Innate immune system: The no man’s land where discover new biomarkers for gluten-related-disorders.

Roberto Assandri, Marta Monari, Anna Colombo, Alessandro Montanelli

Gastroenterology and Hepatology from Bed to Bench, Vol. 8 No. 2 (2015), 17 Esfand 2015, Page Gastroenterol Hepatol Bed Bench 2015;8(2):95-98

Celiac disease (CD) is now considered a multiple and systemic immune-mediate disorder triggered by the ingestion of wheat gluten and related proteins. Following the discovery of a link between gluten and CD, it was demonstrated that gliadin, one of the two principal protein groups comprising gluten, plays a key role in CD. It has since become clear that the different and crucial roles of gliadin in CD result from its ability to activate multiple signaling pathways that modulate CD pathology. Most of these pathways involve the host innate and adaptive immune responses, but some pathways are activated when gliadin interacts with the intestinal cellular compartment.

It is also evidence that a common “wooden horse” of CD and  Non-Celiac Gluten Sensitivity (NCGS)  is the ingestion of gluten and related toxic peptides.

This review cover the current knowledge of immunological and inflammatory process involved in gluten related disorders, in an attempt to track down a marker in the “no man's land” of NCGS biomarkers.

Review Article

Mucosal histopathology in coeliac disease: a rebuttal of Oberhuber’s sub-division of Marsh III

Michael N Marsh, Matt W Johnson, Kamran Rostami

Gastroenterology and Hepatology from Bed to Bench, Vol. 8 No. 2 (2015), 17 Esfand 2015, Page Gastroenterol Hepatol Bed Bench 2015;8(2):99-109

Individuals with particular genetic backgrounds develop immune responses to wheat proteins and become ‘gluten-sensitised’. Mucosal pathology arises through activated mucosal T lymphocytes, resulting in a graded, adverse e reaction between particular genes and wheat proteins. Given these varied influences, the Marsh Classification broadly itemises those stages through which a normal mucosa (Marsh 0) evolves in becoming ‘flat’ (Marsh I, II, III).

Recently, Oberhuber and colleagues suggested that Marsh III lesions required subdividing into a, b, c categories. We critically examined these subdivisions by means of correlative light and scanning electron microscopy (SEM). Our results demonstrate that Oberhuber’s classification is untenable. In our view deriving from our observations, the artificial subdivisions proposed by those authors actually reflect misinterpretations of the true architectural contours of flat mucosae. Although these workers refer to “villous projections”, SEM demonstrates that no such structures are present on flat - or immediately recovering – mucosae.

Our data revealed on the surfaces of flat (Marsh III) mucosae, large open “basins”, surrounded by raised collars - the latter, when viewed in histological section, being easily misconstrued as “villi”. It seems that with subsequent upward growth, these collars coalesce into low ridges, thence becoming broader and higher convolutions.  It is noticeable that there are more open spaces on the surfaces of flat mucosae than was appreciated hitherto.

We conclude that Oberhuber’s revisions of Marsh III into three subcategories (a, b, c), are misinterpretations of the histological appearances of flattened mucosae. Therefore, these subcategories should be resisted by histopathologists when classifying celiac mucosae, since they add nothing either of diagnostic, nor prognostic, value.

Seronegative celiac disease: Where is the specific setting?

Enzo Ierardi, Giuseppe Losurdo, Domenico Piscitelli, Floriana Giorgio, Claudia Sorrentino, Mariabeatrice Principi, Lucia Montenegro, Annacinzia Amoruso, Alfredo Di Leo

Gastroenterology and Hepatology from Bed to Bench, Vol. 8 No. 2 (2015), 17 Esfand 2015, Page Gastroenterol Hepatol Bed Bench 2015;8(2):110-116

The diagnosis of Celiac Disease (CD) relies on the concordance of pathological, serological, genetic and clinical features. For this reason, the diagnosis of CD is often a challenge. Seronegative celiac disease (SNCD) is defined by the negativity of anti-tissue transglutaminase antibodies in the presence of a positive histology on duodenal biopsy samples, i. e. inflammatory infiltrate of intra-epithelial lymphocytes (IELs > 25/100 enterocytes), mild villous atrophy and uneven brush border associated to human leukocyte antigen (HLA) haplotype DQ2 and/or DQ8.

SNCD is characterized by mucosal deposits of tissue transglutaminase (tTG)/anti-tTG immuno-complexes. These may counteract the passage of anti-tTG into the bloodstream, thus explaining seronegativity. Another reason for seronegativity may be found in an incomplete maturation of plasma cells with a consequent failure of antibodies production. This condition often characterizes immunoglobulin deficiencies, and, indeed, SNCD is common in subjects with immunoglobulin deficiencies.

The management of SNCD still remains debated. The treatment option for SNCD may be represented by gluten free diet (GFD), but the usefulness and appropriateness of prescribing GFD are controversial. Some evidences support its use only in SNCD subjects showing CD clear clinical picture and compatible HLA status. The choice of GFD administration could be linked to an investigation able to diagnose SNCD in no doubt even if a reliable test is not currently available. On these bases, a test helping the diagnosis of SNCD is justifiable and desirable.

Th17, Intestinal microbiota and the abnormal immune response in the pathogenesis of Celiac Disease

Clelia Cicerone, Raffaella Nenna, Stefano Pontone

Gastroenterology and Hepatology from Bed to Bench, Vol. 8 No. 2 (2015), 17 Esfand 2015, Page Gastroenterol Hepatol Bed Bench 2015;8(2):117-122

Celiac disease (CD) is an autoimmune enteropathy induced by the ingestion of gluten in genetically predisposed individuals who carry the HLA DQ2 or DQ8 alleles. The etiology is multifactorial involving genetic and environmental factors, immune response, and intestinal dysbiosis. The innate and acquired T-cell mediated immunity play important roles in the pathogenesis of this disease, particularly CD4+ Th17 cells, which have been shown to have critical functions in host defense against bacterial pathogens and in the inflammatory responses to deamidated gluten peptides. We review what is known about the interaction between immune system and intestinal microbiota in the pathogenesis of celiac disease.

The relation between intestinal parasites and some immune-mediated intestinal condition

Rasoul Mohammadi, Ahmad Hosseini-Safa, Mohammad Javad Ehsani Ardakani, Mohammad Rostami-Nejad

Gastroenterology and Hepatology from Bed to Bench, Vol. 8 No. 2 (2015), 17 Esfand 2015, Page Gastroenterol Hepatol Bed Bench 2015;8(2):123-131

The main inflammatory bowel disorders are including celiac disease (CD), inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS). Celiac disease is a digestive and autoimmune disorder that can damage the small intestine and characterized by a multitude gastrointestinal (GI) and extra GI symptoms. IBD (including ulcerative colitis and Crohn’s disease) is a group of inflammatory conditions of the small intestine and colon. The etiology of IBD is unknown, but it may be related to instability in the intestinal microflora that leading to an immoderate inflammatory response to commensal microbiota. Irritable bowel syndrome (IBS) is a common, long-term condition of the digestive system. Bloating, diarrhoea and/or constipation are nonspecific symptoms of IBS. Various studies have shown that some intestinal parasites can effect on immune system of infected hosts and in some cases, they are able to modify and change the host’s immune responses, particularly in autoimmune disorders like celiac disease and IBD. The main objective of this review is to investigate the relationship between intestinal parasites and different inflammatory bowel disorders

Original Article

Phenotypical characterization of the peripheral blood T cells in the patients with celiac disease: Does it differentiate suspicious Celiac disease cases?

Hadi Hossein Nataj Arab, Mohsen Masjedi, Fereshteh Alsahebfosoul, Mojgan Mokhtari, Nahid Jamali, Mohammad Hassan Emami, Ali Saffaei

Gastroenterology and Hepatology from Bed to Bench, Vol. 8 No. 2 (2015), 17 Esfand 2015, Page Gastroenterol Hepatol Bed Bench 2015;8(2):132-139

Background: Celiac disease (CD) is a small bowel enteropathy caused by permanent wheat gluten intolerance. One of the earliest signs of the mucosal immune activation in CD is an increase in the intestinal intraepithelial lymphocytes (iIELs) count in the small intestinal epithelium. Although most of those iIELs express ??TCR, CD is characterized by an increase in the gdTCR+ iIELs.

Objective: The present study aimed to establish whether these immunological changes seen in the intestinal epithelium of CD patients could also be detected in the peripheral blood lymphocytes with special emphasis on the gdTCR+ T cells.

Patients and Method: In this case-control study, totally 29 subjects with acceptable criteria and without any complication who referred to the Al-Zahra Hospital, Isfahan, Iran, were selected. Peripheral blood T cells were analyzed by two color flow cytometry in 13 untreated patients with CD and 16 healthy control subjects.

Results: The mean age of patients was 33.6±3.4 years old and two patients had MARSH IIIB, five patients had MARSH IIIA and six patients had MARSH II histology class. The mean percentages of the gdTCR+ T cells in the patients were significantly higher than the controls (P = 0.015). However, the mean percentages of the ??TCR+ T cells were significantly lower in the untreated patients than the controls (P = 0.025). There were no significant difference between the mean percentages of lymphocytes expressing the CD3, CD4 and CD8 molecules in the patients and the controls.

Conclusion: The change in the percentages of the peripheral blood T cells expressing the ??TCR and ??TCR in the celiac patients could be used in conjunction with the other serological markers to confirm the CD cases and these findings may lead to better understanding of the CD immunpathogenesis.

Key words: Celiac disease; T-Lymphocytes; Blood; Flow cytometry; Iran

Is it necessary to screen for celiac disease in idiopathic osteoporosis?

Bijan Shahbazkhani, Najmeh Aletaha, Ahmad khonche, Benyamin Farahvash, Reza Malekzadeh

Gastroenterology and Hepatology from Bed to Bench, Vol. 8 No. 2 (2015), 17 Esfand 2015, Page Gastroenterol Hepatol Bed Bench 2015;8(2):140-145


Aim: the aim of this study was to investigate that the necessity of screening for celiac disease in idiopathic osteoporotic patients.

Background: Osteopenia and osteoporosis are well-known and prevalent complications of celiac disease. However, the relative prevalence of celiac disease among osteoporotic populations is not known, and the benefit of screening for celiac disease among the osteoporotic population remains controversial.

Patients & methods: We evaluated 560 individuals, 460 with osteoporosis and 100 healthy subjects, from the rheumatology clinic in Imam Khomeini and Shariati Hospital by IgA anti tissue transglutaminase (anti-tTG) for celiac disease. Then individuals with positive serologic test underwent upper GI Endoscopy & 2nd part duodenum biopsies. The clinical findings were evaluated in the both groups and were compared with each other.

Results: Five (?1%) of 460 patients with osteoporosis and 1 (1%) of 100 subjects without osteoporosis had celiac disease by positive serologic & pathology results. Three patients with positive serology & pathology results were female. All patients in osteoporotic group had at least one other symptom of celiac disease. Two of them had anemia and others had chronic abdominal pain, recurrent oral aphtous lesion & chronic bloating.

Conclusions: In the present study, the prevalence of celiac disease in osteoporotic patients is not high enough to justify recommendation for serologic screening of celiac disease in all patients with idiopathic osteoporosis; but in osteoporotic patients with other celiac or gastrointestinal symptoms and signs for example iron deficiency anemia, chronic dyspepsia and bloating, constipation or diarrhea and recurrent aphtous lesions, it is necessary to evaluate for celiac disease.

Key words: Celiac Disease, Osteoporosis, IgA anti tissue transglutaminas

Clinical and immunological relevance of anti-neuronal antibodies in celiac disease with neurological manifestations

Giacomo Caio, Roberto De Giorgio, Alessandro Venturi, Fiorella Giancola, Rocco Latorre, Elisa Boschetti, Mauro Serra, Eugenio Ruggeri, Umberto Volta

Gastroenterology and Hepatology from Bed to Bench, Vol. 8 No. 2 (2015), 17 Esfand 2015, Page Gastroenterol Hepatol Bed Bench 2015;8(2):146-152


Aim: To assess anti-neuronal antibodies (NA) prevalence and their correlation with neurological disorders and bowel habits in celiac disease (CD) patients.

Background: Neurological manifestations are estimated to occur in about 10% of celiac disease patients and NA to central nervous system (CNS) and enteric nervous system (ENS) are found in a significant proportion of them. Little is known about the clinical and immunological features in CD patients with neurological manifestations.

Patients and Methods: NA to CNS and ENS were investigated in 106 CD patients and in 60 controls with autoimmune disorders by indirect immunofluorescence on rat / primate cerebellar cortex and intestinal (small and large bowel) sections.

Results: IgG NA to CNS (titer 1:50 - 1:400) were positive in 23 celiacs (21%), being more frequently detected in those with neurological disorders that in those without neurological dysfunction (49% vs. 8%, P< 0.0001). Of the 26 celiacs (24%) with IgG NA to ENS, 11 out of 12 with an antibody titer > 1:200 had severe constipation. Only one patient with cerebellar ataxia and intestinal sub-occlusion was positive for NA to CNS and ENS. NA to CNS and ENS were found in 7% and 5% of controls, respectively.

Conclusions: In CD the positivity of NA to CNS can be regarded as a marker of neurological manifestations. High titer NA to ENS are associated with severe constipation. The demonstration of NA to CNS and ENS suggests an immune-mediated pathogenesis leading to central neural impairment as well as gut dysfunction (hence constipation), respectively.

Serologic evaluation of Celiac disease in patients with Beta thalassemia major and control

Iraj shahramian, Seyed Mohsen Dehghani, Mahmood Haghighat, NoorMohamad Noori, AliReza Teymoori, Elham Sharafi, Manigheh Kalili

Gastroenterology and Hepatology from Bed to Bench, Vol. 8 No. 2 (2015), 17 Esfand 2015, Page Gastroenterol Hepatol Bed Bench 2015;8(2):153-159


Introduction: Celiac Disease (CD) is an autoimmune disorder triggered by ingestion of gluten in genetically predisposed individuals.  This study reports evaluated prevalence of CD in patients with Beta-thalassemia major.

Materials and Methods: In this case-control study in a period of 3 years  which was performed on 620 children in two groups of  Beta-thalassemia major  patients (n=200) and control (n=420), serum Tissue Transglutamianse (TTG) IgA levels were measured. The two groups were compared together in terms of TTG IgA levels, and p<0.05 was considered significant.

Results: The means of serum TTG IgA levels in patients with Beta-thalassemia major and control groups were 28.81±68.44 and 6.94±6.68 U/mL, respectively, there was a significant difference in favor of the case group (p=0.000). Body mass index in the two case and control groups had a significant difference (t=3.859, p=0.001).  Belonging to each group will change the probability of having less than 20 in TTG IgA (odds=0.285) and it means that belonging to the control group has a protective role. There is only a significant association in the case of all population (r=0.102, p=0.011). Body mass index in the two case and control groups had a significant difference (t=3.859, p=0.001).

Discussion: Probability of CD should be considered since the prevalence of CD is high in patients with and Beta-thalassemia major.  Patients with thalassemia major are recommended to be screened for CD.

Keywords: Celiac disease, Beta-thalassemia major, Growth disorder, Disease risk, HLA


Case Report

An unusual cause of constipation in patient without any underlying disorders

Amir Sadeghi, Shabnam Shahrokh, Mohammad Reza Zali

Gastroenterology and Hepatology from Bed to Bench, Vol. 8 No. 2 (2015), 17 Esfand 2015, Page Gastroenterol Hepatol Bed Bench 2015;8(2):167-170

Constipation is the most common digestive complaint in the general population.it is associated with  considerableadverse effect  on quality of life  and  substantial economic costs  and  often have  no underlying pathology . Non celiac Gluten sensitivity( NCGS)has been described as a cause  of constipation  in  a few study .  We present  a  62-year-old male with long standing constipation without underlying cause  During extensive surveys and not responding to  any conservative treatment  but significant response with gluten free diet(GFD).

Short Cuts