Blockage of T-cell costimulation inhibits T-cell action in celiac disease.

BACKGROUND & AIMS: Celiac disease is an exemplary model of T cell-mediated pathology. Therefore, therapeutic approaches that target T cells may successfully control this disease. CTLA-4 immunoglobulin (CTLA-4Ig) can inhibit T-cell activation by blocking the engagement of CD28. We took advantage of this tool to define the pathogenic role of gliadin-specific T cells in the induction of celiac disease. METHODS: Duodenal biopsy specimens from 7 treated celiac patients were challenged in vitro with gliadin and CTLA-4Ig or CD40-Ig. After 24 hours, the biopsy specimens were analyzed for the presence of characteristic modifications induced by gliadin challenge. RESULTS: CTLA-4Ig down-regulated the expression of CD25, intercellular adhesion molecule 1, interleukin 2, and interferon gamma (stained lamina propria mononuclear cells/mm2; P < 0.05) induced by gliadin challenge, caused apoptosis of gliadin-specific T cells (apoptotic T cells/mm2; P < 0.05), and inhibited the production of antiendomysial antibody (P < 0.01). However, it did not control intraepithelial T-cell migration (P = NS) and Fas expression by enterocytes. Conversely, CD40-Ig only controlled production of antiendomysial antibody. CONCLUSIONS: In an organ culture model, CTLA-4Ig controls many but not all of the immunologic features of celiac disease.

DNA fragmentation is a feature of cystic fibrosis epithelial cells: a disease with inappropriate apoptosis?

Cystic fibrosis (CF) is a single-gene disease caused by mutations in the CFTR gene, which result in disrupted chloride secretions with inspissated mucous secretions by exocrine glands. Nick-end labelling was used to assess DNA fragmentation in 14 CF and 24 control duodenal samples, and in two CF and two control lung tissues. In CF small intestine median 46% (range: 30-82) villus enterocytes show DNA fragmentation (vs. 3% (range: 1-7) in controls P < 0.001) and median 37.5% (range: 23-79) crypt enterocytes show Ki67 antigen (P < 0.001). In CF airways 57% (range: 54-70) of epithelial cells show DNA fragmentation. Inappropriate high DNA fragmentation is a feature of various CF epithelia. This could have great impact in understanding the mechanisms leading to disease.

Gluten-sensitive disease with mild enteropathy.

BACKGROUND & AIMS: Celiac disease is a permanent gluten intolerance strongly associated with HLA class II antigens and possibly showing milder changes of mucosal architecture. Ten patients with symptoms suggesting celiac disease and serum antiendomysium antibodies with normal mucosal architecture were studied. METHODS: Immunohistochemical detection of mucosal immune activation and HLA typings were performed. RESULTS: Mucosal immune activation, with normal mucosal architecture and normal gamma/delta+ intraepithelial lymphocytes counts, was found on a gluten-containing diet. In 3 of 6 patients, multiple biopsy specimens showed one sample with severe villous atrophy. Clinical and immunomorphologic features were strictly gluten dependent. The mucosal immune activation was elicited in vitro by gliadin. Only 4 patients had the typical HLA typing of celiac disease. CONCLUSIONS: Gluten-sensitive celiac-like symptoms may occur in patients with serum antiendomysium antibodies, apparently normal intestinal mucosa, and HLA typing not commonly associated with celiac disease. These patients should undergo multiple biopsies, and signs of immunologic activation should be sought accurately; in the presence of mucosal immune activation, a trial with a gluten-free diet should be encouraged to detect gluten dependency. In vitro immunologic response of small intestinal mucosa to gliadin may support the diagnosis of gluten-sensitive enteropathy.

Definition of the initial immunologic modifications upon in vitro gliadin challenge in the small intestine of celiac patients.

BACKGROUND & AIMS: Mucosal cell-mediated immune response is considered the central event in the pathogenesis of celiac disease. In cultured intestinal explants from celiacs in remission, we have characterized the early stages of gliadin-induced immune activation. METHODS: Intestinal biopsy specimens (15 treated celiacs and 13 controls) were cultured with gliadin or maize prolamine digests for 24 hours as well as for 1, 2, 4, 6, 8, and 12 hours in some subjects. The expression of immunologic markers was detected by immunocytochemistry. RESULTS: Gliadin challenge may initiate two parallel pathways, one of which leads to T-cell activation and another that precedes it. Epithelial cells overexpress DR molecules after 1 hour, and in a second stage T lymphocytes become fully activated. Moreover, T lymphocytes migrate in the upper mucosal layers. T lymphocytes that migrate in the higher lamina propria compartments are mainly CD4+ and show markers of activation; migrating intraepithelial lymphocytes are CD8+ and do not express these markers. CONCLUSIONS: In vitro gliadin challenge is a suitable model to reproduce various immunologic features of celiac lesions; these may be caused by different pathways. The comprehension of these phenomena is essential to clarify the distinctive pathogenic mechanisms leading to disease and may help in defining novel therapeutic approaches.

Morphological method for the diagnosis of human adult type hypolactasia.

The primary adult type hypolactasia is the most common form of genetically determined disaccharidase deficiency. This study examined a large and homogeneous population of the south of Italy: surgical biopsy specimens of proximal jejunum from 178 adult subjects have been assayed for disaccharidase activities; the expression of lactase protein and lactase activity has also been investigated on tissue sections by immunomorphological and enzymohistochemical techniques. Histograms of lactase to sucrase ratio were found to provide a useful distribution of the lactase activity; a lactase to sucrase ratio of 0.17 was found to show discrimination between tissues with persistence of high lactase activity and tissues with adult type hypolactasia. In all 28 subjects with persistent high lactase activity, a uniform distribution of lactase protein and lactase activity in all villus enterocytes was detected, whereas in all 150 subjects with adult type hypolactasia a variable number of villus enterocytes failed to express the lactase. Moreover in hypolactasic samples the lactase activity on tissue sections was constantly detected later than in samples with persistent high lactase activity. The absolute correlation between the immunohistochemical and enzymohistochemical features and the assessment of lactase activity in intestinal homogenates suggests that the morphological criteria are an alternative method for the diagnosis of adult type hypolactasia in human biopsy specimens from proximal small jejunum.

[Erythrohemophagocytic lymphohistiocytosis. A clinical report of 3 cases]. / Linfoistiocitosi eritroematofagica. Contributo clinico di 3 casi.

Three infants suffering from hepatosplenomegaly, pancytopenia, hyperlipidemia, low fibrinogen levels and fever are reported. Two patients died during the first year of life, the third one received allogenic bone transplantation and survives. Clinical and haematological features are consistent with diagnosis of hemophagocytic lymphohistiocytosis.

Familial erythrophagocytic lymphohistiocytosis: adverse prognostic significance of delayed diagnosis.

Familial erythrophagocytic lymphohistiocytosis (FEL) is a rare disorder of the monocyte-macrophage system, for which an autosomal recessive mode of inheritance has been postulated. It is characterized by a dismal prognosis and is peculiar of early infancy. Three new cases of infants affected by FEL are reported. All three patients were diagnosed about three months after the onset of symptoms, and all three died shortly after diagnosis. The need for early diagnosis and prompt, intensive cytotoxic chemotherapy is emphasized.

[Juvenile xanthogranuloma. Description of a case with liver involvement]. / Xantogranuloma giovanile. Descrizione di un caso con interessamento epatico.

Juvenile Xanthogranuloma. Report of a case with hepatic involvement. The Authors present a case of Juvenile Xanthogranuloma (JX) in a 3 months female child with cutaneous and hepatic nodules associated to dyspnea attributable to obstructive bronchopneumopathy. Histologically the lesions are xanthomatous with proliferation of fat-laden histiocytes. The hepatic involvement is characterized by hepatomegaly and yellow nodules on liver surface as seen at laparoscopy. On liver biopsy there is remarkable expansion of portal triad caused by aggregates of large foamy mono-polynuclear histiocytes with Touton giant cells. The cutaneous nodule biopsy shows histiocytic infiltrate in inter-adnexal dermal space with many giant cells holding great lipidic vacuoles. The patient's follow-up is characterized by slow and progressive clinical improvement with resolution of cutaneous, hepatic and pulmonary pathology. The Authors emphasize the differential diagnosis between this systemic form of JX and Langerhans cell Histiocytosis (Histiocytosis X) with multiorgan involvement. This diagnosis is necessary in order to establish therapy and prognosis.

Antigliadin antibody, D-xylose, and cellobiose/mannitol permeability tests as indicators of mucosal damage in children with coeliac disease.

A dual sugar (cellobiose/mannitol) permeability test using an iso-osmolar solution was performed, to compare its ability to predict small-bowel mucosal damage in children affected by coeliac disease with the determination of serum levels of D-xylose and antigliadin antibody. Eighty-three children (67 on gluten-containing diet and 16 on gluten-free diet) were investigated. The D-xylose and the serum antigliadin antibody test predicted accurately 70% and 78% of the small-bowel biopsy results, respectively, whereas the cellobiose-mannitol permeability test predicted 93%. These data confirm the superiority of the permeability test over the D-xylose test, although the former cannot be advocated as a substitute for jejunal biopsy. Our results suggest a complementary use of the permeability test and the antigliadin antibody measurement as screening tests for coeliac disease before applying more invasive procedures.

[Endoscopic surgery of the digestive system: state of the art. Opinion of an endoscopic surgeon]. / Chirurgia endoscopica dell'apparato digerente: stato dell'arte. L'opinione di un endoscopista chirurgo.

The Authors review the possible applications of surgical endoscopy in oesophageal, gastric, biliary, pancreatic and colic diseases. This critical assessment, performed under the abdominal endoscopic surgeon's point of view, is based on the overall experience of about 20 years of surgery, with particular regard to the sclerosis of oesophageal varices, neoplastic obstructions of oesophagus, biliary tract, colon and localized Laser treatment of neoplasms. Based on the results achieved, thanks to selective indications and monitoring by conventional surgical experience, the Authors conclude by staging a better reliability of the surgeon who performs surgical endoscopy to obtain good results after an accurate selection of those cases which can really benefit from endoscopic management.