Stages Of Celiac Disease Research Articles

Small-intestinal TG2-specific plasma cells at different stages of coeliac disease

BackgroundIn coeliac disease, ingestion of gluten induces the production of transglutaminase 2 (TG2)-targeted autoantibodies by TG2-specific plasma cells present at high frequency in the small intestinal mucosa in untreated disease. During treatment with a gluten-free diet (GFD), the number of these cells decreases considerably. It has not been previously investigated whether the cells are also present prior to development of villous atrophy, or in non-responsive patients and those with dietary lapses. We aimed to define the frequency of small bowel mucosal TG2-specific plasma cells in coeliac disease patients with varying disease activity, and to investigate whether the frequency correlates with serum and small intestinal TG2-targeting antibodies as well as mucosal morphology and the number of intraepithelial lymphocytes.ResultsMucosal TG2-specific plasma cells were found in 79% of patients prior to development of mucosal damage, in all patients with villous atrophy, and in 63% of the patients after 1 year on GFD. In these disease stages, TG2-specific plasma cells accounted for median of 2.3, 4.3, and 0.7% of all mucosal plasma cells, respectively. After long-term treatment, the cells were present in 20% of the patients in clinical remission (median 0%) and in 60% of the patients with poor dietary adherence (median 5.8%). In patients with non-responsive coeliac disease despite strict GFD, the cells were found in only one (9%) subject; the cells accounted for 2.4% of all plasma cells. A positive correlation between the percentage of TG2-specific plasma cells and serum TG2 antibody levels (rS = 0.69, P < 0.001) and the intensity of mucosal TG2-targeting IgA deposits (rS = 0.43, P < 0.001) was observed.ConclusionsOur results show that TG2-specific plasma cells are already detectable prior to villous atrophy, and that generally their frequency increases during overt disease. By contrast, on GFD, the percentage of these cells decreases. Overall, the presence of TG2-specific plasma cells in the small bowel mucosa mirrors the presence of gluten in the diet, but the frequency is not always parallel to the level of serum or intestinal TG2 antibodies. These findings increase the knowledge about the development of the TG2 plasma cell responses especially in the early phases of coeliac disease.

Expression pattern of T-helper 17 cell signaling pathway and mucosal inflammation in celiac disease

Objective. The aim was to investigate the mucosal activation of a broad range of genes associated with the T-helper 17 cell (Th17) signaling pathway in children at different stages of celiac disease (CD), including children with increased risk for CD and children with untreated and gluten-free diet (GFD)-treated CD. Material and methods. Small intestinal biopsies were taken from children with untreated and GFD-treated CD, transglutaminase antibody (TGA)-positive children with potential CD, and reference children. Real-time polymerase chain reaction (PCR) arrays were used to study the gene expression pattern of Th17-related genes, and quantitative PCR was used to study the interleukin (IL)-17A expression. Results. The mucosal expression of CD8A was elevated at all stages of CD. Children with untreated CD had diminished levels of IL-17RE, IL-23R, RORc, STAT6, CCL22, NFATC2, IL-18, CD4, CD247, and matrix metalloproteinase (MMP)9 but had elevated levels of MMP3, IL-17, interferon-γ (IFN-γ) and CD8A, compared to references. The majority of the aforementioned genes, being differentially expressed in untreated CD, displayed similar expression in GFD-treated children and references. Children with untreated and GFD-treated CD had elevated expression of IFN-γ but had reduced expression of CD247. Interestingly, children with potential CD displayed reduced FOXP3, IL-21, and IL-17A levels. Conclusion. Mucosal upregulation of Th17 immunity occurs at the late stage of disease and is downregulated with dietary treatment, thus indicating that IL-17 immunity is not a fundamental feature of CD as Th1 immunity, which is not fully downregulated by GFD.

Cysteinyl leukotrienes are secretagogues in atrophic coeliac and in normal duodenal mucosa of children

ObjectiveThe pathophysiology of intestinal inflammation and diarrhoea is complex and involves the arachidonic acid cascade. Prostaglandins induce chloride secretion in healthy subjects and in patients with coeliac disease. Leukotrienes (LTs) are also known inflammatory mediators which have been shown to stimulate ion secretion in ileum and colon of rats and rabbits. The aim of this study was to determine the effects of leukotrienes C4 (LTC4) and D4 (LTD4) in normal and atrophic intestinal mucosa in children.Material and methodsRoutine paediatric intestinal biopsies were obtained from 109 children. Sixty-seven control biopsies and 42 biopsies from children with different stages of coeliac disease were mounted in a modified Ussing chamber. Potential difference (Pd) was measured continuously and tissue resistance (Rt) and the generated current (Im) were calculated.ResultsIn morphologically normal mucosa of duodenum, LTC4 and LTD4 increased Pd and Im in a dose-dependent manner. The increase was more pronounced in the distal than in the proximal part, similar to the response to prostaglandin E2. The induced current was chloride-mediated, since replacement of Cl− with SO42− in the bathing solution eliminated the response to the LTs. The LTC4-induced secretion was significantly decreased in atrophic mucosa, but the response was partially restored after preincubation with the cyclooxygenase inhibitor indomethacin.ConclusionsThe results showed that LTC4 and LTD4 are secretagogues in the duodenal mucosa from healthy children by inducing a net chloride secretion. Restoration of the response in coeliac disease by cyclooxygenase inhibition suggests interactions between the different pathways of the arachidonic cascade in the intestinal mucosa.

Scalloped duodenal folds in childhood celiac disease.

Unlike the adult form, childhood celiac disease has not hitherto been associated with a particular endoscopic pattern. The upper gastrointestinal tracts of 46 children with various stages of celiac disease and of 27 children with conditions other than celiac disease were examined by an endoscopist unaware of the clinical details of the patients. The scalloped configuration of duodenal folds was shown to have a sensitivity of 88% and a specificity of 87% in the diagnosis of subtotal villus atrophy. Attention to this finding, described here for the first time in childhood celiac disease, may be helpful for the diagnosis of this condition.

Differentiation of coeliac disease and other malabsorption diseases using specific serum antigliadin IgG subclass profiles and IgA1 levels.

The differential diagnostic potential of serum gliadin-specific IgG subclass antibodies was assessed by comparing the antigliadin IgG1, 2, 3, 4 profile at different stages of coeliac disease with that of gastro-intestinal infection and also conditions associated with increased intestinal permeability. The IgG subclass profile of untreated coeliac disease was found to be the same as in healthy controls (IgG1 approximately IgG2 > IgG3 > IgG4), with only the magnitude of the individual subclass responses being increased in coeliac patients. Coeliac adults and children on gluten-free diets had different antigliadin IgG subclass profiles with IgG2 being elevated. Increased intestinal permeability or recent gastro-intestinal infection did not alter the antigliadin subclass profile from that observed in healthy individuals. Assessment of the diagnostic potential of antigliadin IgA1 and IgG1-4 measurements in screening for coeliac disease demonstrated that measurement of subclasses of gliadin-specific IgA and IgG was less sensitive and specific compared with the combined use of total antigliadin IgA and IgG. Therefore it is suggested that IgG subclasses should not be used for routine screening for coeliac disease.

Subcellular Localization of Class I (A,B,C) and Class II (DR and DQ) MHC Antigens in Jejunal Epithelium of Children with Coeliac Disease

SummaryThin frozen sections of 11 jejunal biopsies from 10 children at different stages of coeliac disease were stained by immunofluorescence technique using a panel of anti‐HLA class I (A, B, C) and anti‐HLA class II (DR and DQ) monoclonal antibodies. On the epithelium of flattened mucosa, in contrast with control sections, the intensity of the labeling on the basolateral membranes with both anti‐class I and class II DR antibodies decreased strongly from the bottom to the upper part of the crypts, and no bright patchy staining was observed on the apical part of enterocytes with anti‐HLA DR antibodies. Numerous cells with large granules expressing class I and class II DR antigens were found in the epithelium of the small intestine. Children with a fully recovered mucosa expressed MHC antigens identical to those previously observed in normal epithelium. On the other hand, children with intermediate mucosal lesions showed the presence of MHC antigens in varying degrees. The results of this report indicate that immunological mechanisms may play a prominent role in coeliac disease.

Subcellular localization of class I (A,B,C) and class II (DR and DQ) MHC antigens in jejunal epithelium of children with coeliac disease.

Thin frozen sections of 11 jejunal biopsies from 10 children at different stages of coeliac disease were stained by immunofluorescence technique using a panel of anti-HLA class I (A, B, C) and anti-HLA class II (DR and DQ) monoclonal antibodies. On the epithelium of flattened mucosa, in contrast with control sections, the intensity of the labeling on the basolateral membranes with both anti-class I and class II DR antibodies decreased strongly from the bottom to the upper part of the crypts, and no bright patchy staining was observed on the apical part of enterocytes with anti-HLA DR antibodies. Numerous cells with large granules expressing class I and class II DR antigens were found in the epithelium of the small intestine. Children with a fully recovered mucosa expressed MHC antigens identical to those previously observed in normal epithelium. On the other hand, children with intermediate mucosal lesions showed the presence of MHC antigens in varying degrees. The results of this report indicate that immunological mechanisms may play a prominent role in coeliac disease.