Aberrant Intraepithelial Lymphocytes Research Articles

M1190 Natural History of Eosinophilic Gastroenteritis

Background: Collagenous sprue (CS) is a very rare cause of severe malabsorption with an enteropathy that is characterized by villous atrophy and a distinctive band of subepithelial collagen deposition. A poor outcome has been reported historically. Aim: To describe the clinical characteristics, treatment, and prognosis in a contemporary cohort of patients with CS. Methods: We included cases with biopsy-proven CS evaluated at the Mayo Clinic Results: 15 patients (80% females) with a median age of 67 years (range, 53-83) were included. The clinical manifestations were diarrhea (100%), loss of weight (93%), and abdominal pain (14%). Hospitalizationwas required because severe diarrhea in 9 (64%) patients. Hypoalbuminemia and anemia were evident in 9 (64%) and 7 (50%) patients, respectively. Humanleukocyte antigen genes DQ2 or DQ8 were present in 12 (80%) patients (DQ2+ single dose [n=8], DQ2+ double dose [n=3], and DQ2+/DQ8+ [n=1]). Celiac antibodies were present in only 1 patient. A prior diagnosis of celiac disease was evident in 7 (47%) patients. Histologically, all cases had both the abnormal collagen deposition and some degree of villous atrophy. Aberrant (clonal) intraepithelial lymphocytes were detected in 1 (of 12) patients tested by both immunostaining and T-cell clonality analysis. Associated disorders were collagenous gastritis (n=4), collagenous colitis (n=4), small-intestine bacterial overgrowth (n=4), lymphocytic colitis (n=2), lymphocytic gastritis (n=1), autoimmune hepatitis (n=1), and hyposplenism (n=1). All patients received treatment with a combination of a strict gluten-free diet and steroids such as budesonide 9mg/day (n=12), prednisone 30-40 mg/day (n=2) and dexamethasone 8 mg/day (n=1). Parenteral nutrition was necessary in 11 (79%) patients. One patient developed enteropathy-type T-cell lymphoma during followup and received a combination of nitrogen mustard and methylprednisolone. Clinical followup after treatment was available in 12 (92%) patients (median time = 16 months; range, 172), disappearance of diarrhea was observed in 11 with complete histologic remission documented in one case. Three patients died during follow-up because of emaciation, enteropathy-type T-cell lymphoma, and aspiration pneumonia, respectively. Conclusions: We report the largest case series of CS. Treatment with a combination of gluten-free diet and steroids (especially budesonide) was useful to control symptoms in most patients; however, length of follow-up was limited so far to a few months in the majority of our patients. CS was associated with collagen deposition in other organs, autoimmune conditions, and lymphoma.

Defective synthesis or association of T-cell receptor chains underlies loss of surface T-cell receptor–CD3 expression in enteropathy-associated T-cell lymphoma

AbstractEnteropathy-associated T-cell lymphoma, an often fatal complication of celiac disease, can result from expansion of aberrant intraepithelial lymphocytes in refractory celiac disease type II (RCD II). Aberrant intraepithelial lymphocytes and lymphoma cells are intracellularly CD3ϵ+ but lack expression of the T-cell receptor (TCR)–CD3 complex on the cell surface. It is unknown what causes the loss of TCR-CD3 expression. We report the isolation of a cell line from an RCD II patient with the characteristic phenotype of enteropathy-associated T-cell lymphoma. We demonstrate that in this cell line the TCR-α and -β chains as well as the CD3γ, CD3δ, CD3ϵ, and ζ-chains are present intracellularly and that assembly of the CD3γϵ, CD3δϵ, and ζζ-dimers is normal. However, dimerization of the TCR chains and proper assembly of the TCR-CD3 complex are defective. On introduction of exogenous TCR-β chains, but not of TCR-α chains, assembly and functional cell surface expression of the TCR-CD3 complex were restored. Defective synthesis of both TCR chains was found to underlie loss of TCR expression in similar cell lines isolated from 2 additional patients. (Pre)malignant transformation in RCD II thus correlates with defective synthesis or defective association of the TCR chains, resulting in loss of surface TCR-CD3 expression.

The Presence of Small Intestinal Intraepithelial Gamma/Delta T-Lymphocytes Is Inversely Correlated With Lymphoma Development in Refractory Celiac Disease

In refractory celiac disease (RCD) type II, a phenotypically aberrant (CD7+ CD3- CD4/8-cytoplasmicCD3+) intraepithelial lymphocyte (IEL) population is present, and 50-60% of these patients develop enteropathy-associated T-cell lymphoma (EATL). TCRgammadelta+ IELs play an important role in mucosal repair, homeostasis, and tumor surveillance. Recently, human small intestinal TCRgammadelta+ IELs were shown to have regulatory potential in uncomplicated celiac disease (CD). In the present study, we investigated whether TCRgammadelta+ IELs are decreased in RCD II, providing a possible explanation for persisting mucosal damage and inflammation, and the emergence of aberrant T cells with clonal expansion to EATL. Multiparameter flow cytometric immunophenotyping was performed on IELs isolated from fresh small bowel biopsy specimens of relatively large distinct CD patient and control groups (N = 87). A significantly lower percentage of TCRgammadelta+ IELs was found in RCD II as compared to all other CD groups. In contrast, in uncomplicated CD patients significantly more TCRgammadelta+ IELs were found than in controls. Overall, there is a clear negative relation between TCRgammadelta+ IELs and aberrant IELs. Interestingly, TCRgammadelta+ IELs increase again in RCD II after effective therapy. The observed negative relation between TCRgammadelta+ and aberrant IELs, along with their known regulatory capacity in uncomplicated CD, implies that TCRgammadelta+ IELs may play a crucial role in mucosal repair, regaining homeostasis and possibly even tumor surveillance. These cells may be important markers, in addition to the aberrant T cells, to differentiate between disease categories and to evaluate the effectiveness of therapeutic strategies.

Investigation of molecular markers in the diagnosis of refractory coeliac disease in a large patient cohort

Aims:Some patients with coeliac disease, despite strict adherence to a gluten-free diet, continue to have significant symptoms and/or a severe small intestinal histological lesion. The term “refractory coeliac disease” (rCD)...

Novel approaches in the management of refractory celiac disease

Celiac disease is a gluten-sensitive enteropathy, which commits the patient to a life-long gluten-free diet. This is sufficient to treat the overwhelming majority of patients. However, a small group of these patients, mainly those diagnosed above 50 years of age, fails to improve histologically and clinically upon elimination of gluten from the diet. These patients are regarded as suffering from refractory celiac disease. In a subgroup of these patients a pre-malignant intraepithelial lymphocyte population can be detected in the small intestinal mucosa (type II). These patients are at a high risk of developing an enteropathy-associated T-cell lymphoma (50–60% within 4–6 years), which has a very poor prognosis and a 5-year survival of only 8%. The therapeutic challenge in these refractory celiac disease type II patients is targeting the aberrant intraepithelial lymphocytes to eventually prevent enteropathy-associated T-cell lymphoma development. Although management of these patients is difficult and therapeutic options are currently limited, novel treatment modalities are being explored.

Flow cytometric determination of aberrant intra-epithelial lymphocytes predicts T-cell lymphoma development more accurately than T-cell clonality analysis in Refractory Celiac Disease

Background: Refractory celiac disease (RCD) patients with aberrant, often clonal, intraepithelial T-cells are at high risk for development of enteropathy associated T-cell lymphoma (EATL). Early detection of those patients that actually develop EATL is of utmost importance for curative intervention. Aim: First, to establish an optimal cut-off value for the percentage of aberrant lymphocytes, previously determined based on clinical observations, via reference ranges for aberrant T-cells in the duodenal mucosa of celiac disease patient and control groups. Secondly, to compare aberrancy with intestinal T-cell clonality as a prognostic parameter for EATL development in RCD. Methods: Immunophenotyping using flow cytometry was performed on small intestinal biopsy-derived lymphocytes, obtained from distinct celiac disease (CD) patient and control groups ( N = 167 in total). T-cell clonality in duodenal biopsy specimens was assessed by PCR in RCD, ulcerative jejunitis and EATL patients ( N = 31 in total). Results: In 95% of non-refractory CD patients, the highest percentage aberrant T-cells was 20%. Using this cut-off value, EATL development was exclusively seen in RCD with more than 20% aberrant T-cells (median 52% aberrant T-cells, range 27–94%). When compared with T-cell clonality analysis, > 20% aberrancy showed a much higher negative predictive value and sensitivity (both 100%) for EATL development in RCD patients than T-cell clonality analysis (respectively 75% and 78%). Conclusions: Quantification of aberrant T-cells by flow cytometry is preferable to T-cell clonality analysis for identification of RCD patients at risk for EATL development. A cut-off value of 20% is of use in risk stratification, therapeutic options and subsequent follow-up of RCD patients.

Decreased circulating iNKT cell numbers in refractory coeliac disease

Introduction: A small proportion of coeliac disease (CD) patients become refractory (RCD) to a gluten-free diet (GFD) showing uncontrolled immune-mediated enteropathy. Some of these patients exhibit a high risk to develop enteropathy-associated T-cell lymphoma (EATL). Aim: The aim of the study was to find whether a lack of circulating homeostatic T cells, such as Treg, Tγδ + or iNKT cells would be associated with the development of RCD or EATL. Patients and methods: We investigated in a total of 137 CD patients [28 untreated, 80 responsive to GFD and 29 RCD (14 type I and 15 type II)] and 73 age-matched healthy volunteers the frequency of Treg, Tγδ + and iNKT lymphocytes by flow cytometric analysis of peripheral blood. Results: Circulating Tγδ + cell and Treg frequencies in RCD were comparable to those in healthy controls. However, RCD patients had significantly reduced numbers of circulating iNKT cells, as compared to age-matched patients responding to a GFD. This reduction was similar in RCD patients with and without aberrant intraepithelial lymphocytes and in patients with EATL. Circulating iNKT cell numbers were not reduced in untreated coeliac patients. GFD treated patients had a significantly increased proportion of CD4 + iNKT cells. Conclusion: Follow-up studies are necessary to determine whether CD4 + iNKT cells control the immune response against gluten and their absence contributes to the progression to RCD and EATL.