Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease

BACKGROUND & AIMS: The mechanism of intraepithelial lymphocyte hyperplasia, a hallmark of celiac disease, is unknown. We have investigated the role of epithelium-derived interleukin (IL)-15 in the alterations of epithelial homeostasis in refractory celiac sprue, a privileged situation to study the first step of lymphoid transformation and the contribution of intraepithelial lymphocytes to villous atrophy in celiac disease. METHODS: IL-15 expression was assessed in biopsy specimens and isolated enterocytes by combining immunohistochemistry, flow cytometry, and real-time quantitative polymerase chain reaction. The ability of IL-15 to induce growth and survival of clonal intraepithelial lymphocytes lacking surface CD3 and to induce their cytotoxicity and secretion of interferon gamma was tested using soluble IL-15 and coculture in the presence of epithelial cell lines expressing membrane IL-15. RESULTS: IL-15 was massively overexpressed not only in lamina propria but also in the intestinal epithelium of patients with active celiac disease and refractory celiac sprue. IL-15 was not secreted but delivered at the surface of enterocytes. IL-15 specifically induced the expansion and survival of the clonal abnormal intraepithelial lymphocytes that characterize refractory celiac sprue and triggered their secretion of interferon gamma and their cytotoxicity against intestinal epithelial cells. Comparable activating signals could be delivered by IL-15 expressed at the membrane of the T84 enterocyte cell line. CONCLUSIONS: These data provide strong evidence that uncontrolled overexpression of IL-15 in refractory celiac sprue perpetuates epithelial damage and promotes the emergence of T-cell clonal proliferations. Blocking IL-15 might prove useful to treat this severe complication of celiac disease.     

Refractory sprue syndrome with clonal intraepithelial lymphocytes evolving into overt enteropathy-type intestinal T-cell lymphoma

INTRODUCTION: Recently, patients with refractory sprue have been shown to contain a clonal proliferation of phenotypically abnormal intraepithelial lymphocytes in their intestine. Whether this signifies early enteropathy-type intestinal T-cell lymphoma (EITCL) or a reactive condition is not clear. We report on a patient presenting with the findings of refractory sprue who subsequently developed overt EITCL. MATERIAL AND METHODS: Duodenal biopsies from 1997 (refractory sprue) and duodenal and jejunal biopsies from 1998 (intestinal T-cell lymphoma) were compared by immunohistochemistry and PCR for the detection of T-cell receptor (TCR)-gamma gene rearrangements. Clonal PCR products were sequenced. RESULTS: The duodenal biopsies from both 1997 and 1998 and the jejunal tumor biopsy showed villus atrophy and an increase of intraepithelial lymphocytes with an abnormal immunophenotype (CD3+, CD4-, CD8- and TCR-beta-). In all duodenal specimens including the one from 1997, and the jenunal tumor biopsy, an identical clonal amplificate was detected by enzymatic amplification of the TCR-gamma gene. CONCLUSION: These data suggest that refractory sprue containing a clonal proliferation of phenotypically abnormal intraepithelial lymphocytes may represent an early manifestation of EITCL. The detection of immunohistochemical negativity for several antigens normally found on intraepithelial lymphocytes such as CD8 or the TCR-beta chain in combination with clonal T-cell populations by PCR may be helpful in identifying refractory sprue with a malignant transformation.     

Refractory coeliac sprue is a diffuse gastrointestinal disease

BACKGROUND: Refractory coeliac sprue (RCS) with an immunophenotypically aberrant clonal intraepithelial lymphocyte (IEL) population is considered a cryptic form of intestinal T cell lymphoma. AIMS: To investigate the distribution of the abnormal and monoclonal IEL population in the digestive tract of RCS patients. PATIENTS AND METHODS: We compared the frequency of lymphocytic gastritis (LG) and lymphocytic colitis (LC), together with IEL phenotype and T cell clonality, in gastric and colonic samples from 15 adults with RCS (all with aberrant CD3 intracytoplasmic(+) surface(-) CD8(-) clonal IELs on duodenojejunal biopsies), 18 patients with active coeliac disease (ACD), and 10 patients with coeliac disease (CD) on a gluten free diet (GFD-CD) by means of immunohistochemistry and multiplex polymerase chain reaction amplification of the T cell receptor gamma gene (TCR-gamma) rearrangement. Blood samples of nine RCS patients were also tested for clonality. RESULTS: LG was found in 9/14 (64%), 11/18 (61%), and 3/10 (30%) patients with RCS, ACD, and GFD-CD, respectively, while LC was found in 6/11 (55%), 3/4 (75%), and 2/3 (66%) patients. Contrary to CD, all samples from patients with LG and LC showed an aberrant IEL phenotype. Monoclonal TCR-gamma rearrangements were detected in 8/13 (62%), 8/10 (80%), and 4/9 (44%) of gastric, colonic, and blood samples, respectively, from RCS patients, while in CD patients such rearrangements were only found in 2/25 (8%) gastric samples. CONCLUSION: The immunophenotypically aberrant monoclonal IEL population present in the small intestine of patients with RCS frequently disseminates to the blood and the entire gastrointestinal epithelium, suggesting that this is a diffuse gastrointestinal disease.     

Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue

BACKGROUND: Clonal T cell receptor (TCR) gene rearrangements and loss of T cell antigens such as CD8 and TCR-beta in intraepithelial lymphocytes (IELs) may indicate the development of an enteropathy-type intestinal T cell lymphoma (EITCL) in patients with refractory sprue. AIMS: To define the diagnostic value of these markers in duodenal biopsies from patients with villous atrophy as a result of various underlying disorders. PATIENTS AND METHODS: Duodenal biopsies from eight patients with coeliac disease and five patients with villous atrophy caused by defined disorders were compared with three patients with refractory sprue evolving into overt EITCL, two patients with ulcerative jejunitis, and with eight patients with overt EITCL, for expression of CD3, CD4, CD8, and TCR-beta in IELs using immunohistochemistry and for clonal TCR-gamma gene rearrangements using polymerase chain reaction. In addition, biopsies from six consecutive patients with refractory sprue of uncertain cause were examined. RESULTS: Clonal TCR-gamma gene rearrangements were found in all resected tumours of patients with EITCL, in 3/8 duodenal biopsies of patients with EITCL, in 2/2 patients with ulcerative jejunitis, in 2/3 patients with refractory sprue evolving into overt EITCL, and in 1/6 patients with refractory sprue. No rearrangements were found in biopsies from patients with refractory sprue caused by defined disorders or those with coeliac disease. Clonality in duodenal biopsies was associated with an abnormal phenotype of IELs in all cases and in all but one case in patients with evidence of underlying coeliac disease. Specificity for detection of an EITCL using immunohistology was 77% for CD8 and for TCR-beta staining, and 100% for detection of a clonal TCR-gamma gene rearrangement. Sensitivity was 62% for staining with CD8 and clonality investigation, while sensitivity reached 100% for TCR-beta staining in all investigated patients with EITCL. CONCLUSIONS: Clonal proliferations of phenotypically abnormal IELs in refractory sprue represent an early manifestation of EITCL, for which the term "sprue-like intestinal T cell lymphoma" is proposed. This constellation is also found in duodenal biopsies from patients with an overt EITCL and is not related to other sprue syndromes, resulting in a high specificity for detection of an EITCL or refractory sprue evolving into EITCL. Overt EITCL may develop directly from coeliac disease without a precursor lesion (refractory sprue with clonal IELs) being demonstrable in duodenal biopsies or via a "sprue-like intestinal T cell lymphoma". This latter entity is a complication of coeliac disease.     

Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease

BACKGROUND AND AIMS: Epithelium derived interleukin (IL)-15 signalling via IL-15Ralpha is critical for the development, activation, and survival of intraepithelial lymphocytes (IEL). We aimed to better understand the IL-15 driven effects on IEL underlying mucosal damage and lymphomagenesis in coeliac disease (CD). METHODS: Enterocytes, IEL, and lamina propria mononuclear cells (LPMC) were isolated from 46 patients with uncomplicated CD (25 untreated and 21 treated) and 22 controls. IL-15 and IL-15Ralpha expression were determined by immunoblotting. Secretion of IL-15, interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), and granzyme B into cell culture supernatants was assessed by ELISA. The ability of IL-15 to regulate IEL proliferation, perforin/granzyme dependent cytotoxicity, and apoptosis was tested by adding different combinations of IL-15, IL-15 blocking antibody, or chloroquine to IEL cultured alone or with Caco-2 cells as target. IL-15 mucosal levels were also determined by ELISA in five patients with complicated CD (two ulcerative jejunoileites, one refractory sprue, and two enteropathy associated T cell lymphomas) tested for T cell receptor gamma chain clonality. RESULTS: IL-15 was overexpressed in untreated CD enterocytes and LPMC, and in the mucosa of complicated CD patients and uncomplicated untreated CD patients, where its levels correlated with the degree of mucosal damage. Enterocytes from untreated, but not treated, CD patients and controls secreted IL-15. Untreated CD IEL, characterised by higher IL-15Ralpha expression, showed increased proliferation, production of IFN-gamma and TNF-alpha, and perforin/granzyme dependent cytotoxicity, and a decreased propensity to apoptosis in response to IL-15. CONCLUSIONS: Our findings suggest that IL-15 plays a crucial role in the generation of epithelial damage in active CD. Its promotion of IEL survival in CD may predispose to the emergence of T cell clonal proliferations. Blocking IL-15, by suppressing uncontrolled IEL activation and survival, has the potential to provide new therapeutic tools to prevent tissue damage and lymphomagenesis in CD.     

Refractory sprue

Celiac disease is a T cell-mediated disorder that results from intolerance to gluten. The major cause of failure to respond to a gluten-free diet is continuing gluten ingestion. In poorly responsive patients diagnosis of refractory sprue can be established after exclusion of a limited number of conditions. Refractory sprue may occur after an initial response to the diet or without evidence of preexisting celiac disease. The detection of aberrant, clonally expanded, intraepithelial lymphocytes has led to better definition and classification of patients with refractory sprue. Only a few series of patients with well-characterized refractory sprue have been reported in the literature. The prognosis is poor, though some patients respond to corticosteroids and immunosuppressive agents. The presence of an aberrant clonal intraepithelial T-cell population has led to the designation of refractory sprue as a cryptic intestinal T-cell lymphoma.     

An early expansion of CD8alphabeta T cells, but depletion of resident CD8alphaalpha T cells, occurs in the intestinal epithelium during primary simian immunodeficiency virus infection

OBJECTIVES: To evaluate changes in the phenotypic heterogeneity and function of CD8 T cells in the intestinal epithelium during primary SIV infection. DESIGN: Previous studies have shown an increased prevalence of CD8 T cells in the intestinal epithelium in HIV and SIV infections. As intestinal CD8 T cells are a heterogeneous population we evaluated their phenotypic distribution (CD8alphabeta, CD8alphaalpha) and function [interferon (IFN)-gamma production] during primary SIV infection. METHODS: The phenotype and functional potential of CD8 intestinal intraepithelial lymphocytes (IEL) prior to and following SIV infection were determined using flow cytometry. RESULTS: IEL were found to harbor CD8alphabetaCD3, CD8alphaalphaCD3 and CD8alphaalpha+CD3- T-cell subsets. Most of the CD8CD4 double positive IEL expressed CD8alphaalpha homodimers. In primary SIV infection the frequency of CD8alphabetaCD3 T cells increased dramatically whereas the frequency of CD8alphaalpha T cells declined. A higher frequency of CD8alphabetaKi-67 IEL was observed following SIV infection suggesting that local cell proliferation might have contributed to an increased prevalence of CD8alphabeta IEL. In contrast, a severe depletion of CD8alphaalphaCD4 IEL occurred which contributed to the depletion of CD8alphaalpha IEL. The CD8alphabeta IEL were the major producers of IFN-gamma in the intestinal epithelium and the frequency of IFN-gamma-producing CD8alphabeta IEL was enhanced considerably in primary infection. CONCLUSIONS: CD8alphabeta IEL may be important in generating early antiviral responses at the intestinal epithelium. However, alterations in CD8 T-cell subsets and their function may reflect early immunopathogenic events in the intestinal mucosa.     

Age-Related Variation of Intraepithelial Lymphocytes Subsets in Normal Human Duodenal Mucosa

The enumeration of intestinal intraepithelial lymphocytes (IELs), and the phenotyping of CD3⁺CD103⁺ (TcRαβ, TcRγδ) and CD3⁻CD103⁺ IEL subsets constitute useful diagnostic tools for the correct interpretation of the mucosal histology of duodenal/jejunal biopsies in many pathological conditions of the small intestine, particularly celiac disease (CD). This work evaluates the ranges of duodenal IEL counts by flow cytometry in healthy mucosa from pediatric and adult controls, establishing normal reference values for CD3⁺ TcRγδ and CD3⁻ subsets and their variation with age. Seventy-four pediatric controls and 36 adult controls were identified on the basis of their normal histology from more than 1,000 duodenal diagnostic biopsies performed in Caucasian subjects. Total IEL counts and IEL subsets (“IEL lymphogram”) were analyzed by four-color flow cytometry (FCM). IEL represent 7.7%±0.4 (mean±SE) and 8.5%±0.5 of the cells isolated from the epithelium in the pediatric and adult series, respectively. The upper normal range, considered as the 97 percentile, is 14% in pediatrics and 15% in adults. No significant difference was observed between TcRγδIEL percentages in children (6.9%±0.5 of the total IELs) and adults (6.6%±0.8). However, the density of CD3⁻ IELs is significantly higher (p < 0.001) in the mucosa from controls under 3 years (50.2%±2.6) than in adults (25.5%±2.1). IEL lymphogram by flow cytometry is an easy, quick and reliable analysis performed in one of the biopsy specimens obtained during a diagnostic endoscopy, and confers specificity to the histopathological findings. IEL counts below 14% in children and 15% in adults should be considered within a normal range in the evaluation of duodenal mucosa by FCM. No differences with age were observed with respect to TcRγδIEL, while the CD3⁻ IEL fraction was significantly higher on children under 3 years, with a trend to increase again in the elderly.     

Gluten-free diet induces regression of T-Cell activation in the rectal mucosa of patients with celiac disease

Objective: An increase in the number of intraepithelial lymphocytes (IEL) in the rectal epithelium of patients with active celiac disease has been described. No data are available about how they vary during a gluten-free diet. The aim of the study was to assess the effect of a gluten-free diet on T-cell activation in the rectal mucosa of adult patients with celiac disease.
Methods: Frozen duodenal and rectal biopsies were available in four celiac patients (one male, three female, mean age 39 yr) both before and after 7 to 24 months on a gluten-free diet. Biopsy samples were stained using monoclonal antibodies directed against CD3, βF1, TcRδ1, CD25, and HLADR. Numbers of IEL were estimated by counting the peroxidase-stained cells per 100 epithelial cells. Four patients without histological abnormalities were used as control subjects.
Results: In the four patients with active celiac disease but in none of the controls, CD25 was expressed by both duodenal and rectal lamina propria cells and HLADR was expressed by duodenal (4/4) and rectal (2/4) epithelial cells. In addition, two patients with active celiac disease had features of lymphocytic colitis, i.e. , >20 IEL per 100 epithelial cells. After a gluten-free diet, the mean number of rectal CD3⁺βF1⁺ IEL decreased (9% vs 21%) and the expression of CD25 and HLADR was no longer present. These changes mirrored those found in the small intestinal biopsies.
Conclusion: These results suggest that in celiac disease, gluten-driven T-cell activation is not restricted to the proximal part of the intestine but is present on the whole intestinal length. Assessment of the effectiveness of a gluten-free diet through rectal biopsies warrants investigation, as it could lessen discomfort for patients and prove more cost-effective.     

T-large granular lymphocyte leukemia: current molecular concepts

T-large granular lymphocyte (T-LGL) leukemia is a chronic and often indolent T cell lymphoproliferation characterized by extreme expansion of a semi-autonomous cytotoxic T lymphocyte (CTL) clone. Clinically, T-LGL can be associated with various cytopenias; neutropenia constitutes the most frequent manifestation. LGL clone represents a pathologic counterpart of the cytotoxic effector T cell but an abnormal memory CD8 cell seems to provide the supply of the matured LGL population. Analysis of clonal T cell receptor (TCR) rearrangement and complementarity determining region 3 (CDR3) of the TCR beta-chain is a useful tool to investigate clonal expansions, track the frequency of expanded clones and also clinically useful to monitor the response to therapy. The lessons learned from molecular analysis of clonal repertoire support a clinically-derived conclusion that the LGL clone arises in the context of an initially polyclonal immune response or an autoimmune process. Consequently, specific manifestations of T-LGL may be a result of the recognition spectrum of the transformed clone and the cytokines it produces. Due to the often monoclonal manifestation, T-LGL constitutes a suitable model to investigate polyclonal CTL-mediated processes. Application of new technologies, including TCR repertoire analysis by sequencing, clonotypic quantitative PCR and VB flow cytometry facilitate clinical diagnosis and may allow insights into the regulation of TCR repertoire and consequences resulting from the contraction of clonal diversity.     

Aryl Hydrocarbon Receptor Activation Down-Regulates IL-7 and Reduces Inflammation in a Mouse Model of DSS-Induced Colitis

Background and Aims

The pathogenesis of inflammatory bowel disease (IBD) is associated with dysregulation of intestinal immune system. Aryl hydrocarbon receptor (AHR) is believed to control the chronic inflammation in the gut. Besides, interleukin-7 (IL-7) is proved to be an important cytokine that activates mucosal inflammation in IBD. Moreover, intraepithelial lymphocytes (IELs) are one of the key immunological compartments involved in regulating intestinal inflammation. In this study, we investigated the function of 6-formylindolo (3,2-b) carbazole (Ficz), a ligand of AHR, on IL-7, colitis, and IEL phenotypes.

Methods

Colitis was induced by administration of dextran sulfate sodium (DSS) to wild-type C57BL/6J mice for 7 days. Mice were weighted, colon tissues were collected and measured, and histology analyses were performed. IELs were isolated from colon, and the phenotype and activation of IELs were examined using flow cytometry detection. The expression of AHR and IL-7 was measured by immunofluorescence, Western blot, and RT-PCR.

Results

Ficz down-regulated epithelial-derived IL-7 expression in mice with DSS-induced colitis and ameliorated DSS-induced colitis. Ficz also decreased CD8αβ⁺ and CD8⁺ IEL subpopulations, enhanced TCRγδ⁺ IEL subpopulation, and reduced the percentage of activated CD4⁺ and CD8⁺ subpopulations.

Conclusions

Ficz could down-regulate epithelial-derived IL-7 expression in mice with DSS-induced colitis and inhibit inflammation in the gastrointestinal tract of mice. AHR-related compounds might be the new and promising therapeutic medicaments for the treatment of patients with IBD.

     

Intestinal intraepithelial lymphocytes

Recent data on phenotype, differentiation, and functions of intestinal intraepithelial lymphocytes (IEL) in rodents and in humans are reviewed in this article. IEL form a large population of activated T cells located at the interface between the body and the septic intestinal content. Phenotypic studies indicate that IEL are mainly CD8-positive cells that contain both TCR alpha beta and TCR gamma delta cells in variable proportion depending on the species and antigenic intraluminal stimulation. Studies in experimental models suggest a dual origin, both thymus-dependent and thymus-independent of IEL, and a role of the gut epithelium in the differentiation of IEL. Functional studies allow insight on the mechanisms by which IEL can protect the intestinal epithelium or conversely, when abnormally activated, induce epithelial damage.     

Cystic lymphangioma of the mesentery and hyposplenism in celiac disease

Celiac disease is characterized by intestinal inflammation and mucosal atrophy that improves on a gluten-free diet. Delayed diagnosis can result in diet-refractory disease known as refractory sprue, which is linked to other disorders (intestinal lymphoma, ulcerative jejunoileitis, mesenteric lymph-node cavitation, collagenous sprue, malignancy) and carries a poor prognosis. Here we report the case of a young woman diagnosed with Marsh stage 3C celiac disease with intestinal occlusion due to intra-abdominal cystic lymphangioma mimicking mesenteric lymph-node cavitation, and hyposplenism. Despite a number of prognostically negative features, the disease has been managed successfully for the past 2 years with a gluten-free diet. The pathogenesis, prognosis and therapeutic implications are discussed.     

Mucosal intra-epithelial lymphocytes in enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease constitute a neoplastic population.

Loss of response to a gluten-free diet (refractory sprue) and ulcerative jejunitis are complications of celiac disease that may progress to enteropathy-associated T-cell lymphoma (EATL). Both conditions are characterized by the presence of a nonlymphomatous monoclonal T-cell population in the enteropathic mucosa. In EATL, a similar monoclonal population that shows clonal identity with the lymphoma itself is also present in the enteropathic mucosa. In this study we show that in all three circumstances the monoclonal T-cell population is constituted by cytologically normal, noninvasive intraepithelial T lymphocytes that share an identical aberrant immunophenotype with EATL. Patients with refractory sprue and/or ulcerative jejunitis are, therefore, suffering from a neoplastic T-cell disorder for which hematological treatment strategies need to be devised.     

Maladie cœliaque

Celiac disease is an enteropathy due to gluten intake in genetically predisposed individuals (HLA DQ2/DQ8). Celiac disease occurs in adults and children at rates approaching 1% of population in Europe and USA. Clinical features observed in celiac disease are extremely various and anaemia, oral aphthous stomatis, amenorrhea or articular symptoms may be the only presenting manifestations. Diagnosis relies on the evidence of histological villous atrophy in proximal small bowel and the presence of specific serum antibodies. Treatment relies on eviction of gluten (wheat, barley, rye) from diet. Gluten free diet allows prevention of malignant complications such as small bowel adenocarcinoma and lymphoma, and osteopenia. The main cause of resistance to gluten free diet is its poor observance. If not the case, serious complications of celiac disease, such as clonal refractory celiac sprue and intestinal T-cell lymphoma should be suspected. Current therapeutic challenges concern alternative to gluten free diet and new efficient treatments of lymphomatous complications.     

Cytokine Production by Intestinal Intraepithelial Lymphocyte Subsets in Celiac Disease

One of the earliest signs of mucosal immune activation in celiac disease (CD) is an increase in the intraepithelial lymphocyte (IEL) count in the small intestinal epithelium. Though most of those IELs express T cell receptor (TcR)- chains, CD is characterized by an increase in TcR- ⁺ IELs and by the loss of CD3^– IELs. There is currently little evidence that these changes in IEL subset distribution are of relevance in the pathogenesis of CD. We aimed to determine the pattern of cytokine production by IEL subsets isolated from duodenal biopsy specimens from control subjects and CD patients at different stages of the disease. We quantified the capacity of IEL subsets to produce IFN-, TNF-, IL-2, IL-4, and IL-10 by intracellular staining by flow cytometry. All IEL subsets studied displayed a type I cytokine profile in both CD and control subjects, with TcR-⁺ IELs being the main IFN- producers. Untreated CD exhibited a trend toward a superior accumulation of IFN- per cell but a reduced proportion of INF-⁺ cells in vitro in association with a significantly increased apoptotic rate of IELs. IL-4 was almost undetectable in all cases and IL-10 showed a tendency to increase in treated and silent celiac patients. IEL subsets have a similar Th1 profile in controls and CD patients, and the superior in vitro apoptosis of IELs from CD patients may reflect their superior in vivo activation. The induction of IL-10-dependent regulatory Tr1 responses may be of potential clinical significance in this disease and merits further investigation.     

Refractory coeliac disease

A small proportion of coeliac disease (CD) patients fail to improve after a gluten-free diet (GFD) and may be considered as atypical regarding their outcome (refractory coeliac disease). The aim of this study is to diagnose and manage patients with CD who fail to improve after a GFD. Refractory coeliac disease (RCD) is a malabsorption syndrome defined by persisting villous atrophy with, usually, an increase of intraepithelial lymphocytes (IELs) in the small bowel in spite of a strict GFD and comprises a heterogenous group of diseases. Some of these diseases have to be excluded and can be treated by specific therapies like antibiotics in tropical sprue and giardiasis and immune globulin substitution in common variable immunodeficiency, while other malabsorption syndromes are less well defined and may require immunosuppressive therapy. Standardized treatment, however, has not been evaluated in such patients so far. In a subgroup of patients with RCD, an abnormal intraepithelial lymphocyte (IEL) population may be observed with the lack of surface expression of usual T-cell markers (CD3-CD8 and/or the T-cell receptor (TCR)) on IELs associated with T-cell clonality pattern suggest the presence of an early enteropathy-associated T-cell lymphoma (EATL) in a subgroup of patients with RCD. This hypothesis has been supported by studies, which revealed progression into overt intestinal T-cell lymphomas in a subgroup of RCD. Steroid treatment has been reported effective even in patients with underlying early EATL. However, long-term results are unsatisfactory in most of these patients with RCD and parenteral nutrition has to be applied in some of these cases. First results with more aggressive chemotherapies and use of cytokines are under way. Due to the difficulty of diagnostic and therapeutic regimens patients should be referred to tertiary centres for coeliac disease.     

Probe-Based Confocal Laser Microscopy Identifies Criteria Predictive of Active Celiac Sprue

Background  

Celiac sprue is an underdiagnosed chronic intestinal inflammatory disease. Probe-based confocal laser microscopy (CLM) is a novel endoscopic technique for in vivo inspection of the intestinal mucosa that has not been evaluated in celiac sprue yet.     

Increased HLA-DR and decreased CD3 on human intestinal intraepithelial lymphocytes: evidence of activation?

BACKGROUND: Activation of circulating T lymphocytes results in expression of HLA-DR, interleukin-2 receptor (IL-2R), transferrin receptor (TrR), and decreased amounts of surface CD3. AIM: To examine the activation status of human intestinal intraepithelial lymphocytes (IELs) by flow cytometry. PATIENTS AND METHODS: Duodenal biopsy specimens from 12 patients provided a source of intestinal lymphocytes. Dual colour analysis was used to compare activation marker expression by IELs with peripheral blood (PB) T lymphocytes from the same patients. RESULTS: All human IEL populations express HLA-DR and their density of expression is lower than on the small population of HLA-DR+ resting PB T lymphocytes (mean fluorescence intensity (MFI) 52.9, range 19.8-94.8 v 152.6 range, 49.1-320.3; p < 0.01). The density of CD3 was significantly reduced on IELs (MFI 465.8, range 228.7-660), compared with PB T lymphocytes (756.3, range 444.5-1573.7; p < 0.009). IL-2R was not detected on IELs; nor were the activation markers, TrR, M21 C5, or M2 B3. CONCLUSION: HLA-DR expression on IELs together with decreased CD3 expression suggest previous stimulation. However, the absence of additional markers of T cell activation may reflect a unique pathway of activation.     

Video capsule endoscopy in celiac disease: current clinical practice

OBJECTIVE: A complete examination of the small intestine is possible by video capsule endoscopy (VCE). The aim of this study was to evaluate current indications for performing VCE in celiac disease. METHODS: In all 84 celiac disease patients on a gluten‐free diet who had undergone VCE were enrolled at five centers in Europe. The indications, findings and clinical impact of VCE were recorded by a structured questionnaire. VCE was also carried out in 34 consecutive patients with untreated celiac disease (controls) in another center. RESULTS: Out of the 84 patients, 34 had overt symptoms and small intestinal histology compatible with refractory celiac disease. VCE was normal in 9 patients, and 7 had only proximal and one distal atrophy, 14 had intestinal ulcer and 2 an intestinal stricture. VCE was used in the adjustment of immunosuppressive treatment in 9 patients. In the remaining 50 patients, a VCE was performed because of less severe symptoms, 31 of which had an earlier histological recovery. The VCE showed proximal small bowel atrophy in 21 and distal atrophy in 3 patients, and 3 ulcers were seen. In this group the patients received mainly advice with a view to achieving better dietary compliance. Of the 34 newly detected celiac patients, 4 were normal, 27 proximal and 3 had distal small intestinal atrophy in the VCE. CONCLUSIONS: VCE has a definite impact on the management of refractory sprue. In the remaining patients with established celiac disease, the procedure plays a more limited role.