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1.  Effects of Helicobacter pylori eradication on the natural history of lymphocytic gastritis 
Gut  1999;45(4):495-498.
BACKGROUND—Lymphocytic gastritis is characterised by an accumulation of lymphocytes in the surface epithelium of the stomach. Lymphocytic gastritis has been linked to coeliac disease and Helicobacter pylori infection.
AIMS—To determine whether H pylori eradication leads to resolution of the lymphocytic infiltrate and clinical improvement in patients with lymphocytic gastritis, and to determine their HLA status.
METHODS—The Leeds Dyspepsia Questionnaire (LDQ) was administered to 13 patients with lymphocytic gastritis. H pylori serology, 13C urea breath test (UBT), and upper gastrointestinal endoscopy with sampling of the duodenum, antrum, and corpus were done in all cases and the HLA status was determined. Eleven patients had at least one positive test for H pylori. Patients with lymphocytic gastritis and H pylori infection were treated with a one week course of omeprazole, clarithromycin, and metronidazole. Gastric and duodenal intraepithelial lymphocyte (IEL) counts were performed, along with histological assessment of gastric and duodenal biopsies before and after H pylori eradication.
RESULTS—Two months after treatment there was a significant reduction in gastric IEL counts in both antrum and corpus. There was no significant change in duodenal IEL counts before and after eradication. According to the Sydney grading there was significant improvement in corpus inflammation after eradication. The patients histologically H pylori positive before treatment became H pylori negative. Dyspepsia scores also improved significantly after treatment.
CONCLUSIONS—H pylori eradication treatment in patients with lymphocytic gastritis causes significant improvement in the gastric IEL infiltrate, corpus inflammation, and dyspeptic symptoms. H pylori serology is frequently positive when histology and UBT are negative. Lymphocytic gastritis may represent a specific immune response to H pylori infection.


Keywords: lymphocytic gastritis; intraepithelial lymphocytes; Helicobacter pylori; HLA status; coeliac disease
PMCID: PMC1727676  PMID: 10486354
2.  Lymphocytic gastritis and associated small bowel disease: a diffuse lymphocytic gastroenteropathy? 
Journal of Clinical Pathology  1995;48(10):939-945.
AIM--To investigate the natural history of lymphocytic gastritis (LG) and its relation to Helicobacter pylori infection and to coeliac disease using serology, duodenal biopsy and a small intestinal permeability test. METHOD--Twenty two patients diagnosed as having LG between 1984 and 1994 were investigated by upper gastrointestinal endoscopy at which gastric and duodenal biopsy specimens were taken for histological assessment and immunohistology. Serum was collected for measurement of anti-H pylori, anti-gliadin and anti-endomysial antibodies. A lactulose/mannitol absorption test was performed within one week of endoscopy. Control groups were studied by histology, serology and permeability tests. RESULTS--Three patients had been recently diagnosed as having LG while 15 still had the condition after a mean of 13.9 (range two to 38) months. LG involved the antrum alone in three patients, antrum and body in seven, body alone in six, and gastric remnant in two. Gastroduodenal intraepithelial lymphocytes (IELs) were T cells and predominantly of T suppressor (CD8) type. Duodenal IELs were increased compared to age/sex matched controls with chronic gastritis. Four patients had duodenal villous atrophy. Four patients no longer had LG after a mean of 29.3 (10-70) months but had increased gastroduodenal IELs. H pylori was present in four (22%) of 18 patients with LG but H pylori serology was positive in 11 (61%) of 18. There was no difference in seropositivity when compared with age/sex matched controls with dyspepsia. Eleven of 20 patients with LG tested had abnormal lactulose/mannitol absorption (v none of 22 controls with chronic gastritis). Four patients with LG, all with villous atrophy, were seropositive for IgA endomysial antibody. CONCLUSIONS--The persistence of LG with time, the association with increased duodenal IELs and abnormal small intestinal permeability suggests LG may be a manifestation of a diffuse lymphocytic gastroenteropathy related to sensitivity to gluten or some other agent.
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PMCID: PMC502952  PMID: 8537495
3.  Development of lntraepithelial Cells in the Porcine Small Intestine 
Developmental Immunology  2001;8(2):147-158.
The number, phenotype, localisation and development of intraepithelial lymphocytes (IEL) from duodenum (Du) and ileum (Il) were studied by immunohistochemistry (IHC) and light and electron microscopy in unweaned (0–7 weeks old) and six months-old pigs. Developmental changes at birth showed that 38% of the total lymphocytes in the villi were IEL, mainly of the CD2+CD4-CD8- double negative (DN) phenotype. That proportion rose to over 50% at week 5 after birth, resembling adult proportion, although still with fewer cells than in adult pigs. CD4+ cells appeared relatively early in life although they were confined to the lamina propria (LP) and CD8+ cells were found only in low numbers. In the villi of adult animals, almost half of the total number of lymphocytes were IEL (49% Du, 52% Il). Over half of these IEL (52% Du, 53% Il) showed the CD2+CD4-CD8+ phenotype and were localized at the epithelium's basement membrane. Numerous (43% Du, 42% Il) DN IEL were found grouped at the enterocyte nucleus level and relatively few (5% in Du and Il) granular IEL were found apically in the epithelium. These proportions were homogeneously maintained along the villi's tip, middle and bottom, suggesting that the IEL may have their origin in the LP. Therefore, the IEL compartment in the porcine intestine develops slowly with age and is actually composed by a heterogeneous population of cells (null, DN and CD8+). These results may explain the increased susceptibility of young animals to disease during the lactation period and should be taken into account when functional studies are carried out with IEL. The quantitative results of this paper established a model for studies on the effect of age, diet, normal flora, infection and oral immunization on the IEL of the gut.
doi:10.1155/2001/25301
PMCID: PMC2276065  PMID: 11589310
IEL; immune development; lymphocyte; mucosal immunology; small intestine; swine
4.  Intestinal Intraepithelial Lymphocyte Cytometric Pattern Is More Accurate than Subepithelial Deposits of Anti-Tissue Transglutaminase IgA for the Diagnosis of Celiac Disease in Lymphocytic Enteritis 
PLoS ONE  2014;9(7):e101249.
Background & Aims
An increase in CD3+TCRγδ+ and a decrease in CD3− intraepithelial lymphocytes (IEL) is a characteristic flow cytometric pattern of celiac disease (CD) with atrophy. The aim was to evaluate the usefulness of both CD IEL cytometric pattern and anti-TG2 IgA subepithelial deposit analysis (CD IF pattern) for diagnosing lymphocytic enteritis due to CD.
Methods
Two-hundred and five patients (144 females) who underwent duodenal biopsy for clinical suspicion of CD and positive celiac genetics were prospectively included. Fifty had villous atrophy, 70 lymphocytic enteritis, and 85 normal histology. Eight patients with non-celiac atrophy and 15 with lymphocytic enteritis secondary to Helicobacter pylori acted as control group. Duodenal biopsies were obtained to assess both CD IEL flow cytometric (complete or incomplete) and IF patterns.
Results
Sensitivity of IF, and complete and incomplete cytometric patterns for CD diagnosis in patients with positive serology (Marsh 1+3) was 92%, 85 and 97% respectively, but only the complete cytometric pattern had 100% specificity. Twelve seropositive and 8 seronegative Marsh 1 patients had a CD diagnosis at inclusion or after gluten free-diet, respectively. CD cytometric pattern showed a better diagnostic performance than both IF pattern and serology for CD diagnosis in lymphocytic enteritis at baseline (95% vs 60% vs 60%, p = 0.039).
Conclusions
Analysis of the IEL flow cytometric pattern is a fast, accurate method for identifying CD in the initial diagnostic biopsy of patients presenting with lymphocytic enteritis, even in seronegative patients, and seems to be better than anti-TG2 intestinal deposits.
doi:10.1371/journal.pone.0101249
PMCID: PMC4091865  PMID: 25010214
5.  Helicobacter pylori Associated Lymphocytic Gastritis in a Child 
Lymphocytic gastritis (LG) is a rare subtype of chronic gastritis. It is defined as dense proliferation of intraepithelial lymphocytes (IELs) more than 25 lymphocytes per 100 epithelial cells. The known major causes of LG are celiac disease and Helicobacter pylori infection. H. pylori associated LG (HpLG) has more enhanced cytotoxic and apoptotic tendencies than chronic H. pylori gastritis. A 12-year-old girl with postprandial epigastric pain was diagnosed HpLG on endoscopic biopsy. After the 1st eradication therapy, H. pylori bacilli were still found, and urea breathing test was positive. Although the endoscopic finding was partially improved, clinical symptoms and histologic finding were persisted. We could achieve the improvement of clinical symptoms and disappearance of IELs after the 2nd eradication. The discordant of histopathologic and endoscopic improvement occurred after the 1st eradication therapy of HpLG. Therefore the clinical and histopathologic evaluation should be considered as well as endoscopic findings.
doi:10.5223/pghn.2014.17.3.186
PMCID: PMC4209324  PMID: 25349835
Helicobacter pylori; Child; Intraepithelial lymphocyte; Chronic gastritis; Lymphocytic gastritis; Eradication
6.  Cytokine Expression in Pediatric Helicobacter pylori Infection 
Helicobacter pylori infection is one of the most common gastrointestinal infections worldwide and almost invariably causes chronic gastritis in the infected host. A predominant Th1 profile has been demonstrated in H. pylori-infected mucosa from adults, but no previous study has evaluated in situ cytokine expression in children. We therefore examined expression of proinflammatory, anti-inflammatory, and regulatory cytokines by immunohistochemistry in cryopreserved antral biopsy specimens from 10 H. pylori-infected and 10 uninfected children and correlated expression of cytokines with histology scores. Concomitant expression of interleukin-8 (IL-8), gamma interferon (IFN-γ), IL-4, transforming growth factor β, and tumor necrosis factor alpha was seen in 8/10 H. pylori-infected cases and in 5/10 noninfected cases; all H. pylori-infected subjects showed staining for at least two of the cytokines. The proportion of epithelial cytokine-specific staining did not differ significantly between the groups, either in surface or glandular epithelium. Furthermore, no significant differences were noticed between intraepithelial or lamina propria lymphocyte staining in the groups. There was, however, a tendency of higher numbers of IFN-γ- and IL-8-positive cells in the H. pylori-infected group. IFN-γ and IL-8 lamina propria lymphocyte expression correlated significantly with antrum chronic inflammation, but there was no correlation between histology scores and epithelial cytokine expression. When the same techniques were used, the cytokine response appeared to be smaller in H. pylori-infected children than in adults, and there was no clear Th1 dominance. These results therefore suggest a different mucosal immunopathology in children. It remains to be determined whether the gastric immune response is downregulated in children with H. pylori infection and whether this is relevant to the outcome of infection.
doi:10.1128/CDLI.12.8.994-1002.2005
PMCID: PMC1182187  PMID: 16085918
7.  Detection of Celiac Disease and Lymphocytic Enteropathy by Parallel Serology and Histopathology in a Population-Based Study 
Gastroenterology  2010;139(1):112-119.
Background & Aims
Although serological analysis is used in diagnosis of celiac disease, histopathology is considered most reliable. We performed a prospective study to determine the clinical, pathological and serological spectrum of celiac disease in a general population (Kalixanda study).
Methods
A random sample of an adult general population (n=1000) was analyzed by upper endoscopy, duodenal biopsy, and serological analysis of tissue transglutaminase (tTg) levels; endomysial antibody (EMA) levels were analyzed in samples that were tTg+. The cutoff values for diagnosis of celiac disease were villous atrophy with 40 intraepithelial lymphocytes (IELs)/100 enterocytes (ECs).
Results
Samples from 33 subjects were tTg+ and 16 were EMA+. Histological analysis identified 7/1000 subjects (0.7%) with celiac disease; all were tTg+ and 6/7 were EMA+. Another 26 subjects were tTg+ (7/26 EMA+). This was addressed by a second quantitative pathology study, (nested case-control design) using a threshold of 25 IELS/100 ECs. In this analysis, all 13 samples that were tTg+ and EMA+ had ≥25 IELs/100ECs. In total, 16 subjects (1.6%) had serological and histological evidence of gluten-sensitive enteropathy. IELs were quantified in duodenal biopsy samples from seronegative individuals (n=500); 19 (3.8%) had >25 IELs and lymphocytic duodenosis (LD).
Conclusions
Measurement of ≥25 IELs/100 ECs correlated with serological indicators of celiac disease; a higher IEL threshold could miss 50% of cases. Quantification of tTg is a sensitive test for celiac disease; diagnosis can be confirmed by observation of ≥25 IELs/100ECs in duodenal biopsies. Lymphocytic enteropathy (celiac disease and LD) is common in the population (5.4%).
doi:10.1053/j.gastro.2010.04.007
PMCID: PMC2902605  PMID: 20398668
Celiac disease; Lymphocytic enteropathy; Serology; Histology; Epidemiology
8.  Lymphocytic gastritis and coeliac disease: evidence of a positive association. 
Journal of Clinical Pathology  1998;51(3):207-210.
AIMS: To investigate the prevalence of lymphocytic gastritis in patients with coeliac disease. METHODS: Gastric biopsies from 70 patients with coeliac disease were examined by light microscopy for the presence of lymphocytic gastritis, defined as 25 or more intraepithelial lymphocytes/100 gastric columnar epithelial cells. RESULTS: Lymphocytic gastritis was found in seven cases. Positive cases had a mean of 32.1 intraepithelial lymphocytes/100 columnar cells, compared with a mean of 13.9 in negative cases, and 5.15 in noncoeliac controls. No differences were found for age, sex, gastric corpus or antrum, or degree of inflammation in the gastric lamina propria. All intraepithelial lymphocytes were of T cell lineage. Cases not showing lymphocytic gastritis did however show significantly increased gastric intraepithelial lymphocytes compared with non-coeliac controls. Eighteen of 70 cases were positive for Helicobacter pylori, and four of seven cases of lymphocytic gastritis were H pylori positive; no significant difference was observed between H pylori positive and negative patients. Three cases had concomitant ulcerative enteritis, of which none showed lymphocytic gastritis, while five cases had concomitant enteropathy associated T cell lymphoma, of which one showed lymphocytic gastritis. CONCLUSIONS: Lymphocytic gastritis occurred in 10% of patients with coeliac disease. Cases without lymphocytic gastritis nevertheless showed increased gastric intraepithelial lymphocytes. Coeliac disease may on occasion be a diffuse lymphocytic enteropathy occurring in response to gluten. Lymphocytic gastritis outside coeliac disease may involve an immune response to luminal antigens, such as H pylori, not unlike the response to gluten in patients with coeliac disease.
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PMCID: PMC500640  PMID: 9659261
9.  Spontaneous secretion of interferon γ and interleukin 4 by human intraepithelial and lamina propria gut lymphocytes 
Gut  1998;42(5):643-649.
Background—Cytokines secreted by intestinal T lymphocytes probably play a critical role in regulation of the gut associated immune responses. 
Aims—To quantify interferon γ (IFN-γ) and interleukin 4 (IL-4) secreting cells (SC) among human intraepithelial (IEL) and lamina propria (LPL) lymphocytes from the duodenum and right colon in non-pathological situations and in the absence of in vitro stimulation. 
Patients—Duodenal and right colonic biopsy specimens were obtained from patients with no inflammation of the intestinal mucosa. 
Methods—Intraepithelial and lamina propria cell suspensions were assayed for numbers of cells spontaneously secreting IFN-γ and IL-4 by a two site reverse enzyme linked immunospot technique (ELISPOT). 
Results—The relatively high proportion of duodenal lymphocytes spontaneously secreting IFN-γ (IEL 3.6%; LPL 1.9%) and IL-4 (IEL 1.3%; LPL 0.7%) contrasted with the very low numbers of spontaneously IFN-γ SC and the absence of spontaneously IL-4 SC among peripheral blood mononuclear cells. In the basal state, both IFN-γ and IL-4 were mainly produced by CD4+ cells. Within the colon, only 0.2% of IEL and LPL secreted IFN-γ in the basal state, and 0.1% secreted IL-4. 
Conclusions—Compared with peripheral lymphocytes substantial proportions of intestinal epithelial and lamina propria lymphocytes spontaneously secrete IFN-γ and/or IL-4. These cytokines are probably involved in the normal homoeostasis of the human intestinal mucosa. Disturbances in their secretion could play a role in the pathogenesis of gastrointestinal diseases. 


Keywords: intestinal lymphocytes; ELISPOT; interferon γ; interleukin 4
PMCID: PMC1727108  PMID: 9659157
10.  Helicobacter pylori infection, glandular atrophy and intestinal metaplasia in superficial gastritis, gastric erosion, erosive gastritis, gastric ulcer and early gastric cancer 
AIM: To evaluate the histological features of gastric mucosa, including Helicobacter pylori infection in patients with early gastric cancer and endoscopically found superficial gastritis, gastric erosion, erosive gastritis, gastric ulcer.
METHODS: The biopsy specimens were taken from the antrum, corpus and upper angulus of all the patients. Giemsa staining, improved toluidine-blue staining, and H pylori-specific antibody immune staining were performed as appropriate for the histological diagnosis of H pylori infection. Hematoxylin-eosin staining was used for the histological diagnosis of gastric mucosa inflammation, gastric glandular atrophy and intestinal metaplasia and scored into four grades according to the Updated Sydney System.
RESULTS: The overall prevalence of H pylori infection in superficial gastritis was 28.7%, in erosive gastritis 57.7%, in gastric erosion 63.3%, in gastric ulcer 80.8%, in early gastric cancer 52.4%. There was significant difference (P<0.05), except for the difference between early gastric cancer and erosive gastritis. H pylori infection rate in antrum, corpus, angulus of patients with superficial gastritis was 25.9%, 26.2%, 25.2%, respectively; in patients with erosive gastritis 46.9%, 53.5%, 49.0%, respectively; in patients with gastric erosion 52.4%, 61.5%, 52.4%, respectively; in patients with gastric ulcer 52.4%, 61.5%, 52.4%, respectively; in patients with early gastric cancer 35.0%, 50.7%, 34.6%, respectively. No significant difference was found among the different site biopsies in superficial gastritis, but in the other diseases the detected rates were higher in corpus biopsy (P<0.05). The grades of mononuclear cell infiltration and polymorphonuclear cell infiltration, in early gastric cancer patients, were significantly higher than that in superficial gastritis patients, lower than that in gastric erosion and gastric ulcer patients (P<0.01); however, there was no significant difference compared with erosive gastritis. The grades of mucosa glandular atrophy and intestinal metaplasia were significantly highest in early gastric cancer, lower in gastric ulcer, the next were erosive gastritis, gastric erosion, the lowest in superficial gastritis (P<0.01). Furthermore, 53.3% and 51.4% showed glandular atrophy and intestinal metaplasia in angular biopsy specimens, respectively; but only 40.3% and 39.9% were identified in antral biopsy, and 14.1% and 13.6% in corpus biopsy; therefore, the angulus was more reliable for the diagnosis of glandular atrophy and intestinal metaplasia compared with antrum and corpus (P<0.01). The positivity rate of glandular atrophy and intestinal metaplasia of superficial gastritis with H pylori-positivity was 50.7%, 34.1%; of erosive gastritis 76.1%, 63.0%; of gastric erosion 84.8%, 87.8%; of gastric ulcer 80.6%, 90.9%; and of early gastric cancer 85.5%, 85.3%, respectively. The positivity rate of glandular atrophy and intestinal metaplasia of superficial gastritis with H pylori-negativity was 9.9%, 6.9%; of erosive gastritis 42.5%, 42.1%; of gastric erosion 51.1%, 61.9%; of gastric ulcer 29.8%, 25.5%; and of early gastric cancer 84.0%, 86.0%, respectively. The positivity rate of glandular atrophy and intestinal metaplasia of superficial gastritis, erosive gastritis, gastric erosion, and gastric ulcer patients with H pylori positivity was significantly higher than those with H pylori negativity (P<0.01); however, there was no significant difference in patients with early gastric cancer with or without H pylori infection.
CONCLUSION: The progression of the gastric pre-cancerous lesions, glandular atrophy and intestinal metaplasia in superficial gastritis, gastric erosion, erosive gastritis and gastric ulcer was strongly related to H pylori infection. In depth studies are needed to evaluate whether eradication of H pylori infection will really diminish the risk of gastric cancer.
doi:10.3748/wjg.v11.i6.791
PMCID: PMC4250585  PMID: 15682469
Helicobacter pylori; Glandular atrophy; Intestinal metaplasia; Early gastric cancer
11.  Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease 
Gut  2006;55(4):469-477.
Background and aims
Epithelium derived interleukin (IL)‐15 signalling via IL‐15Rα 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‐15Rα expression were determined by immunoblotting. Secretion of IL‐15, interferon γ (IFN‐γ), tumour necrosis factor α (TNF‐α), 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 γ 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‐15Rα expression, showed increased proliferation, production of IFN‐γ and TNF‐α, 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.
doi:10.1136/gut.2005.068684
PMCID: PMC1856172  PMID: 16105889
apoptosis; coeliac disease; cytotoxicity; enterocyte; interleukin 15; intraepithelial lymphocyte; T cell lymphoma
12.  Listeria monocytogenes-induced gamma interferon secretion by intestinal intraepithelial gamma/delta T lymphocytes. 
Infection and Immunity  1993;61(5):2154-2161.
gamma/delta T cells represent a major proportion of intestinal intraepithelial lymphocytes (IEL), and it has been suggested that these IEL serve as a first immune barrier against microbial invasion and that they do so by destroying infected epithelial cells. In the present study, we confirm that both alpha/beta and gamma/delta IEL from naive mice express potent cytotoxicity and produce gamma interferon (IFN-gamma) after T-cell receptor (TCR) engagement by specific monoclonal antibodies (MAb). Intraperitoneal administration of the anti-gamma/delta TCR MAb GL3 caused downregulation of the gamma/delta TCR in IEL, and IEL from gamma/delta TCR-modulated mice failed to express cytotoxic activity and to secrete IFN-gamma after gamma/delta TCR engagement. In contrast, alpha/beta IEL from such mice were still cytolytic and secreted IFN-gamma. Mice were infected orally with virulent Listeria monocytogenes at doses which caused bacterial invasion through the intestinal epithelia. Although alpha/beta and gamma/delta IEL from these mice expressed high cytolytic activities in antibody-redirected killer assays, target cells pulsed with listerial antigens were not lysed. In contrast, IFN-gamma secretion by IEL from L. monocytogenes-infected mice was induced not only by anti-TCR MAb but also by target cells pulsed with listerial antigens, whereas irrelevant antigens, including heat shock protein 60, did not induce IFN-gamma secretion. Furthermore, the number of IFN-gamma-secreting IEL, as assessed by the enzyme-linked immunospot technique, was increased during listeriosis. gamma/delta TCR modulation by GL3 administration abrogated antigen-induced IFN-gamma secretion by IEL from infected mice. These findings suggest that L. monocytogenes induced IFN-gamma secretion by gamma/delta IEL from mice suffering from intestinal L. monocytogenes infection and invasion. Thus, the data provide evidence for a role of IFN-gamma-secreting IEL in local resistance against listeriosis and perhaps other food-borne diseases.
PMCID: PMC280816  PMID: 8478105
13.  Intraepithelial lymphocyte mitosis in a jejunal biopsy correlates with intraepithelial lymphocyte count, irrespective of diagnosis. 
Gut  1986;27(6):675-679.
When there is villus atrophy in a jejunal biopsy, intraepithelial lymphocyte (IEL) mitosis correlates with a diagnosis of coeliac disease. We have examined the significance of IEL mitosis in jejunal biopsies with normal villi. Counts of IEL per 100 villus enterocytes, and IEL mitosis per 1000 IEL, were carried out in 81 jejunal biopsies. Thirty one were from patients with coeliac disease or dermatitis herpetiformis, and many of these, from treated patients, were histologically normal; 40 were from patients with other diagnoses, selected to include biopsies with a high IEL count (greater than 40 IEL per 100 enterocytes) but normal villi. Three coeliacs and 10 dermatitis herpetiformis patients had an IEL count of less than 40, and no IEL mitoses were found in these biopsies. Two dermatitis herpetiformis patients had IEL counts of 43.7% and 43.9%, with no IEL mitoses, but in all other coeliac and dermatitis herpetiformis biopsies high IEL counts were associated with IEL mitotic indices between 0.05% and 1.77%. In the non-coeliac, non-dermatitis herpetiformis group, no IEL mitoses were found in the 22 biopsies with IEL count less than 43%. In the others, IEL counts ranged from 44.8% to 127.0%, and IEL mitoses were present, with mitotic indices ranging from 0.06% to 0.49%. This work shows that IEL mitosis in a jejunal biopsy is not specific for coeliac disease, but occurs whenever there is an increased density of IEL within the villus epithelium.
PMCID: PMC1433342  PMID: 3721290
14.  Immunity to Cryptosporidium muris infection in mice is expressed through gut CD4+ intraepithelial lymphocytes. 
Infection and Immunity  1996;64(7):2556-2562.
The role of gut intraepithelial lymphocytes (IEL) in immunity to cryptosporidial infection was investigated with a murine infection model involving Cryptosporidium muris. Oocyst shedding was monitored in severe combined immunodeficiency (SCID) mice infected with C. muris following intravenous injection of mesenteric lymph node (MLN) cells or intestinal IEL from BALB/c donor mice which were naive or previously infected with C. muris. SCID mice receiving no lymphoid cells developed chronic infections and excreted large numbers of oocysts until the end of the experiment. SCID mice injected with IEL from immune animals, however, were able to overcome the infection, and furthermore, these animals produced fewer oocysts and recovered sooner than ones which received IEL or MLN cells from naive BALB/c donors. Similar levels of protection were obtained in SCID mice injected with either 2 X 10(6) IEL or MLN cells from immune donor mice. Depletion of CD4+ cells from immune IEL, however, abrogated the ability to transfer immunity to SCID mice, while depletion of CD8+ cells only marginally reduced the protective capacity of immune IEL. Finally, control SCID mice which received no lymphocytes had < or = 1% CD4+ cells in the IEL from the small intestine, whereas the IEL from SCID mice recovered from infection, as a result of injection with immune IEL, contained 15% CD4+ cells. Thus, the ability to control C. muris infection correlated with the presence of the protective CD4+ cells in the gut epithelium.
PMCID: PMC174110  PMID: 8698479
15.  Duodenal intraepithelial T lymphocytes in patients with functional dyspepsia 
AIM: To quantify the intraepithelial lymphocytes (IELs) and to document the membrane expression of CD4, CD8, TCRγδ and adhesion and/or activation-associated molecules (CD103, CD28, CD44, CD69, HLA-DR, CD95/Fas) in the duodenal mucosa of patients with functional dyspepsia (FD) in order to provide arguments for an immunological process in FD.
METHODS: Twenty-six FD patients according to Rome II criteria (20 were H pylori negative) were studied and compared to 12 healthy adults. IELs were isolated from five duodenal biopsy samples, then quantified by microscopy and flow cytometry while the membrane phenotypes were determined by cytofluorometry.
RESULTS: Duodenal histological examination was normal. In H pylori negative patients, the number of IELs was not different from that in healthy controls. Median percentage expression of CD4, CD8, or TCRγδ and CD103, CD44, CD28, CD69 on CD3+ IELs, among the adhesion/activation associated molecules tested, was not different from that in healthy controls. In contrast, the median percentage expression of CD95/Fas [22 (9-65) vs 45 (19-88), P = 0.03] and HLA-DR expressing CD3+ IELs [4 (0-30) vs 13 (4-42), P = 0.04] was significantly lower in the H pylori negative FD group than in healthy controls, respectively. The number of IELs was significantly greater in H pylori positive FD patients than in healthy controls [median ratiofor 100 enterocytes 27.5 (6.7-62.5) vs 10.8 (3-33.3), P = 0.02] due to a higher number of CD8+ CD3+ IELs.
CONCLUSION: In H pylori negative FD patients, the phenotypic characterization of IELs suggests that we cannot exclude a role of IELs in FD.
doi:10.3748/wjg.v13.i16.2333
PMCID: PMC4147143  PMID: 17511033
Functional dyspepsia; Intraepithelial T lymphocytes; Gut; CD95/Fas; HLA-DR
16.  Intestinal intraepithelial and splenic natural killer cell responses to eimerian infections in inbred chickens. 
Infection and Immunity  1989;57(7):1879-1884.
Splenic and intestinal natural killer (NK) cell responses were assessed in chickens inoculated with Eimeria parasites. The NK cell activities of both splenic and intestinal intraepithelial lymphocytes (IELs) decreased to a subnormal level during the early phase of eimerian infections but returned to normal or slightly higher than normal levels at about 1 week after the primary inoculation. Lymphocytes obtained from the lamina propria did not show any detectable level of NK cell activity during or following eimerian infections. Significant increases in splenic and intestinal IEL NK cell activities were seen during the early phase of secondary infection. The increase in the IEL NK cell activity that was seen shortly following secondary eimerian infection was accompanied by a substantial increase in the number of IELs expressing the asialo-GM1 antigen. Host strain differences in both splenic and IEL NK cell responses were detected following primary eimerian infections. These results suggest that both splenic and intestinal IEL NK cells may play an important role in the host defense against intestinal protozoan infections.
PMCID: PMC313814  PMID: 2731975
17.  Intraepithelial and lamina propria lymphocytes show distinct patterns of apoptosis whereas both populations are active in Fas based cytotoxicity in coeliac disease 
Gut  2001;49(3):380-386.
BACKGROUND—Lamina propria (LPLs) and intraepithelial (IELs) lymphocytes are markedly increased in coeliac mucosa, and are thought to play a crucial role in the generation of villous atrophy in coeliac disease (CD). However, the mechanisms by which they mediate the killing of enterocytes in this condition are still poorly characterised.
AIM—We investigated Fas mediated cytotoxicity and apoptosis of both LPLs and IELs, isolated from 10 untreated coeliac patients, 10 coeliac patients on a gluten free diet, and 10 biopsied controls.
METHODS—Fas and Fas ligand expression were assessed by flow cytometry and immunocytochemistry. Lymphocyte cytotoxicity against Fas expressing Jurkat cells was determined by the Jam test. The effect of the antagonist ZB4 anti-Fas antibody on apoptotic activity exerted by coeliac lymphocytes against enterocytes was analysed. Lymphocyte apoptosis was assessed by oligonucleosome ELISA.
RESULTS—LPLs and IELs showed increased apoptotic activity and higher levels of Fas ligand expression in untreated CD compared with treated CD patients and controls. Enterocyte apoptosis observed after coculturing coeliac lymphocytes and enterocytes in the presence of ZB4 antibody was reduced. In active CD, LPLs manifested increased apoptosis whereas IELs showed decreased apoptosis.
CONCLUSIONS—Our results support the involvement of the Fas/Fas ligand system in CD associated enterocyte apoptosis. Increased LPL apoptosis is likely to downregulate mucosal inflammation whereas decreased IEL apoptosis could be responsible for autoimmune and malignant complications of CD.


Keywords: apoptosis; coeliac disease; cytotoxicity assay; Fas/Fas ligand system; intraepithelial lymphocytes; lamina propria lymphocytes
doi:10.1136/gut.49.3.380
PMCID: PMC1728419  PMID: 11511560
18.  Small intestinal CD8+TCRγδ+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease  
Intraepithelial lymphocytes (IELs) bearing the γδ TCR are more abundant in the small intestinal mucosa of patients with celiac disease (CD) compared with healthy individuals. However, their role in disease pathogenesis is not well understood. Here, we investigated the functional attributes of TCRγδ+ IELs isolated from intestinal biopsies of patients with either active celiac disease (ACD) or those on a gluten-free diet (GFD). We found that compared with individuals with ACD, individuals on GFD have a higher frequency of CD8+TCRγδ+ IELs that express the inhibitory NK receptor NKG2A and intracellular TGF-β1. TCR triggering as well as cross-linking of NKG2A increased both TGF-β1 intracellular expression and secretion in vitro. Coculture of sorted TCRγδ+NKG2A+ IELs, IL-15–stimulated TCRαβ+ IELs, and HLA-E+ enterocytes resulted in a decreased percentage of cytotoxic CD8+TCRαβ+ IELs expressing intracellular IFN-γ and granzyme-B and surface NKG2D. This inhibition was partially abrogated by blocking either TGF-β alone or both NKG2A and HLA-E. Thus, our data indicate that suppression was at least partially mediated by TGF-β secretion as a result of engagement of NKG2A with its ligand, HLA-E, on enterocytes and/or TCRαβ+ IELs. These findings demonstrate that human small intestinal CD8+TCRγδ+ IELs may have regulatory potential in celiac disease.
doi:10.1172/JCI30989
PMCID: PMC2117760  PMID: 18064301
19.  Immune deviation of 2C transgenic intraepithelial lymphocytes in antigen-bearing hosts 
The present study examined self-tolerance for T cell receptor (TCR) alpha beta intestinal intraepithelial lymphocytes (iIELs) using the 2C transgenic (Tg) mouse model specific for a peptide antigen (Ag) presented by the class I major histocompatibility complex H-2Ld. Although Tg+ T cells were largely deleted from the periphery of Ag+ mice, equivalent numbers of Tg iIELs were present in Ag+ compared to Ag- mice. Tg iIELs in Ag- mice contained CD8 alpha beta, CD8 alpha alpha, and CD4-CD8- subsets, whereas only CD8 alpha alpha and CD4-CD8- Tg iIEL subsets were detected in Ag+ mice. Analysis of surface markers revealed that Tg iIELs in Ag+ mice expressed decreased levels of Thy-1 and increased CD45R/B220 as compared to Ag- Tg iIELs. In response to activation with exogenous peptide or immobilized anti-TCR mAB, iIELs from Ag- mice proliferated at high levels and produced interleukin (IL)- 2 and interferon (IFN)-gamma, while Tg+ iIELs from Ag+ mice proliferated at low levels and failed to produce detectable IL-2 or IFN- gamma. Activation of sorted iIEL subsets from Ag- mice revealed that CD8 alpha alpha and CD4-CD8- subsets produced low levels of IL-2 and IFN-gamma in response to activation with antigen-presenting cells and added peptide or immobilized anti-TCR mAb, while CD8 alpha beta + iIELs responded to endogenous levels of peptide. In response to APC and exogenous peptide, sorted iIEL subsets from Ag+ mice produced IL-2 and IFN-gamma, and proliferated at greatly reduced levels compared to corresponding subsets from Ag- mice. Analysis of cytokine mRNA levels revealed that activation in vitro induced IL-2 mRNA only in Ag-, but not Ag+ iIELs, whereas a high level of IL-4 mRNA induction was detected in Tg+ iIELs from Ag+ mice, and to a lesser degree, from Ag- mice. These data suggest that tolerance for Tg+ iIELs resulted in the deletion of CD8 alpha beta + subsets and the persistence of Tg+ iIEL subsets with decreased sensitivity to endogenous levels of self- peptide. A comparison of the cytokine profiles expressed by Tg+ iIEL subsets in Ag- and Ag+ mice suggested that tolerance induction had involved the functional deviation of cells from TC1 (T helper-1-like) to a less inflammatory TC2 (T helper-2-like) phenotype capable of mediating humoral immune responses in the mucosa.
PMCID: PMC2192706  PMID: 8760803
20.  Cholera Toxin Induces a Transient Depletion of CD8+ Intraepithelial Lymphocytes in the Rat Small Intestine as Detected by Microarray and Immunohistochemistry  
Infection and Immunity  2005;73(9):5595-5602.
Cholera toxin (CT), besides causing intestinal hypersecretion after intragastric administration or during cholera infection, affects a multitude of regulatory mechanisms within the gut mucosal network, including T cells. By use of microarray screening, real-time PCR, and immunohistochemistry, we demonstrate here a rapid depletion of jejunal CD8+ intraepithelial lymphocytes (IEL) in rats after intragastric CT challenge. This depletion may depend on CT-induced migration of IEL, since it was associated with a progressive decrease of CD8+ cells in the epithelium and a contemporary transient increase of such cells, preferentially at the base of the villi, in the lamina propria. A significant decrease in the total number of villous CD8+ cells at 6 and 18 h after CT challenge was detected; this possibly reflects an efflux from the jejunal mucosa. The kinetics of the CD8+ IEL demonstrate the return to normal intraepithelial position at original numbers already 72 h after the single CT dose. The induced migration seems to be dependent on the enzymatic A-subunit of CT, since challenge with neither sorbitol nor CT B-subunit did mimic the effects of CT on CD8+ IEL. Furthermore, a decrease in the level of both RANTES transcript and protein was detected, most likely as a consequence of the CT-induced migration of CD8+ IEL. These results point to a complex interaction between CT, epithelial cells, and IEL, resulting in a disturbance of the gut homeostasis, which might have relevance for the strong immunomodulatory effects of intragastrically administered CT.
doi:10.1128/IAI.73.9.5595-5602.2005
PMCID: PMC1231117  PMID: 16113276
21.  Isolated short stature as a presentation of celiac disease in Saudi children 
Pediatric Reports  2010;2(1):e4.
The aim of this study is to assess the prevalence of isolated short stature as a clinical presentation of celiac disease in Saudi Arab children and whether some of the routine laboratory tests performed to determine the cause of short stature could suggest the diagnosis of celiac disease. A total of 91 children with short stature were included in the study. Extensive endocrine and biochemical assessments, including total protein, serum albumin, calcium phosphate and alkaline phosphatase assays; renal function tests; coagulation profile; anti-endomysial antibodies and anti-tissue transglutaminase antibody, growth hormone, thyroid stimulating hormone, free-thyroxin (FT4) assays; stool tests for giardiasis; bone age; and endoscopic intestinal biopsies, were done for all children. Ten of the 91 children had positive intestinal biopsies in the form of total villous atrophy, an increase in crypt height, and an increase in intra-epithelial lymphocyte (IEL) numbers up to >40 IEL/100 EC (Type 3C) according to the Oberhuber classification, confirming the diagnosis of celiac disease. Five children had mild villous atrophy according to this classification (Type 3A), and they were considered to have potential celiac disease. Seventy-six children had normal intestinal biopsies. Therefore, the prevalence of celiac disease among Saudi children with short stature was 10.9%, and 4.3% of the children were diagnosed as having potential celiac disease. After confirming the diagnosis of celiac disease, all children were kept on a gluten-free diet and all of them showed improvement in their growth rate. We concluded that celiac disease is a very important cause of short stature in children without gastrointestinal complaints in Saudi Arabia. We highly recommend anti-tissue transglutaminase and anti-endomysial antibody screening tests, and a small bowel biopsy to confirm the diagnosis of celiac disease irrespective of the results of the antibody assays, in children with short stature in Saudi Arabia. Once the diagnosis is confirmed, children should be kept on a gluten-free diet so they can catch up their growth early before they develop permanent short stature.
doi:10.4081/pr.2010.e4
PMCID: PMC3094008  PMID: 21589840
celiac disease; short stature; anti-tissue transglutaminase; Saudi; children.
22.  Intraepithelial gamma/delta T cells in duodenal mucosa are related to the immune state and survival time in AIDS. 
Journal of Virology  1996;70(6):3545-3550.
The proportion of T-cell receptor gamma/delta+ cells and the CD4/CD8 ratio relative to all CD3+ intraepithelial lymphocytes (IEL) were determined by immunofluorescence in duodenal mucosa of late-stage (mostly CDC IVC1/D) subjects (n = 21) infected with human immunodeficiency virus type 1 (HIV-1). The gamma/delta fraction (median, 14.2%; range, 1.7 to 59.8%) was increased (P < 0.03) compared with that in HIV- controls (n = 11; median 2.8%; range, 0.3 to 38%). Also, the number of gamma/delta+ IEL per mucosal unit was increased (P < 0.05) in the HIV+ subjects (median, 11.1/U) compared with the controls (3.2/U). Approximately 100% of the gamma/delta+ IEL were CD8-, and most expressed the Vdelta1vJdelta1-encoded epitope (median, 90.9%). The total number of CD3+ IEL tended to be lower than in the controls (67.4 versus 72.9/U). Both the epithelium and the lamina propria contained mainly CD8+ T cells, the median ratios of CD4+ T cells being 1 and 7.6%, respectively. This result accorded with the reduced CD4 cell number in blood (median, 18 X 10(6)/liter). The HIV+ subjects had increased serum levels of neopterin and beta2-microglobulin (both P < 0.0001), probably reflecting immunostimulation. Serum neopterin and beta2-microglobulin were inversely related to duodenal gamma/delta IEL, particularly in the premortal group (r = -0.97 and r = -0.58, respectively). The increased gamma/delta IEL might reflect enhanced intestinal protection in late-phase HIV infection. Short survival expectancy (<7 months) was associated not only with high levels of neopterin and beta2-microglobulin but also with a reduced number of duodenal gamma/delta+ cells (P < 0.03).
PMCID: PMC190229  PMID: 8648688
23.  Role of CXCR3/CXCL10 Axis in Immune Cell Recruitment into the Small Intestine in Celiac Disease 
PLoS ONE  2014;9(2):e89068.
Lymphocytic infiltration in the lamina propria (LP), which is primarily composed of CD4+ Th1 cells and plasma cells, and increased numbers of intraepithelial lymphocytes (IELs), is a characteristic finding in active celiac disease (CD). Signals for this selective cell recruitment have not been fully established. CXCR3 and its ligands, particularly CXCL10, have been suggested to be one of the most relevant pathways in the attraction of cells into inflamed tissues. In addition, CXCR3 is characteristically expressed by Th1 cells. The aim of this work was to investigate the participation of the chemokine CXCL10/CXCR3 axis in CD pathogenesis. A higher concentration of CXCL10 was found in the serum of untreated CD patients. The mRNA levels of CXCL10 and CXCL11 but not CXCL9 were significantly higher in duodenal biopsies from untreated CD patients compared with non-CD controls or treated patients. The results demonstrate that CXCL10 is abundantly produced in untreated CD and reduced in treated patients, and the expression of CXCL10 was found to be correlated with the IFNγ levels in the tissue. Plasma cells and enterocytes were identified as CXCL10-producing cells. Moreover, the CXCL10 expression in intestinal tissues was upregulated by poly I:C and IL-15. IELs, LP T lymphocytes, and plasma cells, which infiltrate the intestinal mucosa in untreated CD, express CXCR3. The CXCR3/CXCL10 signalling axis is overactivated in the small intestinal mucosa in untreated patients, and this finding explains the specific recruitment of the major cell populations that infiltrate the epithelium and the LP in CD.
doi:10.1371/journal.pone.0089068
PMCID: PMC3930692  PMID: 24586509
24.  Ten year follow up study of lymphocytic gastritis: further evidence on Helicobacter pylori as a cause of lymphocytic gastritis and corpus gastritis. 
Journal of Clinical Pathology  1995;48(12):1111-1116.
AIMS--To examine the course of lymphocytic gastritis and its relation to Helicobacter pylori (H pylori) infection in a 10 year follow up. METHODS--Ninety six patients were originally examined for dyspepsia in 1981. Gastroscopies with stepwise biopsies were performed on all the patients initially and after an interval of 10 years. RESULTS--Nine per cent of the patients (9/96) had features of lymphocytic gastritis in gastric biopsy at the first examination, and 12.5% (12/96) at the second examination; 7/9 patients (78%) had persistent lymphocytic gastritis during the follow up; in two the diagnostic features of lymphocytic gastritis had disappeared, and five had a new diagnosis of lymphocytic gastritis at the second examination. At the second examination 9/12 lymphocytic gastritis patients (75%) were H pylori positive histologically, while all had specific antibodies to H pylori. The lymphocytic gastritis patients had higher grades of gastritis (p = 0.009), neutrophilic and eosinophilic granulocytes, mononuclear inflammatory cells, and foveolar hyperplasia in the corpus mucosa, but smaller numbers of H pylori, than the H pylori positive patients without lymphocytic gastritis. The appearance of lymphocytic gastritis during the 10 year interval was associated with increases in the grades of corpus gastritis and neutrophilic granulocytes (p = 0.043 for both). During the follow up, the patients with lymphocytic gastritis, but not the H pylori positive patients without lymphocytic gastritis, appeared to have a significant increase in the grade of intestinal metaplasia in the corpus mucosa (p = 0.043). CONCLUSIONS--In some patients H pylori may cause a gastritis that predominates in the corpus and is associated with an increase in the intraepithelial lymphocyte count. This form of gastritis may cause progression of intestinal metaplasia.
Images
PMCID: PMC503037  PMID: 8567997
25.  Intraepithelial lymphocyte distribution differs between the bulb and the second part of duodenum 
BMC Gastroenterology  2013;13:111.
Background
Evaluation of intraepithelial duodenal lymphocytosis (IDL) is important in celiac disease (CD). There is no established cut-off value for increased number of IELs in the bulb.
We therefore investigated the relation between IEL counts in the bulb and duodenal specimens in non-celiac subjects.
Methods
The number of CD3+ IELs was determined in specimens from the second part of the duodenum and from the bulb in 34 non-celiac subjects. The numbers of IELs in the villus tip and sides were counted and the quotient tip/side was calculated. HLA DQ2/DQ8 and serum antibodies against transglutaminase were analysed.
Results
The mean number of IELs per 100 enterocytes (95% CI) in specimens was 14.7 (11.8-17.6) in the bulb, and 21.2 (17.0-25.5) in the second part of the duodenum (p<0.01). There was no difference in IEL count or distribution comparing patients carrying or lacking HLA DQ2/DQ8.
Conclusions
IEL count in non-celiac, HLA DQ2/DQ8 positive or negative patients is significantly lower in the bulb than in the second part of the duodenum. These findings implicate that the site of biopsy should be taken into account when considering duodenal lymphocytosis.
doi:10.1186/1471-230X-13-111
PMCID: PMC3720215  PMID: 23841671

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