olmesartan-associated enteropathy: results of a national survey

Recently, a new enteropathy has been described: olmesartan‐associated enteropathy. However, the association has been questioned: a phase 3 trial and a cohort study found no association between gastrointestinal events and olmesartan.

Long-Term Outcome of Patients Treated With Double Balloon Enteroscopy for Small Bowel Vascular Lesions

OBJECTIVES:Early rebleeding rate after endoscopic therapy with double balloon enteroscopy (DBE) of hemorrhagic small bowel vascular lesions (SBVL) varies between 10 and 50%. In recent reports, long-term follow-up of patients have been described but rebleeding risk factors are still not well established. The aim of the current study was to identify long-term treatment success rate and rebleeding risk factors after DBE therapy in a large cohort.METHODS:We conducted a single-center, retrospective cohort study in a large French tertiary-referral center between January 2004 and December 2007.RESULTS:Among 261 patients presenting with obscure gastrointestinal bleeding (OGIB), SBVL was present in 133 patients and was treated successfully in 129 (97%) using mainly argon plasma coagulation. Ninety-eight patients were followed up for a mean period of 22.6±13.9 months (range 1–52). Rebleeding rate was 46% (45/98 patients) at 36 months. On multivariate analysis, the total number of observed lesions (hazard ratio (HR): 1.15, 95% confidence interval (CI): 1.06–1.25, P=0.001) and the presence of a valvular and/or arrhythmic cardiac disease (HR: 2.50, 95% CI: 1.29–4.87, P=0.007) were significantly associated with the risk of rebleeding. Complication rate of therapeutic DBE was 2.3% with no mortality.CONCLUSIONS:Endoscopic therapy using DBE for SBVL in patients with recurrent OGIB allows a long-term remission in more than half of the patients. Independent rebleeding risk factors after a first endoscopic therapy are an increased number of SBVL and an associated valvular/arrhythmic heart disease.

Interactions among secretory immunoglobulin A, CD71, and transglutaminase-2 affect permeability of intestinal epithelial cells to gliadin peptides

BACKGROUND & AIMS The transferrin receptor (CD71) is up-regulated in duodenal biopsy samples from patients with active celiac disease and promotes retrotransport of secretory immunoglobulin A (SIgA)-gliadin complexes. We studied intestinal epithelial cell lines that overexpress CD71 to determine how interactions between SIgA and CD71 promote transepithelial transport of gliadin peptides. METHODS We analyzed duodenal biopsy specimens from 8 adults and 1 child with active celiac disease. Caco-2 and HT29-19A epithelial cell lines were transfected with fluorescence-labeled small interfering RNAs against CD71. Interactions among IgA, CD71, and transglutaminase 2 (Tgase2) were analyzed by flow cytometry, immunoprecipitation, and confocal microscopy. Transcytosis of SIgA-CD71 complexes and intestinal permeability to the gliadin 3H-p31-49 peptide were analyzed in polarized monolayers of Caco-2 cells. RESULTS Using fluorescence resonance energy transfer and in situ proximity ligation assays, we observed physical interactions between SIgA and CD71 or CD71 and Tgase2 at the apical surface of enterocytes in biopsy samples and monolayers of Caco-2 cells. CD71 and Tgase2 were co-precipitated with SIgA, bound to the surface of Caco-2 cells. SIgA-CD71 complexes were internalized and localized in early endosomes and recycling compartments but not in lysosomes. In the presence of celiac IgA or SIgA against p31-49, transport of intact 3H-p31-49 increased significantly across Caco-2 monolayers; this transport was inhibited by soluble CD71 or Tgase2 inhibitors. CONCLUSIONS Upon binding to apical CD71, SIgA (with or without gliadin peptides) enters a recycling pathway and avoids lysosomal degradation; this process allows apical-basal transcytosis of bound peptides. This mechanism is facilitated by Tgase2 and might be involved in the pathogenesis of celiac disease.

Diagnostic Yield of Capsule Endoscopy in Refractory Celiac Disease

OBJECTIVES:Capsule endoscopy (CE) allows for the assessment of the small bowel in numerous intestinal diseases, including celiac disease (CD). The main advantage of CE is the complete visualization of the intestinal mucosal surface. The objective of this study was to investigate whether CE can predict the severity of CD and detect complications.METHODS:We retrospectively studied the medical files of 9 patients with symptomatic CD, 11 patients with refractory celiac disease type I (RCDI) and 18 patients with refractory celiac disease type II (RCDII), and 45 patients without CD who were investigated both CE and upper endoscopy or enteroscopy. The type of CD was diagnosed on the basis of a centralized histological review, flow cytometry analysis of intraepithelial lymphocytes, and the analysis of T-cell receptor rearrangement by multiplex polymerase chain reaction.RESULTS:A total of 47 CEs (10, 11, and 26 CEs in the symptomatic CD, RCDI, and RCDII groups, respectively) from the 38 celiac patients and 47 CEs from the 45 nonceliac patients were retrospectively reviewed. Villous atrophy, numerous, or distally located ulcers were more frequent in celiac patients than in controls. Among celiac patients, CE was of acceptable quality in 96% of cases and was complete in 62% of cases. The concordance of CE with histology for villous atrophy was better than that of optic endoscopy (κ coefficient =0.45 vs. 0.24, P<0.001). Extensive mucosal damage on CE was associated with low serum albumin (P=0.003) and the RCDII form (P=0.02). Three cases of overt lymphoma were detected by CE during the follow-up.CONCLUSIONS:CE findings have a satisfactory concordance with histology and nutritional status in patients with symptomatic or refractory CD. Moreover, CE may predict the type of RCD and allows for the early detection of overt lymphoma.

Paracellular versus Transcellular Intestinal Permeability to Gliadin Peptides in Active Celiac Disease

The intestinal permeability of undegraded α9-gliadin peptide 31-49 (p31-49) and 33-mer gliadin peptides is increased in active celiac disease. Two distinct transport pathways have been proposed: paracellular leakage through epithelial tight junctions and protected transcellular transport. To analyze the relative contribution of these pathways, we compared mucosa-to-serosa permeability of small and large permeability markers [ionic conductance (G), mannitol, 182 Da; horseradish peroxidase, 40 kDa] and gliadin peptides [33-mer (p56-88, 3900 Da), 19-mer (p31-49, 2245 Da; and p202-220, 2127 Da), and 12-mer (p57-68, 1453 Da)] in duodenal biopsy specimens mounted in Ussing chambers. The permeability of intact peptides was much higher for p31-49 or 33-mer than for horseradish peroxidase, p202-220, and p57-68. A positive correlation was observed between G, an index of paracellular diffusion of ions, and mannitol permeability. The absence of correlation between G and permeability to intact 33-mer or p31-49 did not favor paracellular diffusion of the peptides. Immunofluorescence studies indicated that 33-mer enters the early endosome antigen 1-positive compartment but escapes the lysosomal-associated protein 2-positive compartment. The results underline that mannitol and ionic conductance G cannot be considered markers of permeability to gliadin peptides. In active celiac disease, increases in transcellular permeability to intact gliadin peptides might be considered in treatment strategies aimed at controlling epithelial permeability to gluten.