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Ghorbanzadeh S, Khojini JY, Abouali R, Alimardan S, Zahedi M, Tahershamsi Z, Tajbakhsh A, Gheibihayat SM. Clearing the Path: Exploring Apoptotic Cell Clearance in Inflammatory and Autoimmune Disorders for Therapeutic Advancements. Mol Biotechnol 2025; 67:2223-2238. [PMID: 38935260 DOI: 10.1007/s12033-024-01222-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 01/22/2024] [Indexed: 06/28/2024]
Abstract
Inflammatory and autoimmune disorders, characterized by dysregulated immune responses leading to tissue damage and chronic inflammation, present significant health challenges. This review uniquely focuses on efferocytosis-the phagocyte-mediated clearance of apoptotic cells-and its pivotal role in these disorders. We delve into the intricate mechanisms of efferocytosis' four stages and their implications in disease pathogenesis, distinguishing our study from previous literature. Our findings highlight impaired efferocytosis in conditions like atherosclerosis and asthma, proposing its targeting as a novel therapeutic strategy. We discuss the therapeutic potential of efferocytosis in modulating immune responses and resolving inflammation, offering a new perspective in treating inflammatory disorders.
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Affiliation(s)
- Shadi Ghorbanzadeh
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Science, Bandar Abbas, Iran
| | - Javad Yaghmoorian Khojini
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, P.O. Box: 8915173143, Yazd, IR, Iran
| | - Reza Abouali
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, Università del Piemonte Orientale, Novara, Italy
| | - Sajad Alimardan
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Zahedi
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Tahershamsi
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Mohammad Gheibihayat
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, P.O. Box: 8915173143, Yazd, IR, Iran.
- Yazd Cardiovascular Research Center, Non-Communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Rysz J, Franczyk B, Radek M, Ciałkowska-Rysz A, Gluba-Brzózka A. Diabetes and Cardiovascular Risk in Renal Transplant Patients. Int J Mol Sci 2021; 22:3422. [PMID: 33810367 PMCID: PMC8036743 DOI: 10.3390/ijms22073422] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
End-stage kidney disease (ESKD) is a main public health problem, the prevalence of which is continuously increasing worldwide. Due to adverse effects of renal replacement therapies, kidney transplantation seems to be the optimal form of therapy with significantly improved survival, quality of life and diminished overall costs compared with dialysis. However, post-transplant patients frequently suffer from post-transplant diabetes mellitus (PTDM) which an important risk factor for cardiovascular and cardiovascular-related deaths after transplantation. The management of post-transplant diabetes resembles that of diabetes in the general population as it is based on strict glycemic control as well as screening and treatment of common complications. Lifestyle interventions accompanied by the tailoring of immunosuppressive regimen may be of key importance to mitigate PTDM-associated complications in kidney transplant patients. More transplant-specific approach can include the exchange of tacrolimus with an alternative immunosuppressant (cyclosporine or mammalian target of rapamycin (mTOR) inhibitor), the decrease or cessation of corticosteroid therapy and caution in the prescribing of diuretics since they are independently connected with post-transplant diabetes. Early identification of high-risk patients for cardiovascular diseases enables timely introduction of appropriate therapeutic strategy and results in higher survival rates for patients with a transplanted kidney.
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Affiliation(s)
- Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
| | - Beata Franczyk
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
| | - Maciej Radek
- Department of Neurosurgery, Surgery of Spine and Peripheral Nerves, Medical University of Lodz, 90-549 Lodz, Poland;
| | | | - Anna Gluba-Brzózka
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
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Zhang K, Mao T, He Z, Wu X, Peng Y, Chen Y, Dong Y, Ruan Z, Wang Z. WITHDRAWN: Diagnostic performance of MASP-2 in the diagnosis of colorectal carcinoma. Pathol Res Pract 2020:153278. [PMID: 33549364 DOI: 10.1016/j.prp.2020.153278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 02/07/2023]
Abstract
This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The publisher regrets that an error occurred which led to the premature publication of this paper. The publisher apologizes to the authors and the readers for this unfortunate error.
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Affiliation(s)
- Keqian Zhang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Tianqi Mao
- Department of Radiology Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Zhicheng He
- Department of Pathology, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Xiaojiao Wu
- Quality Management Section, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Yu Peng
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Yanrong Chen
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Yan Dong
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Zhihua Ruan
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Zhe Wang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China.
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Guad RM, Taylor-Robinson AW, Wu YS, Gan SH, Zaharan NL, Basu RC, Liew CSL, Wan Md Adnan WAH. Clinical and genetic risk factors for new-onset diabetes mellitus after transplantation (NODAT) in major transplant centres in Malaysia. BMC Nephrol 2020; 21:388. [PMID: 32894076 PMCID: PMC7487857 DOI: 10.1186/s12882-020-02052-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 09/02/2020] [Indexed: 12/31/2022] Open
Abstract
Background New-onset diabetes after transplantation (NODAT) is associated with reduced patient and graft survival. This study examined the clinical and selected genetic factors associated with NODAT among renal-transplanted Malaysian patients. Methods This study included 168 non-diabetic patients (58% males, 69% of Chinese ethnicity) who received renal transplantation between 1st January 1994 to 31st December 2014, and were followed up in two major renal transplant centres in Malaysia. Fasting blood glucose levels were used to diagnose NODAT in patients who received renal transplantation within 1 year. Two single nucleotide polymorphisms (SNPs), namely; rs1494558 (interleukin-7 receptor, IL-7R) and rs2232365 (mannose-binding leptin-2, MBL2) were selected and genotyped using Sequenom MassArray platform. Cox proportional hazard regression analyses were used to examine the risk of developing NODAT according to the different demographics and clinical covariates, utilizing four time-points (one-month, three-months, six-months, one-year) post-transplant. Results Seventeen per cent of patients (n = 29, 55% males, 69% Chinese) were found to have developed NODAT within one-year of renal transplantation based on their fasting blood glucose levels. NODAT patients had renal transplantation at an older age compared to non-NODAT (39.3 ± 13.4 vs 33.9 ± 11.8 years, p = 0.03). In multivariate analysis, renal-transplanted patients who received a higher daily dose of cyclosporine (mg) were associated with increased risk of NODAT (Hazard ratio (HR) =1.01 per mg increase in dose, 95% confidence interval (CI) 1.00–1.01, p = 0.002). Other demographic (gender, ethnicities, age at transplant) and clinical factors (primary kidney disease, type of donor, place of transplant, type of calcineurin inhibitors, duration of dialysis pre-transplant, BMI, creatinine levels, and daily doses of tacrolimus and prednisolone) were not found to be significantly associated with risk of NODAT. GA genotype of rs1494558 (HR = 3.15 95% CI 1.26, 7.86) and AG genotype of rs2232365 (HR = 2.57 95% CI 1.07, 6.18) were associated with increased risk of NODAT as compared to AA genotypes. Conclusion The daily dose of cyclosporine and SNPs of IL-7R (rs1494558) and MBL2 (rs2232365) genes are significantly associated with the development of NODAT in the Malaysian renal transplant population.
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Affiliation(s)
- Rhanye Mac Guad
- Department of Biomedical Science and Therapeutics, Faculty of Medicine & Health Science, Universiti Malaysia Sabah, Jalan UMS, 88400, Kota Kinabalu, Sabah, Malaysia.
| | - Andrew W Taylor-Robinson
- Infectious Diseases Research Group, School of Medical & Applied Sciences, Central Queensland University, Rockhampton, QLD, 4702, Australia
| | - Yuan Seng Wu
- Department of Biochemistry, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom, Selangor Darul Ehsan, Malaysia
| | - Siew Hua Gan
- School of Pharmacy, Monash University Malaysia, Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Nur Lisa Zaharan
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Roma Choudhury Basu
- Clinical Investigation Centre, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Constance Sat Lin Liew
- Medical Based Department, Faculty of Medicine & Health Science, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia
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Santos LOD, Bispo AVS, Barros JVD, Laranjeira RSM, Pinto RDN, Silva JDA, Duarte ADR, Araújo J, Sandrin-Garcia P, Crovella S, Bezerra MAC, Belmont TFDM, Cavalcanti MDS, Santos N. CTLA-4 gene polymorphisms are associated with obesity in Turner Syndrome. Genet Mol Biol 2018; 41:727-734. [PMID: 30508004 PMCID: PMC6415610 DOI: 10.1590/1678-4685-gmb-2017-0312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 02/27/2018] [Indexed: 01/15/2023] Open
Abstract
Turner syndrome (TS) is characterized by a set of clinical conditions, including autoimmune/inflammatory diseases and infectious conditions, that can compromise a patient’s quality of life. Here we assessed polymorphisms in CTLA-4 +49A/G (rs231775), PTPN22 +1858G/A (rs2476601), and MBL2 -550 (H/L) (rs11003125), -221(X/Y) (rs7096206) and exon 1 (A/O) in women from northeastern Brazil to determine whether polymorphisms within these key immune response genes confer differential susceptibility to clinical conditions in TS. A case-control genetic association study was performed, including 86 female TS patients and 179 healthy women. An association was observed for the A/G genotype of CTLA-4 +49A/G in TS patients (p=0.043, odds ratio [OR]=0.54). In addition, an association between the CTLA-4 G/G genotype and obesity was detected in TS patients (p=0.02, OR=6.04). Regarding, the -550(H/L) polymorphism in the MBL2 promoter, the frequency of the H/L genotype was significantly higher in the TS group than healthy controls (p=0.01, OR=1.96). The H/H genotype indicated a protective effect in TS patients (p=0.01, OR=0.23). No differences were observed in the distribution of -221(X/Y), MBL2 exon 1 variants, and PTPN22 +1858G/A in any assessed groups. CTLA-4 variants are potentially involved in obesity in this cohort of TS patients from northeastern Brazil.
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Affiliation(s)
| | - Adriana Valéria Sales Bispo
- Instituto Federal de Educação, Ciência e Tecnologia do Sertão Pernambucano, Campus Serra Talhada, Serra Talhada, PE, Brazil
| | | | | | | | | | - Andréa de Rezende Duarte
- Serviço de Genética Medica, Instituto de Medicina Integral Professor Fernando Figueira, Recife, PE, Brazil
| | - Jacqueline Araújo
- Serviço de Endocrinlogia Pediátrica do Hospital das Clínicas, Universidade Federal de Pernambuco, Recife, PE, Brazil
| | | | - Sergio Crovella
- Departmento de Genética, Universidade Federal de Pernambuco, Recife, PE, Brazil
| | | | | | | | - Neide Santos
- Departmento de Genética, Universidade Federal de Pernambuco, Recife, PE, Brazil
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Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes. Mediators Inflamm 2017; 2017:9403754. [PMID: 28751823 PMCID: PMC5485322 DOI: 10.1155/2017/9403754] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 03/24/2017] [Accepted: 04/10/2017] [Indexed: 02/07/2023] Open
Abstract
Increasing evidence links mannan-binding lectin (MBL) to late vascular complications of diabetes. MBL is a complement-activating pattern recognition molecule of the innate immune system that can mediate an inflammation response through activation of the lectin pathway. In two recent animal studies, we have shown that autoreactivity of MBL is increased in the kidney in diabetic nephropathy. We hypothesize that long-term exposure to uncontrolled high blood glucose in diabetes may mediate formation of neoepitopes in several tissues and that MBL is able to recognize these structures and thus activate the lectin pathway. To test this hypothesis, we induced diabetes by injection of low-dose streptozotocin in MBL double-knockout (MBL/DKO) mice. Development of diabetes was followed by measurements of blood glucose and urine albumin-to-creatinine ratio. Fluorophore-labelled recombinant MBL was injected intravenously in diabetic and nondiabetic mice followed by ex vivo imaging of several organs. We observed that MBL accumulated in the heart, liver, brain, lung, pancreas, and intestines of diabetic mice. We furthermore detected increased systemic complement activation after administration of MBL, thus indicating MBL-mediated systemic complement activation in these animals. These new findings indicate a global role of MBL during late diabetes-mediated vascular complications in various tissues.
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Anjosa ZPD, Santos MMS, Rodrigues NJ, Lacerda GAND, Araujo J, Silva JDA, Tavares NDAC, Guimarães RL, Crovella S, Brandão LAC. Polymorphism in ficolin-1 (FCN1) gene is associated with an earlier onset of type 1 diabetes mellitus in children and adolescents from northeast Brazil. J Genet 2016; 95:1031-1034. [PMID: 27994205 DOI: 10.1007/s12041-016-0719-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Interleukin-18 gene promoter polymorphisms and celiac disease in Italian patients. Mol Biol Rep 2014; 42:525-33. [PMID: 25374428 DOI: 10.1007/s11033-014-3796-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Accepted: 10/14/2014] [Indexed: 01/05/2023]
Abstract
Celiac disease (CD) is the most common food-sensitive enteropathy in genetically susceptible individuals. The major genetic risk factors known are specific human leukocyte antigen (HLA)-DQ haplotypes, but other genetic factors are supposed to be involved. Interleukin-18 (IL-18) is a pro-inflammatory cytokine that has an important role in the immune defense and it has the potential to influence inflammatory disorders. IL-18 is able to promote Th1 cell development and it is expressed in the mucosa of the small intestine in celiac patients. Given the IL-18 biological role, and since a few studies have previously suggested its involvement in CD, in order to investigate the role of IL18 gene in the susceptibility to CD we have performed a case-control study, analyzing two IL18 gene promoter polymorphisms, previously reported to impair the transcriptional activity of the gene, (-137G > C and -607C > A, rs187238 and rs1946518 respectively). A total of 556 CD Italian patients and 582 controls, further stratified for HLA class II (DQ) CD risk haplotypes were enrolled. The -607A > C A allele and A/A genotype, as well as the combination of this allele with the -137G allele in the AG haplotype, were associated with an increased risk towards CD development, in particular in HLA-DQ2.2 patients. Although the association was very moderate, our results indicate the possible involvement of IL18 gene in the susceptibility to CD, and for this reason we do think it should deserve further investigation.
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Mannan-binding lectin polymorphisms and serum levels in patients with endometriosis. Eur J Obstet Gynecol Reprod Biol 2014; 181:256-8. [DOI: 10.1016/j.ejogrb.2014.08.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Revised: 07/30/2014] [Accepted: 08/07/2014] [Indexed: 11/23/2022]
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Zupin L, Polesello V, Catamo E, Crovella S, Segat L. Interleukin-10 gene promoter polymorphisms in celiac patients from north-eastern Italy. Hum Immunol 2014; 75:656-61. [DOI: 10.1016/j.humimm.2014.04.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Revised: 01/16/2014] [Accepted: 04/06/2014] [Indexed: 02/08/2023]
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Kovacs M, Papp M, Lakatos PL, Jacobsen S, Nemes E, Polgar M, Solyom E, Bodi P, Horvath A, Molnar K, Szabo D, Cseh A, Muller KE, Dezsofi A, Arato A, Veres G. Low mannose-binding lectin (MBL) is associated with paediatric inflammatory bowel diseases and ileal involvement in patients with Crohn disease. J Crohns Colitis 2013; 7:134-141. [PMID: 22504031 DOI: 10.1016/j.crohns.2012.03.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2011] [Revised: 03/11/2012] [Accepted: 03/12/2012] [Indexed: 02/08/2023]
Abstract
BACKGROUND Mannose-binding lectin (MBL) is a pattern-recognition molecule of the innate immune system and may be involved in the pathogenesis of inflammatory bowel disease (IBD). Our aim was to assess the prevalence of MBL deficiency in a cohort of patients with paediatric-onset IBD and study whether it is associated with the clinical manifestations, serum antibody formation, or genetic factors. METHODS This prospective study included 159 paediatric patients (mean age: 14.0 years) with IBD [107 patients with Crohn disease (CD) and 52 patients with ulcerative colitis (UC)]. Furthermore, 95 controls were investigated. Serum samples were determined for MBL by enzyme-linked immunosorbent assay (ELISA) and for serologic markers [autoantibodies against Saccharomyces cerevisiae (ASCA) and perinuclear components of neutrophils (pANCA)] by indirect immunofluorescent assay. NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism. RESULTS The MBL serum concentration was significantly lower in IBD patients(both with CD and UC) compared to controls (IBD, p=0.007, CD, p=0.04, UC p=0.004). Prevalence of low MBL level (<500 ng/mL) was significantly higher in both CD and UC groups compared to controls (p=0.002 and p=0.006). Furthermore, low MBL level was associated with isolated ileal involvement (p=0.01) and MBL deficiency (<100 ng/mL) with male gender (p=0.004) in patients with CD. We failed to confirm any correlation between MBL deficiency and serum autoantibodies or NOD2/CARD15 variants. CONCLUSIONS Our results suggest that low MBL associated with paediatric-onset IBD and ileal CD may be considered an additional marker of the IBD pathogenesis.
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Affiliation(s)
- Marta Kovacs
- Department of Paediatrics, Petz Aladár County and Teaching Hospital, Győr, Hungary
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Lu Y, Sun G, Liu G, Shi Y, Han Y, Yu F, Xiang X, Li W, Xiao H, Liu X, Li S. Clinical significance of mannose-binding lectin expression in thyroid carcinoma tissues. Pathol Oncol Res 2012; 19:259-66. [PMID: 23250731 DOI: 10.1007/s12253-012-9577-x] [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: 07/16/2012] [Accepted: 09/24/2012] [Indexed: 11/26/2022]
Abstract
Mannose-binding lectin (MBL) plays an important role in the host defence against pathogens and carcinogenesis. This study aimed to analyze differential expression of MBL protein in thyroid cancer tissues and then to investigate the effects of rhMBL in thyroid cancer cells. Tissue specimens from 45 thyroid carcinoma patients and 45 adenoma patients were recruited for immunohistochemical analysis of MBL expression. Cell viability, apoptosis, RT-PCR and Western blot assays were used to detect changes in tumor cell viability, apoptosis, and gene expression, respectively, after treatment of thyroid cancer cells with rhMBL. MBL was differentially expressed in papillary thyroid carcinoma, adenoma, and the distant normal tissues (0.322 ± 0.008, 0.227 ± 0.003, and 0.113 ± 0.003, respectively, P < 0.05). MBL expression was associated with the advanced disease stage, histological grade, or lymph node metastasis in cancer patients (P < 0.05). Moreover, rhMBL treatment of thyroid cancer cells reduced tumor cell viability but induced apoptosis in a dose- and time-dependent manner. rhMBL treatment also downregulated Bcl2 protein expression in thyroid cancer cells (P < 0.05). In addition, expression p53 protein was increased in thyroid cancer cells after rhMBL treatment (P < 0.05). The data from the current study demonstrate that MBL overexpression is associated with advanced thyroid carcinomas, and rhMBL treatment significantly reduced viability but induced apoptosis of thyroid cancer cell lines. Further studies will clarify whether overexpressed MBL in thyroid cancer tissues is functional.
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Affiliation(s)
- Yifang Lu
- Department of Endocrinology (Section I), Tangshan Workers Hospital, Tangshan, China
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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.
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Hodge S, Dean M, Hodge G, Holmes M, Reynolds PN. Decreased efferocytosis and mannose binding lectin in the airway in bronchiolitis obliterans syndrome. J Heart Lung Transplant 2011; 30:589-95. [PMID: 21481686 DOI: 10.1016/j.healun.2011.01.710] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2010] [Revised: 01/04/2011] [Accepted: 01/27/2011] [Indexed: 10/18/2022] Open
Abstract
BACKGROUND Mannose binding lectin (MBL) is a key mediator of both innate immunity and efferocytosis (phagocytosis of apoptotic cells) in the airway. Defective efferocytosis results in a net increase in apoptotic material that can undergo secondary necrosis, leading to tissue damage and chronic inflammation. We have shown reduced MBL and efferocytosis in other chronic inflammatory lung diseases; we therefore hypothesized that reduced MBL and efferocytosis in the airways may be a determinant of bronchiolitis obliterans syndrome (BOS) after lung transplantation. METHODS We investigated MBL (enzyme-linked immunosorbent assay [ELISA]), MBL-mediated complement deposition (UC4, ELISA), and efferocytosis of apoptotic bronchial epithelial cells (flow cytometry) in bronchoalveolar lavage (BAL) and peripheral blood from 75 lung transplant recipients, comprising 16 with stable graft function, 34 stable with proven infection, 25 with BOS, and 14 healthy controls. RESULTS In plasma, MBL levels were highly variable (0-17.538 μg/ml), but increased in infected patients vs control (p = 0.09) or stable groups (p = 0.003). There was a similar increase in UC4 in infected patients and a significant correlation between MBL and UC4. There was no correlation between MBL and time after transplant. In BAL, MBL levels were less variable (0-73.3 ng/ml) and significantly reduced in patients with BOS vs controls and stable groups. Efferocytosis was significantly reduced in the BOS group vs control and stable groups (mean [SEM] control, 20% [1.3%]; stable, 20.5% [2.5%]; infected, 17.3% [2.8%]; BOS, 11.3% [1.5%], p = 0.04). CONCLUSIONS Low levels of MBL in the airway may play a role in reduced efferocytosis, subsequent tissue damage, and BOS after lung transplantation.
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Affiliation(s)
- Sandra Hodge
- Lung Research Laboratory, Hanson Institute and Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia.
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Mannose-binding lectin serine proteases and associated proteins of the lectin pathway of complement: two genes, five proteins and many functions? BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2011; 1824:253-62. [PMID: 21664989 DOI: 10.1016/j.bbapap.2011.05.021] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2011] [Revised: 05/27/2011] [Accepted: 05/27/2011] [Indexed: 10/18/2022]
Abstract
The lectin pathway of the complement system is activated following the binding of carbohydrate-based ligands by recognition molecules such as mannose-binding lectin (MBL) or ficolins. Engagement of the recognition molecules causes activation of associated MBL-associated serine proteases or MASPs, which in turn activate downstream complement molecules to activate the system. Two MASP genes are alternatively spliced during expression to yield 5 proteins, including three proteases (MASP-1, -2 and -3) and two truncated proteins, MAp19 and MAp44. Here we discuss what is currently known about these proteins in terms of their structure and function. MASP-2 is autoactivated following the initial binding events of the pathway and is able to subsequently activate the C4 and C2 substrates required to activate the rest of the pathway. MASP-1 is able to augment MASP-2 activation, but also appears to play other roles, although the physiological significance of these is not yet clear. The roles of the truncated Map19 and Map44 proteins and the MASP-3 protease are currently unknown. The proteases form an interesting sub-family of proteins that clearly should be the focus of future research in order to establish their biological roles. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
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Sheng A, Lan J, Wu H, Lu J, Wang Y, Chu Q, Jia Z, Song M, Liu L, Wang W. A clinical case-control study on the association between mannose-binding lectin and susceptibility to HIV-1 infection among northern Han Chinese population. Int J Immunogenet 2011; 37:445-54. [PMID: 20618520 DOI: 10.1111/j.1744-313x.2010.00946.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Mannose-binding lectin (MBL) is a key molecule of the innate immune system and a competent to bind carbohydrates of a variety of microorganisms, resulting in complement activation and opsonophagocytosis against various pathogens. However, there is no systemic investigation on the MBL's role in innate immune responses against HIV-1 infection among northern Han Chinese. This study investigated the association between MBL and HIV-1 infection susceptibility among northern Han Chinese. A total of 91 HIV-1 infected patients and 91 HIV-1 seronegative healthy individuals were recruited. Six polymorphisms of MBL2 gene were genotyped by pyrosequencing. The quantitative measurement of serum MBL concentration and MBL complex activity were performed by ELISA. The CD4+ T-cell counts were determined by flow cytometry. The plasma viral loads of 91 HIV-1 infected patients were determined by bDNA method. The results show that there is an association between MBL and HIV-1 infection susceptibility among northern Han Chinese. The individuals with B variant, low serum MBL concentration and low MBL complex activity are more susceptible to HIV-1 infection.
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Affiliation(s)
- A Sheng
- School of Public Health and Family Medicine, Capital Medical University, Beijing, China
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Dean MM, Flower RL, Eisen DP, Minchinton RM, Hart DNJ, Vuckovic S. Mannose-binding lectin deficiency influences innate and antigen-presenting functions of blood myeloid dendritic cells. Immunology 2010; 132:296-305. [PMID: 21091907 DOI: 10.1111/j.1365-2567.2010.03365.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Mannose-binding lectin (MBL) is a serum lectin that plays a significant role in innate host defence. Individuals with mutations in exon 1 of the MBL2 gene have reduced MBL ligand binding and complement activation function and increased incidence of infection. We proposed that, during infection, MBL deficiency may impact on dendritic cell (DC) function. We analysed the blood myeloid DC (MDC) surface phenotype, inflammatory cytokine production and antigen-presenting capacity in MBL-deficient (MBL-D) individuals and MBL-sufficient (MBL-S) individuals using whole blood culture supplemented with zymosan (Zy) or MBL-opsonized zymosan (MBL-Zy) as a model of infection. Zy-stimulated MDCs from MBL-D individuals had significantly increased production of interleukin (IL)-6 and tumour necrosis factor (TNF)-α. Stimulation with MBL-Zy significantly decreased IL-6 production by MDCs from MBL-D, but had no effect on TNF-α production. MDCs from both MBL-S and MBL-D individuals up-regulated expression of the activation molecule CD83, and down-regulated expression of homing (CXCR4), adhesion (CD62L, CD49d) and costimulatory (CD40, CD86) molecules in response to Zy and MBL-Zy. MDC from both MBL-D and MBL-S individuals induced proliferation of allogeneic (allo) T cells following Zy or MBL-Zy stimulation; however, MBL-D individuals demonstrated a reduced capacity to induce effector allo-T cells. These data indicate that MBL deficiency is associated with unique functional characteristics of pathogen-stimulated blood MDCs manifested by increased production of IL-6, combined with a poor capacity to induce effector allo-T-cell responses. In MBL-D individuals, these functional features of blood MDCs may influence their ability to mount an immune response.
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Affiliation(s)
- Melinda M Dean
- Australian Red Cross Blood Service, 44 Musk Avenue Kelvin Grove, QLD, Australia.
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Mannose-binding lectin gene (MBL-2) polymorphism in oral lichen planus. Clin Oral Investig 2010; 15:699-704. [PMID: 20499118 DOI: 10.1007/s00784-010-0428-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2009] [Accepted: 05/11/2010] [Indexed: 01/22/2023]
Abstract
TNF-α may be associated with the etiopathogenesis of oral lichen planus (OLP), and it has been suggested that polymorphism of mannose-binding lectin (MBL) increases the in vitro production of TNF- α. The aim of the present study was to assess the relevance of genetic diversity of MBL in OLP. The study sample comprised 90 individuals, 45 OLP patients and 45 healthy volunteers. MBL-2 gene was amplified using real-time PCR. Frequency of A/A genotype was 55.6% in OLP and 53.3% in healthy volunteers. Likewise, A/0 heterozygote genotype was found in 42.2% and 35.6%; 2.2% and 11.1%, had the recessive 0/0 genotype respectively. Frequencies of the "A" and "0" alleles were 77% and 23% in the OLP group and 71.2% in control group. There were no statistically significant differences regarding genotype frequency (p = 0.546) or allele frequency (p = 0.497). In conclusion, no significant association was found between polymorphism of MBL-2 gene and OLP.
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Melo FM, Vasconcelos LRS, Silva BS, Moura P, Cavalcanti MSM, Pereira LMMB, Lacerda HR. Structural polymorphism of the mannose-binding lectin 2 (MBL2 ) gene in HCV-infected patients with a serological marker for thyroid autoimmunity. Int J Immunogenet 2009; 36:377-81. [PMID: 19703233 DOI: 10.1111/j.1744-313x.2009.00871.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We studied the association of the mannose-binding lectin-2 (MBL2) polymorphism with anti-thyroid antibodies (ATA) in hepatitis C virus (HCV)-infected Brazilian patients (n = 162) and 124 healthy volunteers screened for ATA. Our results showed that patients with ATA had higher frequency of genotype 00 than controls. MBL may play a role as disease modifier in HCV infection.
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Affiliation(s)
- F M Melo
- Postgraduate Program in Tropical Medicine, Federal University of Pernambuco (UFPE), Pernambuco, Brazil
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Mannan-binding lectin B allele is associated with a risk of developing more severe gastric mucosal atrophy in Helicobacter pylori-infected Japanese patients. Eur J Gastroenterol Hepatol 2009; 21:781-6. [PMID: 19352197 DOI: 10.1097/meg.0b013e328309c76b] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE Mannan-binding lectin (MBL) is an important constituent of the innate immune system, and deficiency of MBL has been reported to increase the overall susceptibility of an individual to infectious disease. Codon 54 G/A variant of exon 1 (B allele) affects MBL2 gene and alters its activity. We investigated the influence of MBL2 variant on the risk of gastroduodenal diseases and on the severity of Helicobacter pylori-induced gastritis in a Japanese population. METHODS One hundred and two gastric ulcers, 48 duodenal ulcers, 275 nonulcer participants were included in this study. B allele of the MBL2 gene was detected by polymerase chain reaction based restriction fragment length polymorphism. The severity of the histological chronic gastritis in antral biopsy specimens were classified according to the updated Sydney system. RESULTS MBL2 B allele was significantly associated with severity of gastric mucosal atrophy and intestinal metaplasia (atrophy, G/G vs. G/A vs. A/A; P=0.02, A/A vs. others; P=0.009, intestinal metaplasia; G/G vs. G/A vs. A/A; P=0.03, A/A vs. others; P=0.004). When participants were divided into the following three groups according to the severity of gastric atrophy: the nonatrophic gastritis (NA) group, the severe atrophic gastritis (SA) group, and mild atrophic gastritis (MA) group, the frequency of A/A was significantly higher in the SA group than in others (SA vs. MA; odds ratio=8.42, 95% confidence interval=1.05-67.45, SA vs. others; odds ratio=10.06, 95% confidence interval=1.26-80.45). CONCLUSION Our data suggest that the MBL2 codon 54 B allele is associated with a risk of developing more severe gastric mucosal atrophy in H. pylori-infected Japanese patients.
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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.
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Affiliation(s)
- Jacqueline Araujo
- Pediatric Endocrinology Unit of Clinical Hospital, Federal University of Pernambuco, Pernambuco, Brazil
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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.
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Affiliation(s)
- Lorete Maria da Silva Kotze
- Gastroenterology Service, Cajuru Hospital, Pontifical Catholic University of Paraná, Curitiba, Parana, Brazil
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Wang FY, Tahara T, Arisawa T, Shibata T, Yamashita H, Nakamura M, Yoshioka D, Okubo M, Maruyama N, Kamano T, Kamiya Y, Nakamura M, Fujita H, Nagasaka M, Iwata M, Takahama K, Watanabe M, Nakano H, Hirata I. Mannan-binding lectin (MBL) polymorphism and gastric cancer risk in Japanese population. Dig Dis Sci 2008; 53:2904-8. [PMID: 18368489 DOI: 10.1007/s10620-008-0249-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2008] [Accepted: 03/07/2008] [Indexed: 12/22/2022]
Abstract
BACKGROUND Mannan-binding lectin (MBL) is believed to be an important constituent of the innate immune system. It has been reported that the codon 54 G/A polymorphism of exon-1 affects the MBL2 gene and alters its activity. AIMS We investigated the association between polymorphism of the MBL2 gene and gastric cancer risk as well as Helicobacter pylori infection in a Japanese population. METHODS The study cohort comprised 388 gastric cancer patients and 144 healthy volunteers. Polymorphism at codon 54 of exon 1 of the MBL2 gene was investigated by PCR-based restriction fragment length polymorphism analysis. RESULTS There was no significant difference in the distribution of the MBL2 genotype among the gastric cancer patients and healthy controls. However, the carrier of the A allele was more prevalent among patients with a more advanced stage gastric cancer [odds ratio (OR) 1.68, 95% confidence interval (CI) 1.05-2.67; P = 0.03] and also had an increased risk of gastric cancer among patients 65 years of age or younger (OR = 1.6, 95%CI = 1.01-2.52, <0.05). CONCLUSION The codon 54 polymorphism of the MBL2 gene is associated with more advanced phenotypes of gastric cancer and the risk of gastric cancer in Japanese patients 65 years of age or younger.
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Affiliation(s)
- Fang-Yu Wang
- Department of Gastroenterology, Fujita Health University School of Medicine, Aichi Prefecture, 470-1192, Japan
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Milanese M, Segat L, De Seta F, Pirulli D, Fabris A, Morgutti M, Crovella S. ORIGINAL ARTICLE: MBL2 Genetic Screening in Patients with Recurrent Vaginal Infections. Am J Reprod Immunol 2008; 59:146-51. [DOI: 10.1111/j.1600-0897.2007.00549.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Pre- and postoperative levels in serum of mannan-binding lectin associated serine protease-2 -a prognostic marker in colorectal cancer. Hum Immunol 2008; 69:414-20. [PMID: 18638656 DOI: 10.1016/j.humimm.2008.05.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2008] [Revised: 05/16/2008] [Accepted: 05/18/2008] [Indexed: 11/20/2022]
Abstract
Mannan-binding lectin-associated serine protease-2 (MASP-2) is the initiating enzyme of the lectin pathway of complement activation. High preoperative serum levels of MASP-2 are associated with recurrence and poor survival in patients with colorectal cancer (CRC). In this study we investigate the prognostic role of MASP-2 in patients curatively resected for primary CRC. Serum concentrations of MASP-2 were determined in 281 patients prior to surgery and 7 months postoperatively using a time-resolved immunofluorometric assay. End points were recurrent cancer and death within a median follow-up time of 7.9 years. The correlation between pre- and postoperative levels was 0.49. High postoperative levels of MASP-2 were significantly associated with poor survival [p = 0.04; hazard ratio (HR) = 1.35; 95% confidence interval (CI), 1.02-1.80] and recurrence (p = 0.01, HR = 1.6, 95% CI, 1.1-1.6). The inclusion of age, gender, tumor localization, and Dukes stage in multivariate analysis demonstrated that high MASP-2 levels were independently predictive of survival (p = 0.01; HR = 1.5, 95% CI, 1.1-2.0) and recurrence (p = 0.01, HR = 1.6; 95% CI, 1.1-2.4). Combining pre- and postoperative MASP-2 levels did not improve the prediction of survival/recurrence. High postoperative levels of MASP-2 are associated with poor prognosis in patients curatively resected for CRC. A change of the MASP-2 level from preoperative levels was not, per se, predictive of recurrent disease or survival.
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Ytting H, Christensen IJ, Thiel S, Jensenius JC, Svendsen MN, Nielsen L, Lottenburger T, Nielsen HJ. Biological variation in circulating levels of mannan-binding lectin (MBL) and MBL-associated serine protease-2 and the influence of age, gender and physical exercise. Scand J Immunol 2007; 66:458-64. [PMID: 17850591 DOI: 10.1111/j.1365-3083.2007.01991.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) are central components of the MBL pathway of complement activation, and may have potential as clinical biomarkers in colorectal cancer (CRC). Prior to clinical usage, knowledge of the biological variations of the molecules is needed. We here investigate variations of MBL and MASP-2 in healthy persons over time and in relation to gender, age and physical activity. MBL and MASP-2 concentrations were determined in serum from healthy adults over a 3-week period and this was repeated 6 months later (n = 32); during a 24-h period (n = 16); and in relation to physical exercise (n = 14). Concentrations in serum and plasma were compared (n = 198). No significant variation over 6 months and no circadian variation was found for MBL (P = 0.39 and P = 0.34 respectively) or MASP-2 (P = 0.54 and P = 0.55). Physical exercise did not affect the levels (P > 0.8). Serum and plasma levels were only marginally different, and were independent of age and gender. Circulating levels of MBL and MASP-2 are stable over time in healthy individuals, which is advantageous for their potential application as biomarkers.
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Affiliation(s)
- H Ytting
- Department of Surgical Gastroenterology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
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Pine SR, Mechanic LE, Ambs S, Bowman ED, Chanock SJ, Loffredo C, Shields PG, Harris CC. Lung cancer survival and functional polymorphisms in MBL2, an innate-immunity gene. J Natl Cancer Inst 2007; 99:1401-9. [PMID: 17848669 PMCID: PMC6278934 DOI: 10.1093/jnci/djm128] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The relationship among chronic inflammation, innate immunity, and cancer is well established. Mannose-binding lectin (MBL) is a key player in innate immunity. Five polymorphisms in the promoter and first exon of the MBL2 gene alter the expression and function of MBL in humans and are associated with inflammation-related disease susceptibility. These five polymorphisms create six well-characterized haplotypes that result in lower (i.e., LYB, LYC, HYD, and LXA) or higher (i.e., HYA and LYA) serum MBL concentrations. We investigated whether survival of patients with lung cancer was associated with these polymorphisms. METHODS We used a multivariable Cox proportional hazards model to study the association between MBL2 polymorphisms and their haplotypes and diplotypes in 558 white and 173 African American patients with non-small-cell lung cancer in the Baltimore, MD, area and lung cancer mortality. Smoking history and race were obtained from interviews, tumor stage was obtained from medical records, and cause of death was obtained from the National Death Index. All statistical tests were two-sided. RESULTS We found a statistically significant association between the X allele of the promoter Y/X polymorphism (which results in a lower serum MBL concentration) and improved lung cancer survival among white patients (risk ratio [RR] of death from lung cancer with X/X or X/Y genotype compared with Y/Y genotype = 0.61, 95% confidence interval [CI] = 0.46 to 0.81) but not among African American patients (RR = 1.11, 95% CI = 0.69 to 1.77). The associations among white patients were strongest in heavy smokers and were independent of stage. We also found a statistically significant interaction between the Y/X polymorphism and race for lung cancer survival (P(interaction) = .019). The MBL2 LXA haplotype and XA/B diplotype, which are also associated with low serum MBL levels, were statistically significantly associated with improved lung cancer survival among white patients. CONCLUSION The functional Y/X polymorphism of the innate-immunity gene MBL2 and MBL2 haplotypes and diplotypes appear to be associated with lung cancer survival among white patients.
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Affiliation(s)
- Sharon R Pine
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4258, USA
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Seibold F, Boldt ABW, Seibold-Schmid B, Schoepfer AM, Flogerzi B, Müller S, Kun JFJ. Association of deficiency for mannan-binding lectin with anti-mannan antibodies in Crohn's disease: a family study. Inflamm Bowel Dis 2007; 13:1077-82. [PMID: 17480019 DOI: 10.1002/ibd.20156] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND Antibodies against mannan, a component of the yeast Saccharomyces cerevisiae cell wall, are more frequently found in Crohn's disease (CD) patients with low levels of mannan-binding lectin (MBL). MBL concentration depends on genetic polymorphisms. The aim of this study was to evaluate whether low MBL is related to ASCA production in healthy family members of CD patients. METHODS ASCA and MBL concentrations in sera from patients (n=52), and their 158 healthy relatives were measured by enzyme-linked immunosorbent assay (ELISA). Genetic MBL variants were determined by DNA sequencing. RESULTS Thirty-five (67%) patients were ASCA-positive. Twenty-six (74%) of the 35 ASCA-positive patients had low MBL levels (<500 ng/mL), whereas only 4 (24%) of the 17 ASCA-negative patients had low values for MBL (P=0.001). ASCA were found in 38 (24%) family members. Twenty-three (50%) of 46 family members with low values for MBL were ASCA-positive compared to 15 (13%) of 112 family members with normal values for MBL (P<0.0001). ASCA were found in 33 of 104 (32%) family members of ASCA-positive patients and in 5 family members (9%) of ASCA-negative patients (P=0.002). Relatives with mutations leading to MBL deficiency had significantly more frequent ASCA than relatives without these mutations (P=0.018). CONCLUSIONS MBL deficiency is associated with ASCA positivity not only in patients with CD, but also in their relatives. An impaired innate immune system defined by low MBL serum concentrations may lead to an increased reactivity of the specific immune system to mannan antigens, and therefore facilitate the generation of ASCA.
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Affiliation(s)
- Frank Seibold
- Division of Gastroenterology, Inselspital, University of Bern, Bern, Switzerland.
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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.
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Naluai AT, Ascher H, Nilsson S, Wahlström J. Searching for genes influencing a complex disease: the case of coeliac disease. Eur J Hum Genet 2007; 16:542-53. [PMID: 17726483 DOI: 10.1038/sj.ejhg.5201918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Recently, a few genes have been reported to be causative in inflammatory diseases. Still, we are waiting for the vast majority to be discovered. New tools for genotyping and statistical analysis have been developed and emphasis has been put on study design. Coeliac disease (CD) is a disorder, where prolamins in dietary wheat gluten and related proteins from rye or barley are not tolerated. It is one of the most common chronic diseases in humans exceeding a population prevalence of 1%. In this article, we will summarise what is currently known about the genetics influencing CD with the emphasis on the non-HLA genetic component. We will discuss some difficulties when searching for susceptibility genes in disorders with complex inheritance patterns.
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Affiliation(s)
- Asa Torinsson Naluai
- Department of Genomics, The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
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Grasso DL, Guerci VI, Zocconi E, Milanese M, Segat L, Crovella S. MBL2 genetic polymorphisms in Italian children with adenotonsillar hypertrophy. Int J Pediatr Otorhinolaryngol 2007; 71:1013-6. [PMID: 17482281 DOI: 10.1016/j.ijporl.2007.02.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2006] [Revised: 02/22/2007] [Accepted: 02/22/2007] [Indexed: 11/18/2022]
Abstract
We investigated the role of the polymorphisms in the first exon of MBL2 gene in the susceptibility to recurrent tonsillitis in a selected group of Italian children and healthy controls. Significant difference has been observed in MBL2 genotype and allelic frequencies between children with recurrent tonsillitis and healthy controls matched for sex and age. Children characterized by a "low MBL" producer genotype, namely 00, are more prone to recurrent tonsillitis when compared to the healthy controls. To our knowledge this is the first report on the role of MBL2 polymorphisms in adenotonsillar hypertrophy and our results shown that presence of MBL2 00 genotype could be used as a prognostic marker in subjects with adenotonsillar hypertrophy.
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Affiliation(s)
- Domenico Leonardo Grasso
- ENT Department, IRCCS Burlo-Garofolo Children Hospital, Via dell'Istria 65/1, 34100 Trieste, Italy.
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Araujo J, Brandão LAC, Guimarães RL, Santos S, Falcão EA, Milanese M, Segat L, Souza PR, de Lima-Filho JL, Crovella S. Mannose binding lectin gene polymorphisms are associated with type 1 diabetes in Brazilian children and adolescents. Hum Immunol 2007; 68:739-43. [PMID: 17869647 DOI: 10.1016/j.humimm.2007.05.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2007] [Revised: 04/27/2007] [Accepted: 05/24/2007] [Indexed: 11/25/2022]
Abstract
Mannose-binding lectin is an important constituent of the innate immune system, the serum levels of which are greatly affected by polymorphisms of the MBL2 gene: three polymorphisms in exon 1, as well as nucleotide variations in the promoter region of the gene, have been associated with protein deficiency and some infectious and autoimmune disease. The aim of this study was to investigate a possible association between MBL2 gene polymorphisms in patients who have developed type 1 diabetes during childhood and adolescence. We evaluated MBL2 gene polymorphisms in 214 children and adolescents with type 1 diabetes and compared them with a healthy control group, finding significant differences in genotypic and allelic frequencies (p = 0.004 and p = 0.0008, respectively). Our results suggest that patients with type 1 diabetes possessing the 0 allele have a higher risk for developing type 1 diabetes during childhood and adolescence, and that this risk factor is not related to age at diagnosis.
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Affiliation(s)
- Jacqueline Araujo
- Pediatric Endocrinology Unit of Clinical Hospital, Federal University of Pernambuco and Maternal and Children's Institute of Pernambuco, Recife, Brazil
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Worthley DL, Bardy PG, Gordon DL, Mullighan CG. Mannose-binding lectin and gastric cancer. Int J Cancer 2007; 120:2751-2; author reply 2750. [PMID: 17351901 DOI: 10.1002/ijc.22662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Baccarelli A, Hou L, Grillo P, Chow WH. Reply to the letter to the Editor:Helicobacter pylori infection andMBL2 haplotypes: Lack of association or lack of evidence? Int J Cancer 2007. [DOI: 10.1002/ijc.22659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Association of polymorphisms in the first exon of mannose binding lectin gene (MBL2) in Brazilian patients with HCV infection. Clin Immunol 2007; 124:13-7. [PMID: 17513174 DOI: 10.1016/j.clim.2007.04.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2007] [Revised: 04/16/2007] [Accepted: 04/16/2007] [Indexed: 10/23/2022]
Abstract
In our study we investigated the role of the polymorphisms in the first exon of MBL2 gene in the susceptibility to HCV infection and disease progression in a Northeastern Brazilian population. One hundred and eleven patients seen at the Gastroenterology Service of the Oswaldo Cruz Hospital of the University of Pernambuco were included in this study. A total of 165 unexposed, uninfected individuals matched for place of origin were employed as healthy controls. MBL2 genotyping was performed by using a melting temperature assay. The 0 allele was significantly more frequent in the HCV positive group than the healthy controls (34% vs. 20%, p<0.01, respectively) and was associated to an increased risk of HCV-1 infection (O.R.=2.1; C.I. 1.41-3.19). Also genotypes frequencies were significantly different in HCV positive subjects when compared to healthy controls with the 00 and A0 genotypes being significantly overrepresented in HCV infected subject (15% and 37%, respectively) as compared to healthy subjects (6% and 27%, respectively, p<0.01 ) Allele and genotypes frequencies were also evaluated in HCV infected subjects according to their response to pegylated-INFalpha/riboviron therapy. There was a trend for HCV positive responders vs. non-responders to be 0 allele positive and a similar trend was observed for the MBL2 A0 and 00 genotypes, but neither of these reached statistical significance. Our findings indicate that MBL might represent an important antiviral molecule having a protective role in the first stages of HCV infection, as shown by the increased frequency of wild-type alleles in control population as compared to the infected group.
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Abstract
PURPOSE OF REVIEW Increasing numbers of atypical or asymptomatic cases of celiac disease are being diagnosed. This review aims to summarize recent critical research in celiac disease. RECENT FINDINGS Alternative candidate genes outside of the human leukocyte antigen complex continue to be identified, whilst innate and adaptive immune responses to key gliadin epitopes are now both recognized to be important in celiac disease pathogenesis. SUMMARY Serological tests and small bowel biopsy remain the cornerstones of diagnosis. Treatment options other than the restrictive gluten-free diet remain limited.
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Affiliation(s)
- Darren Craig
- Academic Medical Unit, Leeds Institute of Molecular Medicine, Leeds, UK
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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.
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Affiliation(s)
- Daniel-L Worthley
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Room 3D230, Bedford Park, SA, 5042, Australia.
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Baccarelli A, Hou L, Chen J, Lissowska J, El-Omar EM, Grillo P, Giacomini SM, Yaeger M, Bernig T, Zatonski W, Fraumeni JF, Chanock SJ, Chow WH. Mannose-binding lectin-2 genetic variation and stomach cancer risk. Int J Cancer 2006; 119:1970-5. [PMID: 16721783 DOI: 10.1002/ijc.22075] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Deficiency of the mannose-binding lectin (MBL) protein, an antigen-recognition molecule involved in systemic and mucosal innate immunity, is determined by variant alleles in MBL2 gene promoter and exon-1 regions. We conducted a population-based study on 305 stomach cancer cases and 427 controls in Warsaw, Poland to determine whether MBL2 gene variants predispose to stomach cancer. Single nucleotide polymorphisms (SNPs) in MBL2 were determined by TaqMan. The 5 tested MBL2 variants are in complete linkage disequilibrium and comprise 6 different haplotypes. The risk of stomach cancer was increased in subjects carrying the H/H promoter genotype (OR = 1.8, 95%CI 1.1-2.9; p = 0.020) relative to L/L carriers, after adjustment for age, gender, education and smoking. Carrying at least one D exon-1 allele was associated with nonsignificant excess risk (OR = 1.5, 95% CI 0.9-2.4; p = 0.081). In haplotype analysis, the HYD haplotype was associated with increased risk of stomach cancer when compared with HYA, the most common haplotype (OR = 1.9, 95% CI 1.1-3.2; p = 0.021). In diplotype analysis, subjects carrying the YA/D haplotype combination showed the highest risk (OR = 3.0, 95% CI 1.2-7.1; p = 0.015), compared with YA/YA. Further analyses to examine the joint effect of MBL2 and IL-1B polymorphisms, previously shown to predispose to stomach cancer, indicated that the combination of at-risk IL-1B genotypes (CT or TT at location -511) and HYD MBL2 haplotype was associated with a 3.5-fold risk (OR = 3.5, 95% CI 1.6-7.6; p = 0.001). Our findings suggest that the codon 52 D MBL2 variant causing a cysteine > arginine replacement, but not B and C variants producing glycine substitutions, is specifically associated with gastric cancer risk.
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Affiliation(s)
- Andrea Baccarelli
- EPOCA Epidemiology Research Centre, Maggiore Hospital IRCCS Foundation, University of Milan, Milan, Italy.
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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.
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Affiliation(s)
- S Thiel
- Department of Medical Microbiology and Immunology, University of Aarhus, DK8000 Denmark.
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Sørensen R, Thiel S, Jensenius JC. Mannan-binding-lectin-associated serine proteases, characteristics and disease associations. SPRINGER SEMINARS IN IMMUNOPATHOLOGY 2005; 27:299-319. [PMID: 16189649 DOI: 10.1007/s00281-005-0006-z] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2005] [Accepted: 05/26/2005] [Indexed: 11/27/2022]
Abstract
Mannan-binding lectin (MBL)-associated serine proteases (MASPs) circulate in plasma as zymogens in complexes with MBL and with L- and H-ficolin. Upon binding of MBL or ficolin to pathogen-associated molecular patterns, the MASPs are activated. MASP-2 can now cleave C4 and C2 to generate the C3 convertase, C4bC2b. The functions of the other two MASPs, MASP-1 and MASP-3 have not been elucidated. MASP-1 can cleave C2, and with low efficiency also C3, and may serve a function through direct C3 activation. No natural substrate for MASP-3 has been identified. MBL deficiency, occurring at a frequency of about 10%, is the most common congenital immunodeficiency and is associated with susceptibility to infections and autoimmune disorders. Inherited MASP-2 deficiency has been described as the result of a mutation causing the exchange of aspartic acid with a glycine at position 105, a position in the first domain, CUB1, involved in calcium binding. This mutation abolishes the binding to MBL and ficolins, and deprives MASP-2 of functional activity. The index case suffered from recurrent severe infections and autoimmune reactions. The gene frequency of the mutation among Caucasians is 3.6%. It is not found in Chinese, who present a different mutation also associated with MASP-2 deficiency.
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Affiliation(s)
- Rikke Sørensen
- Department of Medical Microbiology and Immunology, Wilhelm Meyers Allé, University of Aarhus, 8000 Aarhus, Denmark.
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da Rosa Utiyama SR, da Silva Kotze LM, de Messias Reason IT. Complement factor B allotypes in the susceptibility and severity of coeliac disease in patients and relatives. Int J Immunogenet 2005; 32:307-14. [PMID: 16164698 DOI: 10.1111/j.1744-313x.2005.00529.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The alternative pathway of complement plays an important role in the pathogenesis of coeliac disease (CD), where factor B (BF) is central to its activation. CD is a gluten-sensitive enteropathy that results from a complex interplay between genetic, immunologic, and environmental factors. In this study we evaluated the association of BF allotypes with the susceptibility and severity of CD, and with the presence of autoantibodies. Seventy-six non-related patients (56 female; 20 male; 2-77 years) and 150 first-degree relatives (87 female, 63 male; 2-75 years) were investigated. As controls, 97 healthy individuals were included (67 female;, 30 male; 1-71 years). The BF allotypes were determined by high-voltage agarose gel electrophoresis, followed by specific immunofixation. Disease severity was evaluated by anti-endomisial antibody (IgA-EmA) titres and histological findings of intestinal mucosa, which showed a high correlation (r = 0.8; P < 0.00001) in samples collected simultaneously. IgA-EmA was detected in all CD patients ingesting gluten, and in 13.3% of the relatives. The IgA-EmA, smooth muscle, mitochondrial, liver-kidney microsomal, nuclear, gastric parietal cells, and thyroid microsome antibodies were tested by indirect immunofluorescence. A significant decrease in BF S (P = 0.026) and an increasing tendency in BF SF allotype (P = 0.06) were observed in CD patients when compared to their relatives. On the other hand, BF S frequency was increased (P = 0.001 RR = 2.32) and BF SF (P = 0.002) decreased in the relatives when compared to the controls. No differences were observed in the distribution of BF phenotypes amongst the CD patients and the control group, and no association was found with CD severity or with the presence of autoantibodies. These results suggest BF SF as a CD susceptibility marker, and BF S as a protection marker of the disease amongst CD families in the Brazilian population.
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Affiliation(s)
- S R da Rosa Utiyama
- Laboratory of Immunopathology, Clinical Hospital, Federal University of Paraná, Curitiba, Paraná, Brazil
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Bouwman LH, Eerligh P, Terpstra OT, Daha MR, de Knijff P, Ballieux BEPB, Bruining GJ, van der Slik AR, Roos A, Roep BO. Elevated levels of mannose-binding lectin at clinical manifestation of type 1 diabetes in juveniles. Diabetes 2005; 54:3002-6. [PMID: 16186405 DOI: 10.2337/diabetes.54.10.3002] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL polymorphisms have been described that are associated with MBL serum concentration, impaired function, and diabetic complications. We investigated 86 new-onset juvenile type 1 diabetic patients and compared these with their nondiabetic siblings and healthy unrelated control subjects. Polymorphisms of MBL exon 1 and promoter were determined, and serum concentration and MBL-complex activity were measured. Although the genetic polymorphisms of MBL were not different between patients and control subjects, MBL serum concentration as well as MBL complex activity was significantly higher in new-onset diabetic patients compared with their siblings matched for high-producing MBL genotypes (P = 0.0018 and P = 0.0005, respectively). The increase in MBL complex activity in high-MBL-producing patients could only partially be explained by high MBL production, as demonstrated by an increased MBL complex activity-to-MBL concentration ratio (P = 0.004). We conclude that MBL serum concentration and complex activity are increased in early-onset diabetic patients upon manifestation independently of genetic predisposition to high MBL production, indicating a possible role in the immunopathogenesis of type 1 diabetes, in addition to the adaptive islet autoimmunity.
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Affiliation(s)
- Lee H Bouwman
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
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