A rare cause of peripheral arthralgia in inflammatory bowel disease: multifocal osteonecrosis.

Osteonecrosis (ON) is characterized by an infarction of osseous tissue in the subchondral regions of the bone. We report the case of a young male patient with ulcerative colitis (UC) developing severe and multifocal, large joint ON resulting in severe disability. Since typical symptoms of ON, like joint pain, might be misinterpreted as common extraintestinal manifestations, ON might easily be overlooked in patients with inflammatory bowel disease (IBD). Plain radiographs detect only advanced cases, MRI is the diagnostic method of choice with a specificity and sensitivity of > 90 %. We discuss the incidence of ON specifically in IBD and provide an update on risk factors like treatment with corticosteroids (CS), although ON has been reported in IBD patients without previous CS treatment. Apart from that, underlying inflammation, thromboembolic events and genetic risk factors might be involved in ON development supporting the hypothesis of a complex cascade. Causative therapies for ON are not available, and surgical interventions like trepanning, core decompression and prosthetic replacement are often necessary. Our intention is to direct attention to this severe complication in the differential work-up of joint pain in IBD patients.

UDCA slows down intestinal cell proliferation by inducing high and sustained ERK phosphorylation.

Ursodeoxycholic acid (UDCA) attenuates colon carcinogenesis in humans and in animal models by an unknown mechanism. We investigated UDCA effects on normal intestinal epithelium in vivo and in vitro to identify the potential chemopreventive mechanism. Feeding of mice with 0.4% UDCA reduced cell proliferation to 50% and suppressed several potential proproliferatory genes including insulin receptor substrate 1 (Irs-1). A similar transcriptional response was observed in the rat intestinal cell line IEC-6 which was then used as an in vitro model. UDCA slowed down the proliferation of IEC-6 cells and induced sustained hyperphosphorylation of ERK1/ERK2 kinases which completely inhibited the proproliferatory effects of EGF and IGF-1. The hyperphosphorylation of ERK1 led to a transcriptional suppression of the Irs-1 gene. Both, the hyperphosphorylation of ERK as well as the suppression of Irs-1 were sufficient to inhibit proliferation of IEC-6 cells. ERK1/ERK2 inhibition in vitro or ERK1 elimination in vitro or in vivo abrogated the antiproliferatory effects of UDCA. We show that UDCA inhibits proliferation of nontransformed intestinal epithelial cells by inducing a sustained hyperphosphorylation of ERK1 kinase which slows down the cell cycle and reduces expression of Irs-1 protein. These data extend our understanding of the physiological and potentially chemopreventive effects of UDCA and identify new targets for chemoprevention.

[Infectious enteritis]. / Enteritis infectiosa.

Infectious diarrhea belongs to the most frequent infections worldwide and can be elicited by a wide array of microbial pathogens. In developed countries transmission occurs much more frequently from contaminated food as compared to direct person-to-person contact, except for enteric viruses which can also be transmitted by aerosol formation after vomiting. In Germany, more than 90% of cases are caused by the four pathogens Norovirus, Rotavirus, Campylobacter and Salmonella. Therapy of infectious diarrhea is mainly supportive. In cases with a severe or prolonged course, signs of inflammation, bloody stool, immunosuppression, comorbidity and in suspected outbreaks, fecal microbial analysis should be performed and a specific therapy should be considered if indicated.

Diagnostic value of confocal endomicroscopy in celiac disease.

BACKGROUND: Improved endoscopic screening with targeted biopsies might enhance diagnostic yield in celiac disease. Confocal endomicroscopy (CEM) allows high-resolution in vivo histological analysis. We compared the endomicroscopic findings during ongoing endoscopy with the histological findings graded according to the Marsh classification. METHODS: Twenty-four patients with celiac disease and six patients with celiac disease that was refractory on a gluten-free diet were examined using CEM. The duodenal mucosa was evaluated by CEM and by conventional histological analysis in respect of villous atrophy, crypt hyperplasia, and increased numbers of intraepithelial lymphocytes (IELs > 40 / 100 enterocytes). The CEM results were assessed as to sensitivity, specificity, and interobserver variability. A Marsh classification score determined by CEM was compared to that obtained by histology. Thirty patients undergoing routine upper gastrointestinal endoscopy were used as controls. RESULTS: Conventional histology showed villous atrophy and crypt hyperplasia in 23 and increased numbers of IELs in 27 of the 30 patients with celiac disease. With CEM, villous atrophy, crypt hyperplasia, and increased IELs were respectively identified in 17, 12, and 22 of the 30 patients. The agreement of the findings on CEM with those of conventional histology was good in relation to villous atrophy (sensitivity 74 %) and increased numbers of IELs (sensitivity 81 %), but inadequate in relation to crypt hyperplasia (sensitivity 52 %). The kappa values for determination of interobserver variability were 0.90 for villous atrophy, 1.00 for crypt hyperplasia, and 0.84 for IEL detection. In the 30 control patients, normal duodenal architecture was found by both histology and endomicroscopy, indicating an overall specificity of 100 %. CONCLUSION: The assessment of duodenal histology by CEM in patients with celiac disease is sensitive and specific in determining increased numbers of IELs and villous atrophy, but insufficient in respect of crypt hyperplasia. For routine use of CEM in patients with celiac disease, the technique would need to be improved.

ZM447439, a novel promising aurora kinase inhibitor, provokes antiproliferative and proapoptotic effects alone and in combination with bio- and chemotherapeutic agents in gastroenteropancreatic neuroendocrine tumor cell lines.

BACKGROUND: Therapeutic approaches to gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still not satisfactory. A new direction in treatment options could be the novel aurora kinase inhibitor ZM447439, which was previously reported to interfere with the mitotic spindle integrity checkpoint and chromosome segregation, but does not interfere with other kinases when used up to 5 muM. METHODS: We evaluated the antineoplastic effects of ZM447439 on growth and apoptosis of the GEP-NET cell lines BON, QGP-1 and MIP-101, representing the different malignant tumor types, using standard cell biological tests as crystal violet assays, caspase activation, DNA fragmentation and cell cycle analysis. RESULTS: ZM447439 dose-dependently inhibited proliferation of all three cell lines with IC(50) values in the nanomolar to low micromolar range. Moreover, aurora kinase inhibition by ZM447439 potently induced apoptosis, which was accompanied by DNA fragmentation and caspase 3 and 7 activation. Furthermore, we observed cell cycle arrest at G(0)/G(1) phase as well as a block in G(2)/M transition. In addition, combined treatment with the chemotherapeutic agents streptozocin and cisplatin augmented significantly the antiproliferative effects of those agents. CONCLUSION: Aurora kinase inhibition by ZM447439 seems to be a promising new therapeutic approach in GEP-NETs, which should be evaluated in further clinical trials.

Use of methotrexate in patients with inflammatory bowel diseases.

Methotrexate (MTX) is one of the immunosuppressants commonly used in inflammatory bowel diseases. There is very good evidence for its use in patients with steroid-dependent or steroid-refractory Crohn's disease for induction as well as maintenance of remission. Optimal dose as well as mode of application is still a matter of debate. The only large randomised controlled trials used 25 mg/wk for induction and 15 to 25 mg/wk for maintenance of remission, both applied intramuscularly. Current guidelines recommend methotrexate in patients with extensive disease, steroid-refractory, and steroid-dependent disease. They even suggest MTX for patients with infrequent relapses in the need of repetitive corticosteroid therapy. In clinical practice it is mainly used in patients who failed treatment with thiopurines (azathioprine or 6-mercaptopurine) or who are intolerant to these drugs. MTX can also be used in paediatric patients, whereas the evidence for its effectiveness in fistulising disease is very weak. Two small studies did not prove that MTX is efficacious in ulcerative colitis. Even though case series suggest otherwise, its use is not recommended by current guidelines for patients with ulcerative colitis.

Immune modulation by non-hodgkin lymphoma in a patient with two primary intestinal T-cell lymphomas and long-standing celiac disease.

Tumors may influence immunologic reactions. Here, we report on a 72-year-old patient who suffered from celiac disease (CD) that had been diagnosed 20 years before. Under a normal diet but without any evidence of enteropathy or CD-associated antibodies, the patient developed a jejunal T-cell lymphoma. It was resected due to perforation and four courses of IMVP-16 were added. The patient started and kept a strict gluten-free diet (GFD). Two years later, he presented with weight loss and a clonally divergent refractory sprue type II with loss of antigen (CD8; T-cell receptor-beta) expression in intraepithelial lymphocytes. At this time point, he showed high titers of CD-associated antibodies, although he was on a strict GFD. This case report highlights several questions: the missing enteropathy under a gluten-containing diet supports the notion of immune suppression in malignant diseases, especially non-Hodgkin lymphoma. Secondly, the patient developed an early form of a second independent T-cell lymphoma (refractory sprue type II) under a strict GFD, then with CD-associated antibodies, which raises the question whether the clonal intraepithelial lymphocytes were stimulating antibody production. Thus, the single detection of CD-associated antibodies in patients with CD is not itself proof of noncompliance with GFD.

[What has been confirmed in the treatment of inflammatory bowel disease?]. / Was ist gesichert in der Therapie chronisch entzündlicher Darmerkrankungen?

The therapy of inflammatory bowel diseases is currently guided by clinical variables. An escalation of immunosuppressive therapy is required in case of treatment failure. However, clinical remission does not necessarily imply mucosal healing. In parallel to the treatment of rheumatoid arthritis a novel concept is emerging suggesting that an early anti-inflammatory treatment can reduce structural changes in inflammatory bowel diseases. The studies supporting this novel therapeutic strategy that mucosal healing might build the future therapeutic goal will be discussed. In order to adjust the therapy, risk factors indicating a complicated disease course will be identified, resulting in the development of an individual disease course. The benefit of these strategies will be discussed together with therapy-associated complications.

[New therapeutic approaches to special diseases of the small intestine]. / Neue therapeutische Ansätze bei speziellen Erkrankungen des Dünndarms.

Numerous reports on fundamental research and clinical studies have appeared in the past 1-2 decades which have contributed decisively to understanding inflammatory diseases of the small intestine. Illustrated by the examples of Crohn's disease, celiac disease, refractory sprue, and Whipple's disease, the rationale and evidence for treatment approaches are presented that are based on these pathophysiological findings. Emphasis is placed on modulation of the intestinal flora with antibiotics and probiotics as well as immunomodulatory/immunosuppressive measures with so-called biological agents. Future treatment options that directly intervene in the disease process are discussed.

Structural and functional changes of the duodenum in human norovirus infection.

BACKGROUND: Norovirus infection is the most frequent cause of infectious diarrhoea in the western world. This study aimed to characterise functionally and histomorphologically the diseased duodenum in human biopsies. METHODS: Norovirus infection was diagnosed by the Kaplan criteria and confirmed by PCR of stool samples. Duodenal biopsies were obtained endoscopically. In miniaturised Ussing chambers, short circuit current, flux measurements and impedance spectroscopy were performed. Histological analysis including apoptosis staining and characterisation of intraepithelial lymphocytes was performed. Tight junction proteins were quantified by immunoblotting. RESULTS: In norovirus infection, epithelial resistance decreased from (mean (SEM)) 24 (2) Omega cm(2) in controls to 10 (1) Omega cm(2). Mannitol flux increased from 113 (24) nmol h(-1) cm(-2) in controls to 242 (29) nmol h(-1) cm(-2). Microdissection revealed a villus surface area reduced by 47% (6.6%). Intraepithelial lymphocytes were increased to 63 (7) per 100 enterocytes, with an increased rate of perforin-positive cytotoxic T cells. Expression of tight junctional proteins occludin, claudin-4 and claudin-5 was reduced. The epithelial apoptotic ratio was doubled in norovirus infection. Furthermore, the basal short circuit current was increased in norovirus infection and could be reduced by bumetanide and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). CONCLUSIONS: Norovirus infection leads to epithelial barrier dysfunction paralleled by a reduction of sealing tight junctional proteins and an increase in epithelial apoptosis, which may partly be mediated by increased cytotoxic intraepithelial lymphocytes. Furthermore, active anion secretion is markedly stimulated. Thus, the diarrhoea in norovirus infection is driven by both a leak flux and a secretory component.

Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients.

BACKGROUND AND AIMS: Impairment of the gastrointestinal mucosal barrier contributes to progression of HIV infection. The purpose of this study was to investigate the effect of highly active antiretroviral therapy (HAART) on the HIV-induced intestinal barrier defect and to identify underlying mechanisms. METHODS: Epithelial barrier function was characterised by impedance spectroscopy and [(3)H]mannitol fluxes in duodenal biopsies from 11 untreated and 8 suppressively treated HIV-infected patients, and 9 HIV-seronegative controls. The villus/crypt ratio was determined microscopically. Epithelial apoptoses were analysed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL) and caspase-3 staining. Tight junction protein expression was quantified by densitometric analysis of immunoblots. Mucosal cytokine production was determined by cytometric bead array. RESULTS: Only in untreated but not in treated HIV-infected patients, epithelial resistance was reduced (13 (1) vs 23 (2) ohm cm(2), p<0.01) and mannitol permeability was increased compared with HIV-negative controls (19 (3) vs 9 (1) nm/s, p<0.05). As structural correlates, epithelial apoptoses and expression of the pore-forming claudin-2 were increased while expression of the sealing claudin-1 was reduced in untreated compared with treated patients and HIV-negative controls. Furthermore, villous atrophy was evident and mucosal production of interleukin 2 (IL2), IL4 and tumour necrosis factor alpha (TNFalpha) was increased in untreated but not in treated HIV-infected patients. Incubation with IL2, IL4, TNFalpha and IL13 reduced the transepithelial resistance of rat jejunal mucosa. CONCLUSIONS: Suppressive HAART abrogates HIV-induced intestinal barrier defect and villous atrophy. The HIV-induced barrier defect is due to altered tight junction protein composition and elevated epithelial apoptoses. Mucosal cytokines are mediators of the HIV-induced mucosal barrier defect and villous atrophy.

Comparative analysis of mononuclear cells isolated from mucosal lymphoid follicles of the human ileum and colon.

Studies of human mucosal lymphoid follicles are rare and have been limited to children's Peyer's patches, which are visible at endoscopy. We investigated lymphoid follicles in ileum biopsies of 87 patients and surgical colon specimens from 66 cancer patients, and examined phenotype and function of isolated follicular immune cells. Two (0-10) and 12 (0-117) follicles per patient were found in ileum and colon samples respectively (P < 0.001). The number of lymphoid follicles mononuclear cells (LFMC) that could be isolated per patient was higher from colon compared with ileum specimens [725 000 (0-23 Mio) versus 100 000 (0-1.3 Mio), P < 0.001]. T cells were predominant in both LFMC and lamina propria mononuclear cells (LPMC), but B cells were more and plasma cells less frequent in LFMC. T cells from mucosal follicles were more frequently CD4-positive and CD62L-positive, but less frequently CD8-positive, CD103-positive and CD69-positive than lamina propria T cells. LFMC from ileum compared with colon showed no differences in mononuclear cell composition. Anti-CD3/CD28 stimulation induced similar proliferation of LFMC and LPMC from ileum and colon, as well as secretion of high levels of interferon-gamma, tumour necrosis factor-alpha and interleukin (IL)-2, but lower levels of IL-4, IL-6 and IL-10. LFMC from colon secreted more IL-2 than those from ileum. Our study shows that mucosal lymphoid follicles can be identified clearly in adult human colon and yield viable immune cells sufficient for phenotypical and functional analysis. The cellular composition of LFMC from ileum and colon is similar, and both secrete predominantly T helper type 1 cytokines.

In vivo diagnosis of acute intestinal graft-versus-host disease by confocal endomicroscopy.

BACKGROUND AND STUDY AIMS: Conventional histology with hematoxylin and eosin (H&E) staining is the accepted standard for diagnosing acute intestinal graft-versus-host disease (GvHD). Confocal endomicroscopy (CEM) is a noninvasive method that allows in vivo histology to be performed during endoscopy. The aim of this study was to evaluate CEM for the diagnosis of acute intestinal GvHD. PATIENTS AND METHODS: This observational pilot study conducted between September 2006 and August 2008 included patients with acute diarrhea after stem cell transplantation, infectious diarrhea, or active ulcerative colitis. CEM (EC-3870CIFK, Pentax, Tokyo, Japan) was performed after intravenous injection of fluorescein 10% and topical application of acriflavine 0.05%. RESULTS: A total of 35 patients with acute diarrhea after stem cell transplantation were examined. In 16 patients, CEM and histology showed no evidence of GvHD. In 14/19 patients with histologically confirmed GvHD, the diagnosis could already be established by CEM during ongoing endoscopy. In GvHD grade IV, near complete destruction of the colonic crypts ("flat mucosa") was visible. Control patients with infectious colitis (N = 15) or ulcerative colitis (N = 15) displayed inflammatory changes but no evidence of GvHD. Altogether, sensitivity of CEM was 74% and specificity was 100 %. CONCLUSIONS: CEM improves rapid diagnosis of acute intestinal GvHD with high accuracy while performing endoscopy. Platelet transfusions and unnecessary biopsy acquisition can be avoided once acute intestinal GvHD has been diagnosed in vivo.

In vivo proliferation of rat lamina propria T lymphocytes: general hyporesponsiveness but increased importance of the CD2 and CD28 pathways.

Lamina propria T lymphocytes (LPL-T) have a low proliferative potential in vitro. We asked whether LPL-T are also hyporesponsive in vivo and whether this is specific for the alphabeta T cell receptor (TCR). Mitogenic mAb directed at the alphabeta TCR, CD2, CD28, or control mAbs plus IL-2 were injected into rats. Proliferation and/or apoptosis were detected by double staining using 5-bromo-2'-deoxyuridine/TUNEL and the alphabeta TCR. LPL-T were hyporesponsive to various stimuli compared to other T cells. The strongest proliferation was found upon CD2/CD28 stimulation (LPL-T: 281 +/- 6%; spleen: 642 +/- 31%). LPL-T proliferation was only detectable at 24 h while proliferation in other compartments also occurred later. Hyporesponsiveness was not caused by enhanced T cell apoptosis upon alphabeta TCR stimulation. In conclusion, stimulation of LPL-T results in much shorter and weaker in vivo proliferation than in other lymphoid organs. Overall, CD2/CD28 costimulation is the strongest T cell stimulus in vivo.

Ciprofloxacin-related acute severe myalgia necessitating emergency care treatment: a case report and review of the literature.

OBJECTIVE: To report a case of an uncommon and up to date unpublished peracute and overwhelming muscle pain following administration of ciprofloxacin. CASE SUMMARY: A 58-year-old male developed fulminating musculoskeletal pain associated with third-time exposure to ciprofloxacin administered for treatment of chronic otitis media. Symptoms resolved slowly after intense combined analgetic therapy and cessation of ciprofloxacin therapy. 24 h after ciprofloxacin discontinuation the symptoms had completely disappeared and no more analgetic treatment was needed. Laboratory values, especially muscle enzymes, did not reveal any pathological pattern. The patient's past medical history highlighted reproducible side effects with both systemic and local administration of ciprofloxacin including milder symptoms of the musculoskeletal system. DISCUSSION: Common side effects of fluoroquinolones include gastrointestinal, central nervous and allergic reactions, but also more uncommon reactions such as tendonitis and rhabdomyolysis. In our case, there had been no signs of rhabdomyolysis. Besides an elevated IgE level no clinical signs of a true anaphylactic reaction associated with release of mast cell mediators had been observed. A pharmacokinetic interaction between ciprofloxacin and the patient's comedication carbamazepine is unlikely to be the responsible mechanism, since fluoroquinolones inhibit cytochrome P450 isoenzyme CYP1A2 but not CYP3A4 which metabolizes carbamazepine. CONCLUSION: To our knowledge, this is the first report describing fulminating musculoskeletal pain following administration of ciprofloxacin without any signs of rhabdomyolysis. Physicians should notice that there is a variety of adverse reactions of this usually well-tolerated agent and they should be aware of unusual complaints of their patients who receive fluoroquinolone treatment.

[Inflammatory bowel disease and pregnancy]. / Chronisch entzündliche Darmerkrankungen und Schwangerschaft.

Inflammatory bowel disease (IBD) affects mainly young people who are often in the process of family planning. Insecurity of patients and their primary physicians concerning the disease course and the appropriate medication is often followed by a decision against the pregnancy. With this overview these central issues will be discussed and practical guidelines will be provided, thus encouraging both sides, that IBD and pregnancy is compatible.

[Fever of unknown origin in gastroenterology]. / Fieber unklarer Genese in der Gastroenterologie.

The gastrointestinal tract may be of major clinical or diagnostic importance in fever of unknown origin. To the classical diseases in this sense belong very different diseases as Whipple's disease, Familiar Mediterranean Fever, isolated mesenterial vasculitis, and manifestations of immune reconstitution inflammatory disease, but also unusual manifestations of otherwise easily recognized diseases like special forms of celiac disease, or inflammatory bowel disease. Endoscopical techniques to obtain biopsies for diagnostic procedures are frequently crucial to solve the diagnostic puzzle. In some cases the bioptic material may not be sufficient to reach a diagnosis and further surgical intervention is necessary (intestinal lymph-nodes or bowel resections) to acquire enough tissue for a definite diagnosis. Nevertheless using these different approaches in most cases of fever of unknown origin the underlying cause can be identified which for many patients means not more or less than significant improvement or even survival.

Histone deacetylases: novel targets for prevention of colitis-associated cancer in mice.

OBJECTIVE: Inhibition of histone deacetylases, well known for its antiproliferative efficacy in vivo, was recently shown to ameliorate inflammation in experimental colitis. Since inflammatory bowel disease is associated with an increased risk of developing colon cancer, here the combined anti-inflammatory and proapoptotic efficacy of histone deacetylase inhibitors was studied in mouse models. METHODS: The novel histone deacetylase inhibitor ITF2357 was compared with suberoylanilide hydroxamic acid in models of experimental colitis. Effects on tumour growth were studied after treatment of mice with azoxymethane and dextran sulphate sodium, and in interleukin 10 (IL10) knockout mice, respectively. Possible underlying mechanisms involving apoptosis and nuclear factor (NF)-kappaB activation were addressed by flow cytometry and western blot. RESULTS: In dextran sulphate sodium- and trinitrobenzene sulphonic acid-induced colitis, treatment with ITF2357 was superior to suberoylanilide hydroxamic acid as shown by macroscopic and histological amelioration of inflammation, by reduced production of interferon gamma (IFN gamma) and by increased production of IL10. In both models of inflammation-mediated tumourigenesis, inhibition of histone deacetylases resulted in a significant suppression of tumour growth in terms of size and number, along with reduced signs of inflammation. As for potential mechanisms of ITF2357 action, increased acetylation of histone 3, reduced production of IFN gamma and enhanced apoptosis in lamina propria mononuclear cells were found to accompany a histone deacetylase-dependent activation of NF-kappaB. CONCLUSIONS: These results indicate that inhibition of histone deactylases can attenuate inflammation-mediated tumour growth, which is paralled by an inhibition of NF-kappaB. Thus histone deacetylase inhibitors provide a promising strategy that combines anti-inflammatory and proapoptotic modes of action.

Mechanisms of epithelial translocation of the alpha(2)-gliadin-33mer in coeliac sprue.

BACKGROUND AND AIMS: The alpha(2)-gliadin-33mer has been shown to be important in the pathogenesis of coeliac disease. We aimed to study mechanisms of its epithelial translocation and processing in respect to transcytotic and paracellular pathways. METHODS: Transepithelial passage of a fluorescence-labelled alpha(2)-gliadin-33mer was studied in Caco-2 cells by using reverse-phase high-performance liquid chromatography, mass spectrometry, confocal laser scanning microscopy (LSM) and fluorescence activated cell sorting (FACS). Endocytosis mechanisms were characterised with rab-GFP constructs transiently transfected into Caco-2 cells and in human duodenal biopsy specimens. RESULTS: The alpha(2)-gliadin-33mer dose-dependently crossed the epithelial barrier in the apical-to-basal direction. Degradation analysis revealed translocation of the 33mer polypeptide in the uncleaved as well as in the degraded form. Transcellular passage was identified by confocal LSM, inhibitor experiments and FACS. Rab5 but not rab4 or rab7 vesicles were shown to be part of the transcytotic pathway. After pre-incubation with interferon-gamma, translocation of the 33mer was increased by 40%. In mucosal biopsies of the duodenum, epithelial 33mer uptake was significantly higher in untreated coeliac disease patients than in healthy controls or coeliac disease patients on a gluten-free diet. CONCLUSION: Epithelial translocation of the alpha(2)-gliadin-33mer occurs by transcytosis after partial degradation through a rab5 endocytosis compartment and is regulated by interferon-gamma. Uptake of the 33mer is higher in untreated coeliac disease than in controls and coeliac disease patients on a gluten-free diet.