|
1
|
Yuan B, Zhou S, Lu Y, Liu J, Jin X, Wan H, Wang F. Changes in the Expression and Distribution of Claudins, Increased Epithelial Apoptosis, and a Mannan-Binding Lectin-Associated Immune Response Lead to Barrier Dysfunction in Dextran Sodium Sulfate-Induced Rat Colitis. Gut Liver 2016; 9:734-40. [PMID: 25717051 PMCID: PMC4625702 DOI: 10.5009/gnl14155] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background/Aims This animal study aimed to define the underlying cellular mechanisms of intestinal barrier dysfunction. Methods Rats were fed 4% with dextran sodium sulfate (DSS) to induce experimental colitis. We analyzed the sugars in 24-hour urine output by high pressure liquid chromatography. The expression of claudins, mannan-binding lectin (MBL), and MBL-associated serine proteases 2 (MASP-2) were detected in the colonic mucosa by immunohistochemistry; and apoptotic cells in the colonic epithelium were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method assay. Results The lactulose and sucralose excretion levels in the urine of rats with DSS-induced colitis were significantly higher than those in the control rats. Mannitol excretion was lower and lactulose/mannitol ratios and sucralose/mannitol ratios were significantly increased compared with those in the control group (p<0.05). Compared with the controls, the expression of sealing claudins (claudin 3, claudin 5, and claudin 8) was significantly decreased, but that of claudin 1 was increased. The expression of pore-forming claudin 2 was upregulated and claudin 7 was downregulated in DSS-induced colitis. The epithelial apoptotic ratio was 2.8%±1.2% in controls and was significantly increased to 7.2%±1.2% in DSS-induced colitis. The expression of MBL and MASP-2 in the intestinal mucosa showed intense staining in controls, whereas there was weak staining in the rats with colitis. Conclusions There was increased intestinal permeability in DSS-induced colitis. Changes in the expression and distribution of claudins, increased epithelial apoptosis, and the MASP-2-induced immune response impaired the intestinal epithelium and contributed to high intestinal permeability.
Collapse
Affiliation(s)
- Bosi Yuan
- Department of Gastroenterology and Hepatology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Shuping Zhou
- Department of Gastroenterology and Hepatology, The First People's Hospital of Huainan, Huainan, China
| | - Youke Lu
- Department of Gastroenterology and Hepatology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Jiong Liu
- Department of Gastroenterology and Hepatology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Xinxin Jin
- Department of Gastroenterology and Hepatology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Haijun Wan
- Department of Gastroenterology and Hepatology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Fangyu Wang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| |
Collapse
|
|
2
|
MBL Deficiency as Risk of Infection and Autoimmunity. ANIMAL LECTINS: FORM, FUNCTION AND CLINICAL APPLICATIONS 2012:933-953. [PMCID: PMC7122001 DOI: 10.1007/978-3-7091-1065-2_42] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
In pathogen recognition by C-type lectins, several levels of complexity can be distinguished; these might modulate the immune response in different ways. Firstly, the pathogen-associated molecular pattern repertoire expressed at the microbial surface determines the interactions with specific receptors (Fig. 42.1). Secondly, each immune cell type possesses a specific set of pathogen-recognition receptors. Thirdly, changes in the cell-surface distribution of C-type lectins regulate carbohydrate binding by modulating receptor affinity for different ligands. Crosstalk between these receptors results in a network of multimolecular complexes, adding a further level of complexity in pathogen recognition (Cambi and Figdor 2005; Thiel et al. 2006) (see 10.1007/978-3-7091-1065-2_23). MBL deficiency is genetically determined and predisposes to recurrent infections and chronic inflammatory diseases. MBL deficiency has been implicated in susceptibility and course of viral, bacterial, fungal, and protozoan infection. More than 10% of the general population may, depending on definition, be classified as MBL deficient, underlining the redundancy of the immune system. MBL-disease association studies have been a fruitful area of research, which implicates a role for MBL in infective, inflammatory and autoimmune disease processes. MBL deficiency predisposes both to infection by extra-cellular pathogens and to autoimmune disease.
Collapse
|
|
3
|
Araujo J, Segat L, Guimarães RL, Brandão LAC, Souza PER, Santos S, Soares TS, Falcão EA, Rodrigues F, Carvalho R, de Lima-Filho JL, Arraes LC, Crovella S. Mannose binding lectin gene polymorphisms and associated auto-immune diseases in type 1 diabetes Brazilian patients. Clin Immunol 2009; 131:254-9. [PMID: 19185543 DOI: 10.1016/j.clim.2008.12.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2008] [Revised: 12/24/2008] [Accepted: 12/28/2008] [Indexed: 11/28/2022]
Abstract
In our study we investigated the possible role of MBL2 functional single nucleotide polymorphisms (SNPs) in the augmented susceptibility to develop other autoimmune diseases in presence of type 1 diabetes (T1D) in a group of Brazilian patients. Patients were stratified for the presence of autoimmune diseases known to be associated with T1D, such as autoimmune thyroid disease (AITD) and celiac disease (CD), and compared with healthy controls (HC). Our findings suggest that MBL2 functional SNPs are more closely related to AITD than to T1D, being MBL2 SNPs frequencies in T1D patients not affected by AITD comparable to the HC ones, while significantly different between AITD patients and patients not affected by the disease. Thus, the association between MBL2 polymorphisms and T1D that we previously reported, seems to result from the stronger association of MBL2 SNPs with another autoimmune disease, the AITD, frequently associated with T1D.
Collapse
Affiliation(s)
- Jacqueline Araujo
- Pediatric Endocrinology Unit of Clinical Hospital, Federal University of Pernambuco, Pernambuco, Brazil
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
4
|
da Silva Kotze LM, de Carvalho EG, da Rosa Utiyama SR, Nisihara RM, Messias-Reason I. Mannan-binding lectin levels related to spontaneous abortion in Brazilian patients with celiac disease. Dig Dis Sci 2008; 53:3152-7. [PMID: 18478332 DOI: 10.1007/s10620-008-0268-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2007] [Accepted: 03/26/2008] [Indexed: 12/09/2022]
Abstract
Low concentration of mannan-binding lectin (MBL) has been related to unexplained spontaneous abortion (SA), which has also been observed in an increased frequency in patients with celiac disease (CD). In this study, plasma levels of MBL were determined in patients with CD and irritable bowel syndrome (IBS) in order to investigate whether there is an association of MBL levels and the occurrence of SA in these patients. MBL concentration was determined in 46 patients with CD (28 without and 18 with report of SA) and 38 patients with IBS (25 without and 13 with report of SA). A higher frequency of SA was observed in women with CD when compared to IBS patients (23.2 vs. 13.9%; P = 0.046). No significant difference was observed in MBL concentrations between patients with CD, IBS, and healthy controls, nor between patients with or without occurrence of SA. These results suggest that the serum levels of MBL and the occurrence of SA in women with CD and IBS are not causally related.
Collapse
Affiliation(s)
- Lorete Maria da Silva Kotze
- Gastroenterology Service, Cajuru Hospital, Pontifical Catholic University of Paraná, Curitiba, Parana, Brazil
| | | | | | | | | |
Collapse
|
|
5
|
de Carvalho EG, da Rosa Utiyama SR, da Silva Kotze LM, de Messias Reason IT. Serum mannan-binding lectin levels in patients with celiac disease: an analysis of clinical and autoimmune features. Dig Dis Sci 2007; 52:2145-51. [PMID: 17393323 DOI: 10.1007/s10620-007-9792-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2006] [Accepted: 01/29/2007] [Indexed: 01/29/2023]
Abstract
Mannan-binding lectin (MBL) is the central protein in the activation of complement through the lectin pathway. MBL plasma concentration is genetically determined and varies significantly among individuals. Recent findings suggest that MBL is associated with the pathogenesis of celiac disease (CD). In this study, MBL and C-reactive protein (CRP) levels were determined in 101 celiac patients and 120 controls, with the aim to associate with the presence of gluten in the diet, disease severity, and the presence of concomitant autoimmune diseases. MBL concentration was determined by ELISA and CRP by nephelometry, using a high-sensitivity method. EmA-IgA and other autoantibodies were tested by indirect immunofluorescence. Although a significant increase in MBL levels was observed in male patients compared to female (P = 0.024), the absence of any other association suggests that circulating MBL and CRP concentrations are not associated with clinical and autoimmune CD features in Brazilian patients.
Collapse
|
|
6
|
Abstract
Mannose-binding lectin (MBL) is a pattern-recognition molecule that binds to characteristic carbohydrate motifs present on the surface of many different pathogens. MBL binding stimulates the immune system via the lectin pathway of complement activation. In certain clinical situations, often characterized by pre-existing immune compromise, MBL deficiency increases the risk of infectious and other disease-specific complications. Many of the key pathogenic processes inherent to common gastroenterological diseases, such as infection, immunological damage, and carcinogenesis, have been linked to MBL. This editorial reviews the biology of MBL, outlines key disease associations to document the breadth of influence of MBL, and finally, highlights the relevance of MBL to both gastroenterological health and disease.
Collapse
Affiliation(s)
- Daniel-L Worthley
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Room 3D230, Bedford Park, SA, 5042, Australia.
| | | | | | | |
Collapse
|
|
7
|
Abstract
Mannan-binding lectin (MBL) is a plasma protein of the innate immune system with the ability to initiate antimicrobial and inflammatory actions. MBL deficiency is common. More than 10% of the general population may, depending on definition, be classified as MBL deficient, underlining the redundancy of the immune system. Ongoing research attempt to illuminate at which conditions MBL deficiency may lead to disease. With examples, this review illustrates the diversity of results obtained so far.
Collapse
Affiliation(s)
- S Thiel
- Department of Medical Microbiology and Immunology, University of Aarhus, DK8000 Denmark.
| | | | | |
Collapse
|
|
8
|
Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Rispo A, Griffin M, Issekutz T, Quaratino S, Londei M. Unexpected role of surface transglutaminase type II in celiac disease. Gastroenterology 2005; 129:1400-13. [PMID: 16285941 DOI: 10.1053/j.gastro.2005.07.054] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2004] [Accepted: 07/14/2005] [Indexed: 01/23/2023]
Abstract
BACKGROUND & AIMS In celiac disease (CD), transglutaminase type II (TG2) has 2 fundamental roles: (1) as the autoantigen recognized by highly specific autoantibodies and (2) the modifier of pathogenic gliadin T-cell epitopes. It follows that inhibition of TG2 might represent an attractive strategy to curb the toxic action of gliadin. Here we studied the validity of this strategy using the organ culture approach. METHODS Duodenal biopsy specimens from 30 treated patients with CD, 33 untreated patients with CD, and 24 controls were cultured with or without gliadin peptides p31-43, palpha-9, and deamidated palpha-9 for 20 minutes, 3 hours, and 24 hours. In 31 patients with CD and 16 controls, TG2 inhibitor R283 or anti-TG CUB 7402 or anti-surface TG2 (6B9) mAbs were used in cultures. T84 cells were also cultured with or without peptides with or without TG inhibitors. Mucosal modifications after culture were assessed by immunofluorescence, in situ detection of TG activity, confocal microscopy, and fluorescence-activated cell sorter analysis. RESULTS The enzymatic inhibition of TG2 only controlled gliadin-specific T-cell activation. The binding of surface TG2 contained gliadin-specific T-cell activation and p31-43-induced actin rearrangement, epithelial phosphorylation, and apoptosis, both in organ cultures and T84 cells. CONCLUSIONS These data indicate a novel and unexpected biological role for surface TG2 in the pathogenesis of CD suggesting a third role for TG2 in CD. These results have a specific impact for celiac disease, with wider implications indicating a novel biologic function of TG2 with possible repercussions in other diseases.
Collapse
Affiliation(s)
- Luigi Maiuri
- Institute of Child Health, University College London, London, England
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
9
|
Boniotto M, Braida L, Baldas V, Not T, Ventura A, Vatta S, Radillo O, Tedesco F, Percopo S, Montico M, Amoroso A, Crovella S. Evidence of a correlation between mannose binding lectin and celiac disease: a model for other autoimmune diseases. J Mol Med (Berl) 2005; 83:308-15. [PMID: 15645196 DOI: 10.1007/s00109-004-0623-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2004] [Accepted: 10/26/2004] [Indexed: 01/23/2023]
Abstract
Celiac disease is a multifactorial disorder caused, in genetically susceptible patients, by the ingestion of dietary gluten. Very little is known about the genetic factors, but there is a strong association of two HLA haplotypes (DQ2 or alpha1*05, beta1*02 and DQ8 or alpha1*0301, beta1*0302) with the disease. We investigated the relationship between polymorphisms in the first exon of the MBL2 gene, which encodes for mannose binding lectin (MBL) and celiac disease. Moreover we studied the MBL role by immunohistochemistry and TUNEL. Results were confirmed by clinical findings. We enrolled 149 Italian celiac patients; 116 were characterized by the presence of DQ2 or DQ8. The HLA haplotype was established by allelic specific PCR while the MBL2 genotype was resolved by melting temperature assay. Immunohistochemistry and TUNEL assays were performed on serial sections of biopsy specimens from celiac patients and healthy controls. MBL2 allele and genotype frequencies varied significantly between celiac patients and healthy controls. The frequencies of the 0 allele were 28% in DQ2 or DQ8 celiac patients, 36% in HLA atypical celiac patients, and 22% in healthy controls. Interestingly, the MBL2 0/0 genotype was present in 7 of 33 HLA atypical celiac patients (21%) and in 13 of 116 HLA typical celiac patients (13%) but in only 7 of 147 healthy controls (5%). Furthermore, we found that MBL2 genotype is strongly associated with the occurrence of secondary autoimmune diseases. Immunohistochemistry and TUNEL findings support a role of MBL2 in the clearance of apoptotic cells. In conclusion, MBL2 variants, responsible for lower MBL levels, are associated with celiac disease and higher risk of developing autoimmune diseases. Here we propose a role for MBL in the disease which could be easily applied to other autoimmune disorders.
Collapse
Affiliation(s)
- Michele Boniotto
- Department of Sciences of Reproduction and Development, University of Trieste, Via dell'Istria 65/1, 34100 Trieste, Italy
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|