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Steffen Thiel - One of the best experts on this subject based on the ideXlab platform.
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Diabetes Is Associated with Increased Autoreactivity of Mannan-Binding Lectin
Journal of diabetes research, 2017Co-Authors: Esben Axelgaard, Steffen Thiel, Jakob Appel Østergaard, Troels Krarup HansenAbstract:Mannan-Binding Lectin (MBL) has been reported to be involved in the pathophysiology of diabetic nephropathy. MBL is a pattern-recognition molecule of the innate immune system that initiates the Lectin pathway of the complement system upon recognition of evolutionary conserved pathogen-associated molecular patterns or to altered self-tissue. Our group have previously shown direct effects of MBL on diabetes-induced kidney damage, and we hypothesized that MBL may cause autoactivation of the complement system via Binding to neoepitopes induced by hyperglycemia. In the present study, we induced diabetes in MBL knockout mice and in wild type C57BL/6J mice by low-dose streptozotocin injection and measured blood glucose and urine albumin-to-creatinine ratio to monitor development of diabetes. After 24 weeks, fluorescently labelled recombinant MBL was injected intravenously in diabetic MBL knockout mice after which the distribution was investigated using in vivo fluorescence imaging. Mice were subjected to in vivo and ex vivo imaging 24 hours after injection. MBL was found to accumulate in the kidneys of diabetic mice as compared to healthy control mice (). These findings support the hypothesis of a significant role of MBL and the complement system in the pathophysiology of diabetic nephropathy.
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Effect of Optimization of Glycaemic Control on Mannan-Binding Lectin in Type 1 Diabetes
Hindawi Limited, 2017Co-Authors: Gry Høst Dørflinger, Steffen Thiel, Jakob Appel Østergaard, Charlotte Brink Holt, Troels Krarup HansenAbstract:Objective. Mannan-Binding Lectin (MBL) concentration in plasma is increased in subjects with type 1 diabetes and associated with increased mortality and risk of diabetic nephropathy. Recent findings show that pancreas transplantation reduces MBL concentration. Whether the increased MBL concentration is reversed by improved glycaemic control remains unknown. We investigated the effects of improved glycaemic control on MBL concentration in patients with type 1 diabetes. Methods. We measured MBL, fructosamine, and HbA1cat baseline and after 6 weeks in 52 type 1 diabetic patients following the change from conventional insulin therapy to insulin pump therapy. Results. After initiation of insulin pump therapy, the total daily insulin dose was significantly reduced (from 51 ± 18 IE/day to 39 ± 13 IE/day, P
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Diabetes Is Associated with Increased Autoreactivity of Mannan-Binding Lectin
Hindawi Limited, 2017Co-Authors: Esben Axelgaard, Steffen Thiel, Jakob Appel Østergaard, Troels Krarup HansenAbstract:Mannan-Binding Lectin (MBL) has been reported to be involved in the pathophysiology of diabetic nephropathy. MBL is a pattern-recognition molecule of the innate immune system that initiates the Lectin pathway of the complement system upon recognition of evolutionary conserved pathogen-associated molecular patterns or to altered self-tissue. Our group have previously shown direct effects of MBL on diabetes-induced kidney damage, and we hypothesized that MBL may cause autoactivation of the complement system via Binding to neoepitopes induced by hyperglycemia. In the present study, we induced diabetes in MBL knockout mice and in wild type C57BL/6J mice by low-dose streptozotocin injection and measured blood glucose and urine albumin-to-creatinine ratio to monitor development of diabetes. After 24 weeks, fluorescently labelled recombinant MBL was injected intravenously in diabetic MBL knockout mice after which the distribution was investigated using in vivo fluorescence imaging. Mice were subjected to in vivo and ex vivo imaging 24 hours after injection. MBL was found to accumulate in the kidneys of diabetic mice as compared to healthy control mice (p
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circulating Mannan Binding Lectin m l h ficolin and colLectin liver 1 levels in patients with acute liver failure
Liver International, 2015Co-Authors: Tea Lund Laursen, Steffen Thiel, Thomas Damgaard Sandahl, Sidsel Stoy, Frank V Schiodt, William M Lee, Hendrik Vilstrup, Henning GronbaekAbstract:Background The complement system is activated in liver diseases including acute liver failure (ALF); however, the role of the Lectin pathway of complement has scarcely been investigated in ALF. The pathway is initiated by soluble pattern recognition molecules: Mannan-Binding Lectin (MBL), M-, L- and H-ficolin and colLectin-liver-1 (CL-L1), which are predominantly synthesised in the liver.
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polymorphisms in Mannan Binding Lectin mbl associated serine protease 2 affect stability Binding to mbl and enzymatic activity
Journal of Immunology, 2009Co-Authors: Steffen Thiel, Rudi Steffensen, Søren E. Degn, Martin Kolev, Annette Hansen, Marieta M Ruseva, Jens C. JenseniusAbstract:Mannan-Binding Lectin-associated serine protease 2 (MASP-2) is an enzyme of the innate immune system. MASP-2 forms complexes with the pattern recognition molecules Mannan-Binding Lectin (MBL), H-ficolin, L-ficolin, or M-ficolin, and is activated when one of these proteins recognizes microorganisms and subsequently cleaves complement factors C4 and C2, thus initiating the activation of the complement system. Missense polymorphisms of MASP-2 exist in different ethnic populations. To further characterize the nature of these, we have produced and characterized rMASP-2s representing the following naturally occurring polymorphisms: R99Q, D120G, P126L, H155R, 156_159dupCHNH (CHNHdup), V377A, and R439H. Only very low levels of CHNHdup were secreted from the cells, whereas quantities similar to wild-type MASP-2 were found intracellularly, indicating that this mutation results in a misfolded protein. We found that D120G and CHNHdup could not associate with MBL, whereas R99Q, P126L, H155R, V377A, R439H, and wild-type MASP-2 bound equally well to MBL. Accordingly, when D120G and CHNHdup were mixed with MBL, no activation of complement factor C4 was observed, whereas R99Q, P126L, and V377A cleaved C4 with an activity comparable to wild-type MASP-2 and H155R slightly better. In contrast, the R439H variant was deficient in this process despite its normal Binding to MBL. This variant was also not able to autoactivate in the presence of MBL and Mannan. We find the R439H variant is common in Sub-Saharan Africans with a gene frequency of 10%. Our results indicate that individuals with different types of MASP-2 defects may be identified through genotyping.
David C. Kilpatrick - One of the best experts on this subject based on the ideXlab platform.
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Mannan-Binding Lectin in malignancy
Molecular immunology, 2012Co-Authors: Anna St. Swierzko, David C. Kilpatrick, Maciej CedzynskiAbstract:Complement may play a dual role in cancer: it may contribute either to the development or to the inhibition of tumour growth. Its components may be candidate biomarkers facilitating the disease detection, its progress or effectiveness of therapy. Additionally, complement deficiencies may increase the risk of infections and contribute to the higher mortality, especially in patients undergoing aggressive chemotherapy. In this paper, possible cancer associations of one of the factors activating complement via the Lectin pathway, Mannan-Binding Lectin (MBL), are discussed.
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Successful haemopoietic stem cell transplantation does not correct Mannan-Binding Lectin deficiency.
Bone marrow transplantation, 2004Co-Authors: David C. Kilpatrick, Karen Stewart, Elaine K. Allan, Lorna A. Mclintock, Tessa L. Holyoake, Marc TurnerAbstract:It has been reported that in allogeneic stem cell transplantation, the Mannan-Binding Lectin (MBL) status of the donor has prognostic value for the recipient. Two MBL-deficient patients, with coexisting haematological malignancy, were identified who were treated with bone marrow from donors with normal MBL concentrations. Although both patients engrafted successfully and remain in complete remission, neither seroconverted to the MBL sufficiency status of his donor over a follow-up period exceeding 2 years. This does not support the concept of MBL replacement by stem cell therapy, and does not provide an explanation for high MBL concentrations in stem cell donors protecting recipients from post transplant infections.
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Consensus statement on the future of Mannan-Binding Lectin (MBL)-replacement therapy.
Biochemical Society Transactions, 2003Co-Authors: David C. KilpatrickAbstract:Prepared by David C. Kilpatrick on behalf of the speakers and delegates. There follows a consensus statement on the future of Mannan-Binding Lectin replacement therapy to ‘wrap up’ this series of articles.
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Introduction to Mannan-Binding Lectin.
Biochemical Society Transactions, 2003Co-Authors: David C. KilpatrickAbstract:Mannan-Binding Lectin (MBL) was first discovered as a plasma opsonin for baker9s yeast and was independently characterized biochemically. It belongs to the small subfamily of colLectins: C-type Lectins possessing a collagen-like domain. MBL is synthesized by the liver and secreted into the bloodstream. It is believed to be an important component of innate immunity, acting as an ante-antibody and/or as a disease modifier. It is thought to influence disorders as diverse as meningococcal disease, rheumatoid arthritis, cystic fibrosis and recurrent miscarriage. Lack of MBL may be most relevant in the context of a co-existing secondary immune deficiency. Replacement therapy, first carried out 30 years ago with unfractionated plasma, appears promising. The development of a recombinant product should permit the extension of MBL therapy to randomized clinical trials of sufficient size to provide clear evidence about the physiological significance of this intriguing glycoprotein.
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Mannan-Binding Lectin and hepatitis C infection.
Clinical and experimental immunology, 2003Co-Authors: David C. Kilpatrick, T. E. S. Delahooke, C. Koch, Marc Turner, P. C. HayesAbstract:SUMMARY Japanese patients with chronic hepatitis C infection unresponsive to treatment with interferon possessed genotypes disproportionately conferring low Mannan-Binding Lectin (MBL) concentrations. Our aims were to confirm or refute this finding in European patients at the MBL protein level, and to investigate whether a low circulating concentration of MBL might influence susceptibility to, or disease progression from, hepatitis C viral infection. Serum samples obtained from 180 hepatitis C patients and 566 blood donors were assayed for MBL. MBL concentrations were related to disease characteristics retrieved from patients’ records. MBL concentrations were higher in hepatitis C patients (median 2·5 µg/ml versus 1·3; P
Jens C. Jensenius - One of the best experts on this subject based on the ideXlab platform.
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Mannan-Binding Lectin polymorphisms and serum levels in patients with endometriosis
European journal of obstetrics gynecology and reproductive biology, 2014Co-Authors: Christina Kruse, Hans Jørgen Nielsen, Rudi Steffensen, Jens C. JenseniusAbstract:Abstract Objective To investigate a possible association between endometriosis and low levels of Mannan-Binding Lectin (MBL). Study design Case-control study of blood samples from 100 patients with endometriosis compared with results from a group of 350 blood donors. Result The frequency of MBL levels Conclusion No association was found between endometriosis and low levels of MBL.
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Mannan-Binding Lectin in cerebrospinal fluid: a leptomeningeal protein.
Fluids and barriers of the CNS, 2012Co-Authors: Hansotto Reiber, Jens C. Jensenius, Bárbara Padilla-docal, Alberto Juan Dorta-contrerasAbstract:Background Mannan-Binding Lectin (MBL), a protein of the innate immune response is attracting increasing clinical interest, in particularly in relation to its deficiency. Due to its involvement in brain diseases, identifying the source of MBL in CSF is important. Analysis of cerebrospinal fluid (CSF) can provide data that discriminates between blood-, brain-, and leptomeninges-derived proteins. To detect the source of MBL in CSF we need to consider three variables: the molecular size-dependent concentration gradient between CSF and blood, the variation in transfer between blood and CSF, and the CSF MBL concentration correlation with the albumin CSF/serum quotient (QAlb), i.e., with CSF flow rate.
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Mannan-Binding Lectin and Mannan-Binding Lectin-Associated Serine Protease 2 in Acute Pancreatitis
Pancreas, 2011Co-Authors: Srdan Novovic, Anders Møller Andersen, Annette Kjær Ersbøll, Lars N. Jorgensen, Hans Jørgen Nielsen, Jens C. Jensenius, Mark Berner HansenAbstract:Objectives:Complement activation may play a prominent role in acute pancreatitis (AP). Mannan-Binding Lectin (MBL) and MBL-associated serine protease 2 (MASP-2) participate in complement activation. The objective of the present study was to evaluate the role of MBL and MASP-2 as markers in AP with r
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polymorphisms in Mannan Binding Lectin mbl associated serine protease 2 affect stability Binding to mbl and enzymatic activity
Journal of Immunology, 2009Co-Authors: Steffen Thiel, Rudi Steffensen, Søren E. Degn, Martin Kolev, Annette Hansen, Marieta M Ruseva, Jens C. JenseniusAbstract:Mannan-Binding Lectin-associated serine protease 2 (MASP-2) is an enzyme of the innate immune system. MASP-2 forms complexes with the pattern recognition molecules Mannan-Binding Lectin (MBL), H-ficolin, L-ficolin, or M-ficolin, and is activated when one of these proteins recognizes microorganisms and subsequently cleaves complement factors C4 and C2, thus initiating the activation of the complement system. Missense polymorphisms of MASP-2 exist in different ethnic populations. To further characterize the nature of these, we have produced and characterized rMASP-2s representing the following naturally occurring polymorphisms: R99Q, D120G, P126L, H155R, 156_159dupCHNH (CHNHdup), V377A, and R439H. Only very low levels of CHNHdup were secreted from the cells, whereas quantities similar to wild-type MASP-2 were found intracellularly, indicating that this mutation results in a misfolded protein. We found that D120G and CHNHdup could not associate with MBL, whereas R99Q, P126L, H155R, V377A, R439H, and wild-type MASP-2 bound equally well to MBL. Accordingly, when D120G and CHNHdup were mixed with MBL, no activation of complement factor C4 was observed, whereas R99Q, P126L, and V377A cleaved C4 with an activity comparable to wild-type MASP-2 and H155R slightly better. In contrast, the R439H variant was deficient in this process despite its normal Binding to MBL. This variant was also not able to autoactivate in the presence of MBL and Mannan. We find the R439H variant is common in Sub-Saharan Africans with a gene frequency of 10%. Our results indicate that individuals with different types of MASP-2 defects may be identified through genotyping.
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New perspectives on Mannan-Binding Lectin-mediated complement activation.
Immunobiology, 2007Co-Authors: Søren E. Degn, Steffen Thiel, Jens C. JenseniusAbstract:Abstract The complement system is an important part of the innate immune system, mediating several major effector functions and modulating adaptive immune responses. Three complement activation pathways exist: the classical pathway (CP), the alternative pathway (AP), and the Lectin pathway (LP). The LP is the most recently discovered, and least characterized. The CP and the LP are generally viewed as working through the generation of the C3 convertase, C4bC2b, and are here referred to as the “standard” pathways. In addition to the standard CP and LP, so-called bypass pathways have also been reported, allowing C3 activation in the absence of components otherwise believed critical. The classical bypass pathways are dependent on C1 and components of the AP. A recent study has shown the existence also of a Lectin bypass pathway dependent on Mannan-Binding Lectin (MBL) and AP components. The emerging picture of the complement system is more that of a small “scale-free” network where C3 acts as the main hub, than that of three linear pathways converging in a common terminal pathway.
D C Kilpatrick - One of the best experts on this subject based on the ideXlab platform.
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Mannan Binding Lectin and its role in innate immunity
Transfusion Medicine, 2002Co-Authors: D C KilpatrickAbstract:Summary Mannan-Binding Lectin (MBL) is a plasma colLectin (C-type Lectin with a collagen-like domain) and is considered an important component of innate immunity. Circulating MBL is genetically determined for the major part, but plasma concentration is also markedly influenced by nongenetic factors. The carbohydrate-Binding ability of MBL can be inhibited by simple sugars like mannose, fucose and N-acetylglucosamine, but its greatest avidity appears to be for repeating mannose-based structural patterns typical of microbial surfaces. By this means, MBL can bind to a wide variety of bacteria and other microbes, neutralizing them and/or opsonizing them by activating complement using the recently discovered Lectin pathway of complement activation. Individual humans differ 1000-fold in MBL concentration, and individuals with low circulating MBL appear to be more vulnerable to infections in a number of clinical settings, especially when combined with secondary immune deficiency. The best evidence that MBL deficiency or insufficiency is physiologically relevant comes from a rapidly expanding literature of clinical studies. MBL insufficiency appears to be a significant risk factor for infections in infants, and for individuals of any age undergoing chemotherapy or post-transplant immunosuppression. Moreover, MBL appears to have a significant influence on the course of certain chronic diseases like rheumatoid arthritis and cystic fibrosis. Replacement therapy with a plasma-derived product is safe and seems promising, while recombinant MBL provides hope for large-scale therapeutic applications. Randomized clinical trials of MBL therapy, which are now on the horizon, should provide unambiguous evidence for the physiological significance of MBL in innate immunity.
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Mannan Binding Lectin concentration and risk of miscarriage
Human reproduction (Oxford England), 1999Co-Authors: D C Kilpatrick, L. Starrs, S. Moore, V. Souter, W.a. ListonAbstract:Recurrent miscarriage is associated with low concentrations of Mannan-Binding Lectin (MBL), but it is not known below which value relative MBL deficiency becomes a significant risk factor. The sera of 397 patients (male and female) suffering from recurrent miscarriage and 376 controls were assayed for MBL and the data analysed. It was found that the lower the cut-off value, the greater the statistical strength of the association. It was concluded that only MBL concentrations
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Mannan Binding Lectin and the sudden infant death syndrome
Forensic Science International, 1998Co-Authors: D C Kilpatrick, V. S. James, C. Caroline Blackwell, Donald M. Weir, N.f Hallam, Anthony BusuttilAbstract:Mannan Binding Lectin (MBL) may be important for innate immunity and some cases of sudden infant death syndrome (SIDS) may be preceded by bacterial infection. Therefore, relative MBL deficiency might be associated with susceptibility to SIDS. We measured MBL concentrations in 46 SIDS infants and 26 controls. The proportion of subjects with low MBL values was similar in the two groups. However, the mean for the SIDS group (3 μg/ml) was higher than that of the controls (2.2 μg/ml; P
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Mannan Binding Lectin and the sudden infant death syndrome.
Forensic science international, 1998Co-Authors: D C Kilpatrick, V. S. James, C. Caroline Blackwell, Donald M. Weir, N.f Hallam, Anthony BusuttilAbstract:Mannan Binding Lectin (MBL) may be important for innate immunity and some cases of sudden infant death syndrome (SIDS) may be preceded by bacterial infection. Therefore, relative MBL deficiency might be associated with susceptibility to SIDS. We measured MBL concentrations in 46 SIDS infants and 26 controls. The proportion of subjects with low MBL values was similar in the two groups. However, the mean for the SIDS group (3 micrograms/ml) was higher than that of the controls (2.2 micrograms/ml; P < 0.05). We interpret this difference as due to acute phase responses and suggest these findings are consistent with the view that some cot deaths are preceded by bacterial infections.
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Phospholipid-Binding activity of human Mannan-Binding Lectin.
Immunology letters, 1998Co-Authors: D C KilpatrickAbstract:Some C-type Lectins possess phospholipid-Binding ability, which may be of physiological importance. Human Mannan-Binding Lectin (MBL) was found to bind specifically to solid-phase phosphatidylserine (PS), phosphatidylinositol (PI) and phosphatidylcholine (PC), but not cardiolipin (CL), in a concentration-dependent manner. This property was inhibited by EDTA and by monosaccharides, and exhibited a similar pH dependence to the carbohydrate (Mannan)-Binding activity of MBL. These findings may be of immunological relevance.
Chantal Dumestre-pérard - One of the best experts on this subject based on the ideXlab platform.
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Phospholipase A2 Receptor–Related Membranous Nephropathy and Mannan-Binding Lectin Deficiency
Journal of The American Society of Nephrology, 2016Co-Authors: Stephane Bally, Denise Ponard, Julien Faure, John Rendu, Frédérique Dijoud, Hanna Debiec, Pierre Ronco, Chantal Dumestre-pérardAbstract:Most patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies against phospholipase A2 receptor (PLA2R). C3 and C5b-9 are found in immune deposits of IMN kidney biopsy specimens, but the pathway of complement activation in IMN remains elusive. We report the case of a patient who developed IMN with intense staining for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1. Measurement of Mannan Binding Lectin (MBL) antigenic level and activity revealed MBL deficiency. Genotyping revealed a heterozygous (A/C) polymorphism in codon 57 of MBL2 exon 1 associated with homozygous and heterozygous variations in the promoter region at -550 (L/L) and -221 (X/Y), respectively, suggesting that the patient harbored the LXA/LYC haplotypes linked to MBL deficiency. Genetic sequencing in 77 consecutive patients with IMN identified four patients with MBL2 promoter and coding region variations associated with MBL deficiency and the same complement pattern in immune deposits as the index patient. In contrast, patients with wild-type MBL2 had immune deposits with intense Cd4 staining. Thus, IMN can develop in patients with complete MBL deficiency, with complement activated mainly by the alternative pathway, whereas the Lectin pathway is also activated in those with wild-type MBL2.
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Aspergillus conidia activate the complement by the Mannan-Binding Lectin C2 bypass mechanism.
Journal of Immunology, 2008Co-Authors: Chantal Dumestre-pérard, Bertrand Lamy, Delphine Aldebert, Catherine Lemaire-vieille, Renée Grillot, Jean-paul Brion, Jean Gagnon, Jean-yves CesbronAbstract:Innate immunity is the major host defense against invasive aspergillosis. To determine whether the colLectin Mannan-Binding Lectin (MBL) is involved in the initial protective immunity through complement activation against opportunistic fungal infections caused by Aspergillus, we performed in vitro studies on 29 different strains of Aspergillus conidia from five different species. Incubation of Aspergillus conidia in human normal serum leads to activation of the alternative pathway, whereas neither the classical nor the Lectin pathways through C4 and C2 cleavage are activated. Complement response to conidia was investigated using a MBL-deficient serum and reconstitution experiments were conducted with MBL/MASPs complexes. We found that MBL can directly support C3 activation by a C2 bypass mechanism. Finally, a stronger activation of the alternative pathway was observed for the clinical strains isolated from patients with invasive aspergillosis, compared with the environmental strains.