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Human Leukocyte Antigen (HLA) Haplotype Does Not Influence the Inflammatory Pattern of Duodenal Lymphocytosis Linked to Irritable Bowel Syndrome. ACTA ACUST UNITED AC 2020; 56:medicina56120660. [PMID: 33260434 PMCID: PMC7761368 DOI: 10.3390/medicina56120660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/23/2020] [Accepted: 11/25/2020] [Indexed: 11/17/2022]
Abstract
Background and objectives: Duodenal lymphocytosis (DL) is a condition characterized by enhanced infiltration of intraepithelial lymphocytes (IELs) in the duodenal mucosa, and it can be linked to both gluten- and non-gluten-related diseases, such as irritable bowel syndrome (IBS). Materials and methods: We retrospectively selected patients with DL linked to IBS. Formalin-embedded biopsy samples of the duodenum were collected. CD3 lymphocyte immunohistochemistry was used for IELs. The real-time polymerase chain reaction was used to quantify the amount of mRNA coding for tissue transglutaminase 2 (tTG2), interferon-gamma (IFNγ), toll-like receptor 2 (TLR2), and myeloid differentiation primary response 88 (MyD88). All subjects underwent DQ2-8 haplotype analysis. Controls were represented by subjects with IBS without DL. Results: Thirty-two patients with IBS-DL were retrospectively recruited. Fourteen subjects (43.8%) had a DQ2-8 haplotype. DQ2-8 positive subjects had similar levels compared to negative ones for tTG2, IFNγ, TLR2, and MyD88. Cigarette smoke did not influence molecular expression in our study. Smokers had a statistically higher IELs count than non-smokers (54.2 ± 7.7 vs. 36.0 ± 8.8, p < 0.001). A significant, direct correlation between IELs and duodenal expression of IFNγ was found (r = 0.36, p = 0.04). Conclusions: IBS with DL showed higher expression of inflammatory markers than controls, but DQ2-8 haplotype did not seem to affect their expression. Smoking might increase IELs infiltration.
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Use of small-bowel capsule endoscopy in cases of equivocal celiac disease. Gastrointest Endosc 2020; 91:1312-1321.e2. [PMID: 31923404 DOI: 10.1016/j.gie.2019.12.044] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 12/22/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Seronegative villous atrophy (SNVA), raised intraepithelial lymphocytes (IELs), and crypt hyperplasia on duodenal histology can be secondary to celiac disease (CD) or other causes such as medications or infections. Our aims were to assess the role of small-bowel capsule endoscopy (SBCE) in these patients and to ascertain whether findings on SBCE at diagnosis can predict disease outcome. METHODS Patients (n = 177) with SNVA, IELs, ± crypt hyperplasia on duodenal histology were studied. These patients all had an equivocal diagnosis of CD. RESULTS Overall, 56 patients (31.6%) had a positive SBCE. Thirty-three patients (58.9%) had disease affecting the proximal third of the small bowel (SB). The diagnostic yield of SBCE was 40.0% (22 patients), 51.4% (18 patients), 27.0% (10 patients), and 14.0% (7 patients) in patients with an unknown cause for SNVA (SNVA-UO), patients with SNVA who responded to a gluten-free diet (SNVA-CD), patients with a known cause for SNVA, and patients with railed IELs ± crypt hyperplasia, respectively. In SNVA-UO, SBCE at diagnosis was more likely to be positive in patients with persistent SNVA (10, 90.9%) and persistent SNVA with lymphoproliferative features (4, 80.4%) than patients with spontaneous resolution of SNVA (8, 20.5%) (P = .0001). All patients in the SNVA-CD group who eventually developed adverse events had a positive SBCE (P = .022). They also had more extensive SB disease than those without adverse events (50% vs 1% P = .002). More extensive SB disease on SBCE correlated with a higher SNVA-related mortality in patients with SNVA-UO and SNVA-CD (P = .019). Severity of histology did not correlate with mortality (P = .793). CONCLUSIONS A positive SBCE at diagnosis predicts a worse outcome. More importantly, more extensive disease in these patients is associated with poor survival. Targeting patients with extensive disease at diagnosis with more aggressive therapy can help to improve prognosis.
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Lerner A, Ramesh A, Matthias T. The Revival of the Battle between David and Goliath in the Enteric Viruses and Microbiota Struggle: Potential Implication for Celiac Disease. Microorganisms 2019; 7:microorganisms7060173. [PMID: 31207872 PMCID: PMC6616392 DOI: 10.3390/microorganisms7060173] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/04/2019] [Accepted: 06/11/2019] [Indexed: 02/08/2023] Open
Abstract
The human gut is inhabited by overcrowded prokaryotic communities, a major component of which is the virome, comprised of viruses, bacteriophages, archaea, eukaryotes and bacteria. The virome is required for luminal homeostasis and, by their lytic or synergic capacities, they can regulate the microbial community structure and activity. Dysbiosis is associated with numerous chronic human diseases. Since the virome can impact microbial genetics and behavior, understanding its biology, composition, cellular cycle, regulation, mode of action and potential beneficial or hostile activities can change the present paradigm of the cross-talks in the luminal gut compartment. Celiac disease is a frequent autoimmune disease in which viruses can play a role in disease development. Based on the current knowledge on the enteric virome, in relation to celiac disease pathophysiological evolvement, the current review summarizes the potential interphases between the two. Exploring and understanding the role of the enteric virome in gluten-dependent enteropathy might bring new therapeutic strategies to change the luminal eco-event for the patient’s benefit.
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Affiliation(s)
- Aaron Lerner
- AESKU.KIPP Institute, Mikroforum Ring 2, 55234 Wendelsheim, Germany.
| | - Ajay Ramesh
- AESKU.KIPP Institute, Mikroforum Ring 2, 55234 Wendelsheim, Germany.
| | - Torsten Matthias
- AESKU.KIPP Institute, Mikroforum Ring 2, 55234 Wendelsheim, Germany.
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Lerner A, Ramesh A, Matthias T. The Revival of the Battle between David and Goliath in the Enteric Viruses and Microbiota Struggle: Potential Implication for Celiac Disease. Microorganisms 2019. [PMID: 31207872 DOI: 10.3390/microorganisms7060173.pmid:31207872;pmcid:pmc6616392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023] Open
Abstract
The human gut is inhabited by overcrowded prokaryotic communities, a major component of which is the virome, comprised of viruses, bacteriophages, archaea, eukaryotes and bacteria. The virome is required for luminal homeostasis and, by their lytic or synergic capacities, they can regulate the microbial community structure and activity. Dysbiosis is associated with numerous chronic human diseases. Since the virome can impact microbial genetics and behavior, understanding its biology, composition, cellular cycle, regulation, mode of action and potential beneficial or hostile activities can change the present paradigm of the cross-talks in the luminal gut compartment. Celiac disease is a frequent autoimmune disease in which viruses can play a role in disease development. Based on the current knowledge on the enteric virome, in relation to celiac disease pathophysiological evolvement, the current review summarizes the potential interphases between the two. Exploring and understanding the role of the enteric virome in gluten-dependent enteropathy might bring new therapeutic strategies to change the luminal eco-event for the patient's benefit.
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Affiliation(s)
- Aaron Lerner
- AESKU.KIPP Institute, Mikroforum Ring 2, 55234 Wendelsheim, Germany.
| | - Ajay Ramesh
- AESKU.KIPP Institute, Mikroforum Ring 2, 55234 Wendelsheim, Germany.
| | - Torsten Matthias
- AESKU.KIPP Institute, Mikroforum Ring 2, 55234 Wendelsheim, Germany.
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Losurdo G, Principi M, Iannone A, Giangaspero A, Piscitelli D, Ierardi E, Di Leo A, Barone M. Predictivity of Autoimmune Stigmata for Gluten Sensitivity in Subjects with Microscopic Enteritis: A Retrospective Study. Nutrients 2018; 10:nu10122001. [PMID: 30567296 PMCID: PMC6315522 DOI: 10.3390/nu10122001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/10/2018] [Accepted: 12/14/2018] [Indexed: 02/07/2023] Open
Abstract
Non-celiac gluten sensitivity (NCGS) is an emerging gluten-related condition. We investigated whether the presence of autoimmune stigmata in a group of patients with clinical suspicion of NCGS and a histological picture of microscopic enteritis (ME) could be a predictive factor of NCGS. Patients with ME were followed up by periodical examinations. At baseline, we collected data about previous clinical history, including autoimmune diseases. NCGS was diagnosed according to Salerno criteria; other causes of ME were diagnosed according to well-established protocols. Patients with celiac disease were excluded. Student's and chi-square tests were used in univariate analysis. Kaplan-Meier curves and Cox regression were used to estimate hazard ratios (HR). Sixty-three patients were included. Twenty-two had a final diagnosis of NCGS; the remaining 41 had non-gluten-related causes of ME. Prevalence of autoimmune thyroiditis was higher among NCGS patients (40.1%) than in other ME (14.6%; p = 0.03). NCGS showed higher positivity rate for anti-gliadin (27.3% versus 2.5%; p = 0.006) and anti-nucleus (45.4% versus 12.2%; p = 0.005). Autoimmune thyroiditis had a non-significant trend (p = 0.06) for NCGS diagnosis, (HR = 2.4). Both anti-gliadin (HR = 2.4; p = 0.04) and anti-nucleus (HR = 2.7; p = 0.04) were directly associated with NCGS diagnosis. In conclusion, NCGS may have a cohort of autoimmune stigmata that can precede its diagnosis.
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Affiliation(s)
- Giuseppe Losurdo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari (Italy), Piazza G. Cesare 11, 70124 Bari, Italy.
| | - Mariabeatrice Principi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari (Italy), Piazza G. Cesare 11, 70124 Bari, Italy.
| | - Andrea Iannone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari (Italy), Piazza G. Cesare 11, 70124 Bari, Italy.
| | - Antonio Giangaspero
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari (Italy), Piazza G. Cesare 11, 70124 Bari, Italy.
| | - Domenico Piscitelli
- Section of Pathology, Department of Emergency and Organ Transplantation, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy.
| | - Enzo Ierardi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari (Italy), Piazza G. Cesare 11, 70124 Bari, Italy.
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari (Italy), Piazza G. Cesare 11, 70124 Bari, Italy.
| | - Michele Barone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari (Italy), Piazza G. Cesare 11, 70124 Bari, Italy.
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Losurdo G, Principi M, Iannone A, Amoruso A, Ierardi E, Di Leo A, Barone M. Extra-intestinal manifestations of non-celiac gluten sensitivity: An expanding paradigm. World J Gastroenterol 2018; 24:1521-1530. [PMID: 29662290 PMCID: PMC5897856 DOI: 10.3748/wjg.v24.i14.1521] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 03/27/2018] [Accepted: 03/30/2018] [Indexed: 02/06/2023] Open
Abstract
Non celiac gluten sensitivity (NCGS) is a syndrome characterized by a cohort of symptoms related to the ingestion of gluten-containing food in subjects who are not affected by celiac disease (CD) or wheat allergy. The possibility of systemic manifestations in this condition has been suggested by some reports. In most cases they are characterized by vague symptoms such as ‘foggy mind’, headache, fatigue, joint and muscle pain, leg or arm numbness even if more specific complaints have been described. NCGS has an immune-related background. Indeed there is a strong evidence that a selective activation of innate immunity may be the trigger for NCGS inflammatory response. The most commonly autoimmune disorders associated to NCGS are Hashimoto thyroiditis, dermatitis herpetiformis, psoriasis and rheumatologic diseases. The predominance of Hashimoto thyroiditis represents an interesting finding, since it has been indirectly confirmed by an Italian study, showing that autoimmune thyroid disease is a risk factor for the evolution towards NCGS in a group of patients with minimal duodenal inflammation. On these bases, an autoimmune stigma in NCGS is strongly supported; it could be a characteristic feature that could help the diagnosis and be simultaneously managed. A possible neurological involvement has been underlined by NCGS association with gluten ataxia, gluten neuropathy and gluten encephalopathy. NCGS patients may show even psychiatric diseases such as depression, anxiety and psychosis. Finally, a link with functional disorders (irritable bowel syndrome and fibromyalgia) is a topic under discussion. In conclusion, the novelty of this matter has generated an expansion of literature data with the unavoidable consequence that some reports are often based on low levels of evidence. Therefore, only studies performed on large samples with the inclusion of control groups will be able to clearly establish whether the large information from the literature regarding extra-intestinal NCGS manifestations could be supported by evidence-based agreements.
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Affiliation(s)
- Giuseppe Losurdo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University “Aldo Moro” of Bari, Bari 70124, Italy
| | - Mariabeatrice Principi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University “Aldo Moro” of Bari, Bari 70124, Italy
| | - Andrea Iannone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University “Aldo Moro” of Bari, Bari 70124, Italy
| | - Annacinzia Amoruso
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University “Aldo Moro” of Bari, Bari 70124, Italy
| | - Enzo Ierardi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University “Aldo Moro” of Bari, Bari 70124, Italy
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University “Aldo Moro” of Bari, Bari 70124, Italy
| | - Michele Barone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University “Aldo Moro” of Bari, Bari 70124, Italy
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Ierardi E, Losurdo G, Piscitelli D, Giorgio F, Amoruso A, Iannone A, Principi M, Di Leo A. Biological markers for non-celiac gluten sensitivity: a question awaiting for a convincing answer. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2018; 11:203-208. [PMID: 30013743 PMCID: PMC6040034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Non Celiac Gluten Sensitivity (NCGS) is characterized by immunological, morphological or symptomatic manifestations precipitated by gluten ingestion in individuals without celiac disease (CD). The most important challenge in NCGS is the diagnosis, currently based only on clinical observation. The "Salerno criteria" have been pointed out to achieve a reliable diagnosis even if they lack immediacy and practicality, thus making questionable patient's adherence. Therefore, biological indicators supporting the clinical diagnosis of NCGS are advisable. For these reasons, many attempts have been performed in order to identify possible serological, immunological, histopathological, immunohistochemical and pathophysiological aspects characterizing this condition with the aim of using them for diagnostic purposes. In the present narrative review, we carried out an update of the current scenario of potential markers of NCGS. The main fault of available studies is that, in most cases investigations have been pointed out towards molecules, which cannot be searched in the current laboratories of clinical analysis. Therefore, the matter has been confined within basic research. Additionally, in these studies, sensitivity and specificity of biological markers were not computable. This is a relevant limit, since an ideal test for NCGS should have a good discriminative power against both CD and other causes of microscopic enteritis. Until now, serological tests have failed, while the search for a soluble marker indicative of activation of innate immune system as well as immunohistochemistry could be the promising bases for the development of appropriate investigations in the future.
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Affiliation(s)
- Enzo Ierardi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Italy
| | - Giuseppe Losurdo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Italy
| | - Domenico Piscitelli
- Section of Pathology, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Italy
| | - Floriana Giorgio
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Italy
| | - Annacinzia Amoruso
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Italy
| | - Andrea Iannone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Italy
| | - Mariabeatrice Principi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Italy
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Italy
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Ierardi E, Losurdo G, Iannone A, Piscitelli D, Amoruso A, Barone M, Principi M, Pisani A, Di Leo A. Lymphocytic duodenitis or microscopic enteritis and gluten-related conditions: what needs to be explored? Ann Gastroenterol 2017; 30:380-392. [PMID: 28655974 PMCID: PMC5479990 DOI: 10.20524/aog.2017.0165] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 05/10/2017] [Indexed: 02/07/2023] Open
Abstract
Microscopic enteritis (ME) is characterized by abnormal infiltration of intraepithelial lymphocytes in intestinal mucosa. It was described as duodenal lymphocytosis or lymphocytic duodenitis until the dedicated Consensus Conference of 2015. ME represents a common feature of several gluten-mediated and non-gluten related diseases; therefore, it is an umbrella term embracing several conditions. The most frequent causes of ME are gluten-related disorders (celiac disease, non-celiac gluten sensitivity, wheat allergy), Helicobacter pylori infection and drug-related damages. Less frequently, ME may be secondary to inflammatory bowel disease, some autoimmune conditions, immunoglobulin deficiencies, blood malignancies, infections and irritable bowel syndrome. Therefore, the differential diagnosis of ME may be challenging. The diagnosis of ME needs to be driven by predominant symptoms and patient history. However, it is often difficult to achieve an immediate identification of the underlying condition, and a broad variety of diagnostic tests may be required. Ultimately, long-term surveillance is needed for a final diagnosis in many cases, since a hidden or quiescent condition may be disclosed after a period of latency. In any case, strict collaboration between the clinician and the pathologist is pivotal. The treatment of ME should be personalized, depending on the underlying disease. For gluten-related conditions (celiac disease, gluten sensitivity, wheat allergy, dermatitis herpetiformis), a gluten-free diet may be proposed. For other conditions, a targeted etiologic treatment is necessary. In conclusion, ME represents a novel entity that is attracting increasing interest. The growing epidemiologic trend confirms that it will become a common condition in clinical practice.
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Affiliation(s)
- Enzo Ierardi
- Section of Gastroenterology (Enzo Ierardi, Giuseppe Losurdo, Andrea Iannone, Annacinzia Amoruso, Michele Barone, Mariabeatrice Principi, Antonio Pisani, Alfredo Di Leo)
- Correspondence to: Prof. Enzo Ierardi, Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, Piazza Giulio Cesare, Bari, University of Bari, Italy, Tel.: +39 080 5594033, Fax: +39 080 5593088, e-mail:
| | - Giuseppe Losurdo
- Section of Gastroenterology (Enzo Ierardi, Giuseppe Losurdo, Andrea Iannone, Annacinzia Amoruso, Michele Barone, Mariabeatrice Principi, Antonio Pisani, Alfredo Di Leo)
| | - Andrea Iannone
- Section of Gastroenterology (Enzo Ierardi, Giuseppe Losurdo, Andrea Iannone, Annacinzia Amoruso, Michele Barone, Mariabeatrice Principi, Antonio Pisani, Alfredo Di Leo)
| | - Domenico Piscitelli
- Section of Pathology (Domenico Piscitelli), Department of Emergency and Organ Transplantation, AOU Policlinico, Piazza Giulio Cesare, Bari, University of Bari, Italy
| | - Annacinzia Amoruso
- Section of Gastroenterology (Enzo Ierardi, Giuseppe Losurdo, Andrea Iannone, Annacinzia Amoruso, Michele Barone, Mariabeatrice Principi, Antonio Pisani, Alfredo Di Leo)
| | - Michele Barone
- Section of Gastroenterology (Enzo Ierardi, Giuseppe Losurdo, Andrea Iannone, Annacinzia Amoruso, Michele Barone, Mariabeatrice Principi, Antonio Pisani, Alfredo Di Leo)
| | - Mariabeatrice Principi
- Section of Gastroenterology (Enzo Ierardi, Giuseppe Losurdo, Andrea Iannone, Annacinzia Amoruso, Michele Barone, Mariabeatrice Principi, Antonio Pisani, Alfredo Di Leo)
| | - Antonio Pisani
- Section of Gastroenterology (Enzo Ierardi, Giuseppe Losurdo, Andrea Iannone, Annacinzia Amoruso, Michele Barone, Mariabeatrice Principi, Antonio Pisani, Alfredo Di Leo)
| | - Alfredo Di Leo
- Section of Gastroenterology (Enzo Ierardi, Giuseppe Losurdo, Andrea Iannone, Annacinzia Amoruso, Michele Barone, Mariabeatrice Principi, Antonio Pisani, Alfredo Di Leo)
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Losurdo G, Giorgio F, Piscitelli D, Montenegro L, Covelli C, Fiore MG, Giangaspero A, Iannone A, Principi M, Amoruso A, Barone M, Di Leo A, Ierardi E. May the assessment of baseline mucosal molecular pattern predict the development of gluten related disorders among microscopic enteritis? World J Gastroenterol 2016; 22:8017-8025. [PMID: 27672296 PMCID: PMC5028815 DOI: 10.3748/wjg.v22.i35.8017] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 06/30/2016] [Accepted: 07/21/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate mucosal baseline mRNA expression of tissue transglutaminase 2 (tTG2), interferon gamma (IFNγ), toll-like receptor 2 (TLR2) and Myeloid Differentiation factor 88 (MyD88) in patients with microscopic enteritis (ME).
METHODS We retrospectively enrolled 89 patients with ME of different etiology, which was defined within a 2-year mean period of follow-up. Baseline histological examination was performed on Hematoxylin-Eosin stained sections and CD3 lymphocyte immunohistochemistry was used for intraepithelial lymphocyte count (IELs). ME was defined according to the criteria of Bucharest Consensus Conference. For each patient, formalin embedded biopsy samples of the duodenum referred to the period of ME diagnosis were retrieved. Real-time polymerase chain reaction (RT-PCR) was used to detect the amount of mRNA coding for tTG2, IFNγ, TLR2 and MyD88, and the quantity was expressed as fold change compared to controls. Control group was represented by duodenal normal specimens from 15 healthy subjects undergoing endoscopy for functional symptoms. Comparisons among continuous variables were performed by One way analysis of variance (ANOVA) and Bonferroni’s test. The χ2 test was used for categorical variables. Pearson’s test was used to evaluate correlations. Receiver operating curves were drawn for all four markers to estimate sensitivity and specificity in discriminating the development of CD and GS.
RESULTS After a period of follow up of 21.7 ± 11.7 mo, the following diagnoses were achieved: gluten related disorders in 48 subjects (31 CD; 17 GS) and non-gluten related ones in 41 (29 Irritable Bowel Syndrome - IBS; 12 Others). CD patients had the highest tTG2 levels (8.3 ± 4.5). The ANOVA plus Bonferroni analysis showed that CD > Other ME > GS = IBS > negative controls. A cut off value of 2.258 was able to discriminate between CD and GS with a sensitivity of 52.94% and a specificity of 87.1%. Additionally, CD patients had the highest IFNγ levels (8.5 ± 4.1). ANOVA plus Bonferroni demonstrated CD > Other ME > GS = IBS > negative controls. A cut off of 1.853 was able to differentiate CD and GS with a sensitivity of 47.06% and a specificity of 96.77%. Patients with non gluten-related causes of ME exhibited the highest TLR2 levels (6.1 ± 1.9) as follows: Other ME > CD = GS = IBS > negative controls. TLR2 was unable to discriminate CD from GS. Patients with CD overexpressed MyD88 levels similarly to non gluten-related causes of DL (7.8 ± 4.9 and 6.7 ± 2.9), thus CD = Other ME > GS = IBS > negative controls. A cut off of 3.722 was able to differentiate CD from GS with a sensitivity of 52.94% and a specificity of 74.19%. IELs count (15-25 and more than 25/100 enterocytes) strongly correlated with mRNA levels of all tested molecules (P < 0.0001).
CONCLUSION Our results confirm that a single marker is unable to predict a discrimination among ME underlying conditions as well as between CD and GS. Mucosal high levels of tTG and IFNγ mRNA may predict the development of CD more than GS with high specificity, despite an expected low sensitivity. TLR2 does not discriminate the development of CD from GS. MyD88 levels indicate that intestinal permeability is more increased when a severe intestinal damage underlies ME in both gluten related and unrelated conditions. Therefore, the results of the present paper do not seem to show a clear translational value.
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Giorgio F, Principi M, Losurdo G, Piscitelli D, Iannone A, Barone M, Amoruso A, Ierardi E, Di Leo A. Seronegative Celiac Disease and Immunoglobulin Deficiency: Where to Look in the Submerged Iceberg? Nutrients 2015; 7:7486-504. [PMID: 26371035 PMCID: PMC4586545 DOI: 10.3390/nu7095350] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/27/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In the present narrative review, we analyzed the relationship between seronegative celiac disease (SNCD) and immunoglobulin deficiencies. For this purpose, we conducted a literature search on the main medical databases. SNCD poses a diagnostic dilemma. Villous blunting, intraepithelial lymphocytes (IELs) count and gluten "challenge" are the most reliable markers. Immunohistochemistry/immunofluorescence tissue transglutaminase (tTG)-targeted mucosal immunoglobulin A (IgA) immune complexes in the intestinal mucosa of SNCD patients may be useful. In our experience, tTG-mRNA was similarly increased in seropositive celiac disease (CD) and suspected SNCD, and strongly correlated with the IELs count. This increase is found even in the IELs' range of 15-25/100 enterocytes, suggesting that there may be a "grey zone" of gluten-related disorders. An immune deregulation (severely lacking B-cell differentiation) underlies the association of SNCD with immunoglobulin deficiencies. Therefore, CD may be linked to autoimmune disorders and immune deficits (common variable immunodeficiency (CVID)/IgA selective deficiency). CVID is a heterogeneous group of antibodies dysfunction, whose association with CD is demonstrated only by the response to a gluten-free diet (GFD). We hypothesized a familial inheritance between CD and CVID. Selective IgA deficiency, commonly associated with CD, accounts for IgA-tTG seronegativity. Selective IgM deficiency (sIgMD) is rare (<300 cases) and associated to CD in 5% of cases. We diagnosed SNCD in a patient affected by sIgMD using the tTG-mRNA assay. One-year GFD induced IgM restoration. This evidence, supporting a link between SNCD and immunoglobulin deficiencies, suggests that we should take a closer look at this association.
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Affiliation(s)
- Floriana Giorgio
- Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.
| | - Mariabeatrice Principi
- Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.
| | - Giuseppe Losurdo
- Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.
| | - Domenico Piscitelli
- Section of Pathology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.
| | - Andrea Iannone
- Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.
| | - Michele Barone
- Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.
| | - Annacinzia Amoruso
- Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.
| | - Enzo Ierardi
- Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.
| | - Alfredo Di Leo
- Section of Gastroenterology, University Hospital Policlinico, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.
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