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Background Inflammatory bowel diseases (IBD) associated with primary immunodeficiency (PID) remain poorly known. We aimed to isolate characteristics of IBD associated with PID. Methods Using a GETAID register, we reviewed medical files of recorded patients with PID and IBD (Crohn’s disease, ulcerative colitis (UC) or microscopic colitis) followed in 9 adult university hospitals. Results of genetic investigations were available for 46 patients (62%). Results 74 patients (30 F, 44M) were included with a mean age of 26 years (median: 24 years) at diagnosis of IBD. Forty-four (59%) patients had Crohn’s disease with anoperineal lesions in 12, 26(35%) patients had microscopic (mainly lymphocytic) colitis and 4 patients had UC. PID was predominantly antibody deficiency in 40(54%) patients [34 common variable immunodeficiency, 4 X-linked agammaglobulinemia, 2 selective IgA deficiencies], disease of immune dysregulation in 18(24%) patients [CTLA4, LRBA, NFKB1, TNFAi3, XIAP deficiencies, STAT3 and STAT1 hyperactivation], phagocytosis deficiency in 15(20%) patients (12 chronic granulomatous diseases (CGD), 3 congenital neutropenia] and C1s deficiency (n=1). In order of frequency, Crohn’s disease was associated with antibody deficiencies (52%), phagocytosis deficiencies (29%) and immune dysregulation (18%), microscopic colitis with antibody deficiencies (65%), immune dysregulation (27%) and more rarely with phagocytosis deficiencies (8%) and UC with antibody deficiencies (75%) and immune dysregulation (25%). 46% of patients received immunoglobulin supplementation, 70% steroids, equally corticosteroids and budesonide, 49% biotherapy mainly anti-TNF-alpha antibody (38%) and ustekinumab (16%), 23% immunosuppressive drugs, mainly azathioprine and sirolimus and 18% aminosalicylates. Three patients (2 CGD, 1 XIAP) had been treated with allogeneic stem cell transplantation (SCT) and one patient (TNFRS13B deficiency) with autologous SCT. Eleven (15%) patients had intestinal surgery, mainly ileocecal resection. During follow-up [mean: 16 years], 51% of patients had transient or sustained clinical remission mainly with an anti-TNF-alpha antibody, ustekinumab, steroids (budesonide) and specific therapy (targeted therapy such as abatacept and ASCT), 41% of patients had severe infections, 22% developed neoplasia mainly gastrointestinal dysplasia and/or cancers (n=8), B cell lymphoma (n=3) and 4 patients died. Conclusion At adulthood in our series, IBD associated with PID are mainly Crohn’s disease and lymphocytic colitis. The first most frequent associated PID is antibody deficiency. Biotherapies (anti-TNF-alpha antibody, ustekinumab), steroids and specific therapies are commonly used to induce clinical remission.

Resume But Evaluer la pertinence clinique des examens extemporanes du curage ganglionnaire, des recoupes ureterales et uretrale lors la cystectomie totale pour cancer urothelial et definir les consequences sur la poursuite de l’intervention. Methode Etude retrospective monocentrique portant sur 182 patients operes d’un carcinome urothelial de vessie cT = 3bN0M0 entre 2016 et 2018. Le bilan d’extension comprenait un scanner thoraco-abdomino-pelvien injecte avec temps tardifs et un TEP scanner au 18-FDG. Aucun patient n’a recu de chimiotherapie neoadjuvante. Les performances diagnostiques des examens extemporanes ont ete calculees comparativement a l’examen definitif. L’impact du resultat sur l’intervention initialement planifiee a ete determine. Resultats Les examens extemporanes ont ete positifs sur 29 curages (15,9 %), 59 recoupes ureterales (16,6 %) et 20 recoupes uretrales (10,9 %). Pour l’examen des curages ganglionnaires, la sensibilite, specificite et les valeurs predictives positive et negative ont ete respectivement de 93,5 %, 100 %, 100 % et 98,7 %. Pour les recoupes ureterales les memes valeurs ont ete respectivement de 91,5 %,100 %, 100 % et 98,4 %. Enfin, pour les recoupes uretrales, toutes les valeurs etaient de 100 %. La prise en charge a ete modifiee pour tous les patients ayant un examen extemporane positif sauf une recoupe uretral positive qui n’a pas entraine d’uretrectomie. Conclusion Les examens extemporanes sont utiles au cours de la cystectomie totale pour carcinome urothelial. Les performances des examens extemporanes realises sont excellentes (sensibilite et specificite). La positivite de l’examens extemporanes a conduit a modifier la prise en charge durant l’intervention dans l’ensemble des cas etudies a l’exception d’un cas.

To determine the usefulness of the frozen section exams of lymph nodes dissection, ureteral and urethral section during radical cystectomy for urothelial carcinoma and define the impact on the surgical procedure.A retrospective, single-center study of data collected from 182 patients who underwent radical cystectomy for an cT=3bN0M0 urothelial bladder cancer between 2016 and 2018. Bladder cancer extension was determined by thoracoabdominal CT with contrast enhancement and urography and an 18-FDG PET scanner. No patient received neoadjuvant chemotherapy. The diagnostic performance of the frozen section exams was related to final examinations. The impact of the result on the initial intervention was determined.The frozen section were positive in 29 lymph nodes dissections (15.9 %), 59 (16.6 %) ureteral and 20 (10.9 %) ureteral recessions. With lymph nodes exams, sensitivity, specificity and positive and negative predictive values were 93.5 %, 100 %, 100 %, and 98.7 %, respectively. With ureteral sections exams the same values were 91.5 %, 100 %, 100 %, and 98.4 % respectively. With urethral section exams, all the values were of 100 %. Finally, all the procedure has been modified for all patients with positive frozen section exam except one positive urethral section that did not give rise to radical urethrectomy.Frozen section exams were useful to the urologist during radical cystectomy for urothelial carcinoma. The performances of the frozen section exams carried out were excellent. The information of the urologist of the positive frozen section leeds to modify its management during the intervention in all the studied cases with the exception of one case.

Objectifs La maladie de Lapeyronie touche jusqu’a 9 % de la population masculine. Elle se manifeste par des douleurs et une deformation de la verge en erection. Les traitements medicamenteux apportent un faible benefice et les traitements chirurgicaux presentent des effets secondaires non negligeables. Depuis 1996, la lithotritie extracorporelle (lec) est utilisee comme alternative therapeutique non invasive et justifie d’evaluer ses resultats avec les nouveaux lithotripteurs de contact. Methodes De janvier 2017 a avril 2018, nous avons teste prospectivement 2 lithotripteurs de contact successivement : urogold [44 patients : groupe 1 (g1)] puis dornier [34 patients : groupe 2 (g2)] selon 2 schemas therapeutiques distincts. Les criteres d’exclusions etaient : une taille de plaque > 4 cm, un retrecissement circonferentiel ou un antecedent de lec. L’âge median etait respectivement de 58 et 64 ans dans g1 et g2. Selon les recommandations du fabriquant, g1 recevait une seance unique de 3000 impacts et g2 recevait 4 seances de 4000 impacts. Nous avons analyse l’impact du traitement sur la douleur (evaluee par l’echelle visuelle analogique) et l’angulation de la verge en erection. Resultats Dans g1 : 25/44 patients (57 %) presentaient une douleur avant la lec et dans g2 : 14/34 (41 %). Une disparition complete a ete observee chez 18 patients (72 %) du g1 et 12 (86 %) du g2. Une diminution de la douleur a ete constatee pour 5 patients (20 %) de g1 et 1 (7 %) de g2. Une deformation significative prelec existait chez 36 patients de g1 (82 %) et 28 de g2 (82 %). Les proportions de patients avec une angulation de 10 a 40°, 40 a 70° et > 70° etaient de 48 %, 25 % et 9 % pour g1 et 29 %, 35 % et 17 % pour g2. Dans g1 et g2 respectivement : 12 (33 %) et 13 patients (46 %) presentaient une correction de 20° ; 8 (22 %) et 8 (29 %) presentaient une correction de 20 a 40°. Conclusion La lec est un traitement alternatif, non invasif, de la maladie de Lapeyronie, dont le benefice reste discute. Dans cette etude, qui n’avait pas pour but de comparer deux lithotripteurs, > 2/3 des patients presentaient une disparition complete de la douleur et > 50 % presentaient une amelioration d’angulation. Il reste a standardiser le schema therapeutique et realiser une etude comparant les lithotripteurs.

Introduction La granulomatose oro-faciale (GOF) est une inflammation chronique du visage se presentant sous la forme d’une tumefaction des tissus oro-faciaux atteignant de facon preferentielle les levres, secondaire a une infiltration granulomateuse sans necrose caseeuse. L’etiologie de la GOF est inconnue mais l’hypothese d’une localisation oro-faciale de la maladie de Crohn (MC) est fortement suspectee. L’objectif de ce travail etait de rapporter l’aspect clinique, para-clinique, genetique et therapeutique d’une serie de 29 patients atteints de GOF sans MC au diagnostic. Materiel et methodes Etude retrospective bicentrique. Etaient colliges : donnees demographiques, atteinte clinique, histologie, examens complementaires, traitements recus et leur efficacite. Un sequencage de 70 genes impliques dans la maladie de Crohn en technique New Generation Sequencing (NGS) est en cours chez 6 patients. Resultats La cohorte comportait 29 patients (9 hommes, 20 femmes) sans MC au diagnostic (âge moyen au diagnostic = 37,6 ans). Les caracteristiques etaient les suivantes : antecedent d’atopie = 38 %, antecedents de recurrences herpetiques = 21 %, œdeme indure labial = 100 % des cas (atteinte des deux levres = 31 %), erytheme labial = 48 %, atteinte peri-labiale erythemateuse ± infiltree = 38 % des cas ( Fig. 1 ), atteinte de la muqueuse buccale = 34 % des cas (hypertrophie et erytheme gingival, aspect pavimenteux des faces internes de joues, langue plicaturee). L’examen histologique trouvait un granulome sans necrose caseeuse dans 18 biopsies sur 28. Biologiquement, il existait 2 lymphopenies isolees et moderees, 7 cas d’elevation de l’enzyme de conversion de l’angiotensine, 2 cas d’hypergammaglobulinemie, 1 cas d’ASCA positifs, 1 cas de quantiferon positif sans tuberculose prouvee. Il n’y avait pas d’anomalies sur les 21 imageries thoraciques faites. Trois coloscopies sur les 9 realisees trouvaient des anomalies avec granulome a la biopsie. Divers traitements etaient donnes ( Fig. 2 ), les plus efficaces etaient les cyclines, la corticotherapie intra-lesionnelle ou systemique avec des reponses partielles a totales mais avec des rechutes. Deux remissions completes prolongees sous infliximab etaient constatees. Discussion Il s’agit de la 1ere serie francaise de GOF et la 1ere serie analysant l’efficacite therapeutique des divers traitements utilises. Les traitements les plus efficaces etaient la corticotherapie intra-lesionnelle et l’infliximab. Une etude recente trouvait des polymorphismes de NOD2 dans la GOF faisant evoquer un lien avec la MC. Une analyse par NGS est en cours chez nos patients. Conclusion Notre etude souligne l’efficacite potentielle de l’infliximab dans la GOF et les resultats d’analyse genetique en cours chez nos patients, permettront de conforter ou non l’hypothese d’un spectre entre MC et GOF.

Celiac disease (CD) is a chronic inflammatory enteropathy caused by the ingestion of gluten. A safe and efficient but unpleasant treatment exists for CD in form of a strict gluten-free diet. Thus, there is a need for new treatment strategies, which are based on the improved and advanced understanding of the pathophysiology of CD. The first strategy consists in reducing or even eliminating major antigenic motifs in gluten, responsible for the inflammatory reaction. The use of less immunogenic wheat was suggested but this seems rather difficult to realize. However, a complete digestion of the immunogenic parts of gluten looks very promising. This can be obtained by the use of polymers, capable to sequester gluten proteins or even better via the exogenous administration of propyl-endopeptidases, with two different enzymes under development. Another approach could be the use of inhibitors of tissue transglutaminase, a strategy which is under clinical investigation. Alternatively, inhibition of the site of liaison of immunostimulatory peptides with HLA molecules was suggested and is also under investigation in vivo. For patients suffering from refractory sprue, the inhibition of IL15 might be of therapeutic interest with the hope to improve the fatal outcome of many of these patients. However, the ultimate treatment approach is in form of prevention and the role of infectious agents, such as Rotavirus, in disease onset has to be considered.

Resume La muqueuse intestinale est protegee par un systeme lymphoide complexe. Les cellules effectrices sont les plasmocytes a IgA localises dans le chorion et les lymphocytes T distribues dans le chorion et l'epithelium. Ils proviennent de precurseurs sensibilises par les antigenes intraluminaux dans les plaques de Peyer. En outre, certains LT se differencient au contact de l'epithelium intestinal a partir de precurseurs medullaires. Le systeme immunitaire associe a l'intestin possede une double fonction de protection vis-a-vis des micro-organismes pathogenes et de regulation pour eviter des reponses immunitaires excessives et potentiellement deleteres lors de stimulations par des antigenes non pathogenes tels les proteines alimentaires.

Celiac disease is an enteropathy related to autoimmune diseases induced by gluten in genetically predisposed individuals. Its prevalence is of 1% in Europe and United States. Its clinical presentation is extremely various and diagnosis relies on the detection of specific serum antibodies and on the demonstration of intestinal villous atrophy. Treatment relies on a life-long gluten free diet which prevents bone, autoimmune and malignant complications. The keystone of its pathogenesis is the interaction of gliadin peptides with HLA DQ2/8 molecules, the main genetic risk factor, which induces the activation of CD4+ T-cells in the lamina propria. Yet, complementary mechanisms are necessary to provoke the loss of tolerance to gluten which involves the cytokine IL-15 responsible of the activation/expansion of intraepithelial lymphocytes, a hallmark of the origin of the severe lymphomatous complications. The burden of the gluten-free diet leads to a strong demand for alternative treatments. Numerous strategies have been identified to prevent the recognition of gliadin peptides by the immune system. Their efficiency and safety remained to be evaluated, the most attainable strategy today being oral therapy by enzymes able to eliminate gluten immunogenicity.

Objectifs Decrire les specificites de l’abord retroperitoneal d’une nephrectomie partielle droite laparoscopique assistee par robot Da-Vinci. Methodes Une tumeur renale exophytique de 2 cm de score RENAL et PADUA de 4/10 et 6/14 chez une patiente de 74 ans (IMC 31) a ete traitee par voie retroperitoenale robot-assistee. L’installation, la position des trocarts et du robot sont les points cles de l’intervention, dans cet espace de travail limite. L’abord direct du pedicule renal s’effectue par le reperage du muscle psoas, l’ouverture du fascia de Gerota puis le reperage de la veine cave. Une fois, artere et veine renale controlees, le rein est libere de sa graisse permettant d’acceder a la lesion puis d’effectuer la nephrectomie partielle apres clampage simple de l’artere renale. Resultats L’encombrement spatial du robot necessite des specificites dans le positionnement des trocarts. La sequence de l’intervention est ensuite la meme que celle utilisee en voie laparoscopique classique. La voie retroperitoneale a permis un acces direct premier au pedicule et a la partie posterieure du rein et ainsi realiser une tumorectomie sans decollement colique ni ouverture de la cavite abdominale. La duree de clampage vasculaire etait de 11 minutes avec des pertes sanguines negligeables. L’examen anatomopathologique a montre un carcinome renale papillaire Fuhrman 2, pT1aNxR0. Conclusion La nephrectomie partielle par voie laparoscopique retroperitoneale assistee par robot est une technique chirurgicale parfaitement adaptee pour les tumeurs renales posterieures. La standardisation de la technique permet a l’operateur et a son assistant d’optimiser les resultats carcinologiques avec un faible taux de complications.

Adult refractory sprue is a poorly defined disorder. We did a multicentre national study of patients with refractory sprue to characterise their clinical and pathological profile and outcome, and to assess the frequency and prognostic significance of phenotypic and molecular abnormalities in the intraepithelial T-cell population.Patients with severe symptomatic villous atrophy mimicking coeliac disease but refractory to a strict gluten-free diet, and with no initial evidence of overt lymphoma, were diagnosed at gastrointestinal referral centres between 1974 and 1998. Fixed and/or frozen duodenojejunal biopsy samples were reanalysed and immunostained with CD3 and CD8 monoclonal antibodies to find out the phenotype of intraepithelial lymphocytes (IEL). TCRgamma gene rearrangements were assessed on frozen biopsy samples by multiplex fluorescent PCR.There were 21 patients with refractory sprue and 20 controls with coeliacs disease. 16 (84%) of 19 assessed patients had an aberrant intraepithelial lymphoid intestinal population expressing intracytoplasmic CD3 but not surface CD8. Clonal intestinal TCRgamma gene rearrangements were found in 13 (76%) of 17 patients assessed; four (out of 12 assessed) had clonal dissemination to the blood. The 16 patients with an aberrant phenotype all had uncontrolled malabsorption; three subsequently developed overt T-cell lymphoma, and eight died. The three (16%) patients without aberrant clonal IEL made a complete clinical and histological recovery with steroid therapy plus a gluten-free diet.An immunophenotypically aberrant clonal intraepithelial T-cell population (similar to that of most cases of enteropathy-associated T-cell lymphoma) can be found in up to 75% of patients with refractory coeliac sprue; its identification by simple diagnostic techniques represents a marker of poor outcome (including occurrence of overt T-cell lymphoma). We suggest that refractory sprue associated with an aberrant clonal IEL may be the missing link between coeliac disease and T-cell lymphoma and may be classified as cryptic enteropathy-associated T-cell lymphoma.

We recently showed that refractory sprue is distinct from coeliac disease, the former being characterized by abnormal intraepithelial T-lymphocytes expressing a cytoplasmic CD3 chain (CD3c), lacking CD3 and CD8 surface expression, and showing TCRgamma gene rearrangements. To take advantage of the abnormal phenotype of CD3c + CD8 - intraepithelial lymphocytes (IEL) in refractory sprue we developed a simple method to distinguish coeliac disease from refractory sprue.Comparative immunohistochemical studies using anti-CD3 and anti-CD8 antibodies were applied on paraffin-embedded and frozen biopsy specimens in refractory sprue (n = 6), coeliac disease (n = 10), healthy controls (n = 5) and suspected refractory sprue (n = 6). Comparable results were obtained on fixed and frozen biopsy specimens. In four of the six patients with suspected refractory sprue, abnormal CD3c + CD8 - IEL and TCRgamma gene rearrangements were found, as in refractory sprue; the remaining two patients had normal (CD3 + CD8 +) IEL and no TCRgamma gene rearrangements. Both patients had coeliac disease, as one failed to comply with a gluten-free diet, while the other was a slow responder.This simplified immunostaining method using anti-CD3 and anti-CD8 antibodies on paraffin sections can distinguish active coeliac disease from refractory sprue and should prove useful in clinical practice.

We have previously demonstrated that anti-LFA-1 monoclonal antibody (mAb) can efficiently protect against rejection of small bowel allograft in a mouse model. The aim of the present work was to determine, in the same model, the optimum conditions for utilisation of anti-LFA-1 mAb and the effects of calcineurin-dependent drugs on the immunosuppression induced by anti-LFA-1 mAb treatment.Foetal small intestines of C57Bl/6 (H-2b) mice were transplanted into adult C3H/He (H-2k) mice. Recipients were treated with anti-LFA-1 mAb alone (with or without day-1 injection), or combined to cyclosporin (20 mg.kg-1.j-1 for 14 days), or to tacrolimus (1 mg.kg-1.j-1 from day 0 to day 7). Biopsies were performed after engraftment from day 5 to day 30.Administration of anti-LFA-1 mAb alone is sufficient to induce significant prolongation of intestinal allograft survival, provided that the treatment starts one day before engraftment. This tolerogenic effect is reversed by the transitory administration of tacrolimus (p = 0.008).Treatment with anti-LFA-1 mAb has to be started before the allogeneic response has begun. Calcineurin-dependent drugs can modulate the tolerogenic effect induced by anti-LFA-1. A transgenic mice model should give precise details about underlying mechanisms of these interactions, before a possible utilisation of anti-LFA-1 mAb in intestinal transplantation in humans.

Small bowel transplantation is still hampered by a high morbidity and mortality linked to the heavy non specific immunosuppression which is required by the transplantation of this lymphoid organ. Adhesion molecules appear to be potential targets for specific immunosuppression. The aim of the study was to investigate the effect of a transitory administration of anti-LFA-1 or anti-alpha 4 monoclonal antibodies (mAb) in the prevention of rejection in a model of fetal small-bowel transplantation in mice.The small bowel of C57BL/6 (H-2b) fetus (16 to 20 days of gestation) was transplanted into adult C3H/He mice (H-2k) or C57BL/6 recipient mice. Recipients were treated with a short course of either anti-LFA-1 mAb alone, either with anti-alpha 4 mAb alone, or with both mAb. Biopsies with histological study of the grafts were performed between post-operative day 5 and 60. A score of development and rejection was assigned to each sample.Normal intestinal development with no sign of rejection was observed in 24/28 syngenic grafts till post-operative day 45. In the absence of treatment, intense rejection was observed as soon as day 5 and all allogenic grafts were rejected (n = 22). In contrast, in anti-LFA-1 mAb treated mice, 18/20 allogenic grafts developed normally with minimal signs of rejection. In anti-alpha 4 treated mice, a transient protective effect on small bowel allograft survival was observed on day 7 but thereafter, all grafts were massively rejected within a few days (n = 18). The combination of both mAb didn't improve the survival of the grafts when compared to anti-LFA-1 mAb treated grafts (n = 10).These results demonstrate that a transitory administration of anti-LFA-1 mAb, but not of anti-alpha 4 mAb, is able to prolong significantly the survival of non vascularized small bowel fetal grafts in mice. Our results are promising for the possible use of the anti-LFA-1 mAb in clinical intestinal transplantation.

Langerhans cell histiocytosis (LCH) is a rare disease with a wide clinical spectrum. Although little is known of gastrointestinal involvement in LCH, it may be a major clinical problem. We investigated clinical, pathologic, and immunohistochemical features of digestive tract LCH involvement in children.Selection criteria consisted of the presence of LCH with digestive symptoms, and histologic confirmation of gastrointestinal involvement. Seven children (2%) met the criteria among 348 cases of LCH in a French national retrospective survey from 1983 to 1993. Two children whose LCH was diagnosed in 1994 were also selected.Nine children with LCH and digestive tract involvement were studied. Clinical features at presentation included skin (9/9) and mucosal (4/9) involvement, failure to thrive (5/9), diarrhea (7/9), bloody stools (4/7), vomiting (4/9), and hypoalbuminemia (8/9). Five of the nine children died; factors associated with a poor prognosis included young age, organ dysfunction (stage 4), and need for parenteral nutrition. Unlike control biopsy specimens, LCH cells of children with digestive tract involvement disclosed expression of the mucosal homing receptor integrin alpha 4 beta 7 on frozen skin and digestive tract biopsy specimens.Cutaneous, mucosal, and digestive tract involvement in LCH is a clinicopathologic entity. The prognosis and treatment of LCH depend on the extent of the disease; therefore the treatment of these disseminated forms should not be delayed. Thus children with cutaneous LCH and digestive symptoms should undergo digestive tract biopsies. Studies of homing receptors may contribute to our understanding of the mechanisms of dissemination in LCH.

Small intestinal transplantation would represent the best definitive treatment for patients who have short bowel syndrome following pathological conditions such as necrotizing enterocolitis or midgut volvulus. These patients are indeed dependent on long-term parenteral nutrition, which is associated with complications such as liver impairment and infections1.

Intractable diarrhoea can be defined as a severe syndrome of diarrhoea persisting over 1 month in spite of digestive rest and intravenous feeding. It is a rare syndrome, mainly observed in children. Miscellaneous causes have been identified. The aim of this chapter is to review immunological disorders responsible for intractable diarrhoea in children. The possible role of autoimmunity will be considered first, then the association of intractable diarrhoea and immunodeficiencies.

Monoclonal antibodies reactive with T cells, T cell subsets, B cells, monocytes, and natural killer cells were used to characterize the nature of mucosal lymphocytes in the human small intestine by application of the immunoperoxidase technique to tissue sections for light and electron microscopic examination. In addition, for comparison, peripheral blood mononuclear cells (PBL) were studied by immunoelectron microscopy. Most of the intraepithelial lymphocytes (IEL) were T cells (Leu-1+, T3+) and expressed the phenotype associated with cytotoxic/suppressor T cells (Leu-2a+, T8+). In contrast, a majority of T lymphocytes in the lamina propria expressed the phenotype associated with helper/inducer T cells (Leu-3a+, T4+). These observations confirm and extend the findings previously reported. In addition, a small number of cells in the lamina propria with the ultrastructural features of macrophages were found to react with anti-Leu-3a and anti-T4 antibodies. Although many IEL contained cytoplasmic granules and had ultrastructural features similar to those of circulating granular lymphocytes, none of these cells reacted with anti-Leu-7 (HNK-1), anti-T10, or anti-M1 antibodies. This suggests that IEL may not be related to circulating large granular lymphocytes, which are Leu-7+, T10+, M1+ and are associated with natural killer activity. Not only Leu-7+ PBL, but T8+, T4+, or T3+ mucosal lymphocytes or PBL also may contain cytoplasmic granules. Therefore, the cytoplasmic granules are not restricted to one cell type, in particular, to Leu-7+ cells.

We have demonstrated that although intestinal epithelial cells in fetuses and young rats do not express Ia antigens, in adult rats intestinal epithelial cells do express Ia antigens, as indicated by immunoperoxidase staining with monoclonal antibodies. Ia expression by intestinal epithelial cells appeared to be related to an increase in the number of intraepithelial lymphocytes (IEL). Most of the IEL were T cells and expressed the phenotype associated with cytotoxic/suppressor T cells, and a large number contained cytoplasmic granules. To directly study a possible modulating effect of IEL on intestinal epithelium, an Ia-negative intestinal epithelial cell line (IEC 17) of rat origin was cultured in the presence of supernatants obtained from Con A- or PHA-stimulated lymphocytes. IEL, as well as spleen cells but not bone marrow cells, were able to secrete a factor(s) capable of inducing Ia antigens on IEC 17 cells, as judged by immunoperoxidase staining and radioimmunoassay. Ia-positive IEC 17 cells were detectable after 12 hr and maximum Ia expression was obtained by 48-hr incubation. Persistence of Ia expression by intestinal epithelial cells required the continued presence of Ia-inducing factor in the medium. Lymphocyte proliferation was not essential for the secretion of the Ia-inducing factor(s). The characteristics and the kinetics of secretion of the Ia-inducing factor were similar to that of an interferon-like activity, but not of interleukin 2. Con A-induced supernatants from IEL and spleen cells were also capable of suppressing the growth of IEC 17 cells. The results of this study indicate that IEL, because of their close association with intestinal epithelial cells, may be involved in modulating a variety of epithelial cell functions, including the expression of Ia antigens. This leads us to speculate that Ia-positive epithelial cells, like Ia-positive macrophages and dendritic cells, may be involved in antigen presentation to T lymphocytes.

Demonstration of an increase in Acetylcholinesterase activity within the terminal nerves of the aganglionic segment in Hirschsprung's disease can provide a useful additional criterion to the diagnosis of this disease. The value as well as the limitations of this histochemical investigation, when performed on superficial suction biopsies, is evaluated. 135 rectal biopsies taken from 123 children were studied. In 28 biopsies performed on children with Hirschsprung's disease, the correct diagnosis was established in 19 cases suggested in 5 and missed in 2. Conversely in 107 control specimens, the results of the histochemical method were correctly negative on 97 occasions and falsely positive on 2.

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. Here, we conducted a genome-wide association study (GWAS) involving 1,554 cases/1,973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from the EPITHYR consortium. Our results confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 (rs334729) and 16q23.2 (rs16950982), which were associated with TSH levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. The frequency of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans and may explain part of the highest DTC incidence observed in Oceanians.Competing Interest StatementThe authors have declared no competing interest.Funding StatementINCA (grant number 9533) and ARC (grant number PGA120150202302), Ligue Nationale Contre le Cancer, Agence Nationale pour la Recherche (ANR), the Direction Generale de la Sante, the Agence Francaise de Securite Sanitaire de l alimentation, de lenvironnement et du travail (ANSES), CHILDTHYR EEC program, and the Fondation de France. JG and CX were the recipient of a PhD fellowship from Region Ile-de-France.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All participants provided informed consent and each study was approved by their governing ethics committee.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. (Less)

National audience; Modular Data Compression to Optimally Locate Regular Segments in Sequences. Application to DNA Sequence Analysis