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Steffen Thiel - One of the best experts on this subject based on the ideXlab platform.

  • remote ischemic preconditioning does not influence Lectin Pathway protein levels in head and neck cancer patients undergoing surgery
    PLOS ONE, 2020
    Co-Authors: Kristine Frederiksen, Steffen Thiel, Julie Brogaard Larsen, Annemette Hvas, Andreas Engel Krag, Birgitte Jul Kiil
    Abstract:

    Background Cancer patients who undergo tumor removal, and reconstructive surgery by transfer of a free tissue flap, are at high risk of surgical site infection and ischemia-reperfusion injury. Complement activation through the Lectin Pathway (LP) may contribute to ischemia-reperfusion injury. Remote ischemic preconditioning (RIPC) is a recent experimental treatment targeting ischemia-reperfusion injury. The study aims were to investigate LP protein plasma levels in head and neck cancer patients compared with healthy individuals, to explore whether RIPC affects LP protein levels in head and neck cancer surgery, and finally to examine the association between postoperative LP protein levels and the risk of surgical site infection. Methods Head and neck cancer patients (n = 60) undergoing tumor resection and reconstructive surgery were randomized 1:1 to RIPC or sham intervention administered intraoperatively. Blood samples were obtained preoperatively, 6 hours after RIPC/sham, and on the first postoperative day. LP protein plasma levels were measured utilizing time-resolved immunofluorometric assays. Results H-ficolin and M-ficolin levels were significantly increased in cancer patients compared with healthy individuals (both P ≤ 0.02). Conversely, mannan-binding Lectin (MBL)-associated serine protease (MASP)-1, MASP-3, colLectin liver-1 (CL-L1), and MBL-associated protein of 44 kilodalton (MAp44) levels were decreased in cancer patients compared with healthy individuals (all P ≤ 0.04). A significant reduction in all LP protein levels was observed after surgery (all P 0.13). Conclusions The LP was altered in head and neck cancer patients. LP protein levels were reduced after surgery, but intraoperative RIPC did not influence the LP. Postoperative LP protein levels were not associated with surgical site infection.

  • circulating Lectin Pathway proteins do not predict short term cardiac outcomes after myocardial infarction
    Clinical and Experimental Immunology, 2019
    Co-Authors: Steffen Thiel, Charlotte B Holt, Jakob Appel Ostergaard, Torben Hansen, Linda Mellbin, Peder Sorensson, Mette Bjerre
    Abstract:

    Despite improvements in treatment, coronary artery disease is still responsible for one-third of all deaths globally, due predominantly to myocardial infarction (MI) and stroke. There is an important potential in developing new strategies for treatment of patients with these conditions. Inflammation, and in particular the actions of the complement system, has emerged as part of the pathogenesis in reperfusion injury in patients with MI. To further qualify this, we examined the association between the plasma levels of Lectin Pathway proteins and myocardial end-points, left ventricular ejection fraction (LVEF) and infarct size in a cohort of patients with ST-elevation myocardial infarction (STEMI). A blood sample was drawn the day after percutaneous coronary intervention from 73 patients with STEMI. The primary end-points, LVEF and infarct size, were measured with magnetic resonance imaging 6-9 days after the infarct. Complement pattern-recognition molecules of the Lectin Pathway (mannan-binding Lectin, H-ficolin, L-ficolin and M-ficolin) were analysed along with soluble membrane attack complex (sMAC) and C-reactive protein (CRP) in plasma with immunofluorometric assays <50%. CRP correlated negatively with LVEF, regression coefficient = -0·17 (P = 0·01). None of the Lectin Pathway proteins correlated to LVEF or infarct size, nor did soluble membrane attack complex (sMAC). There were no differences in plasma levels of these complement proteins when comparing patients with ejection fraction <50% to patients with ejection fraction <50%. Pattern-recognition molecules of the Lectin Pathway and sMAC do not predict short-term cardiac outcomes after MI.

  • Lectin Pathway proteins of the complement system in normotensive pregnancy and pre eclampsia
    American Journal of Reproductive Immunology, 2019
    Co-Authors: Julie Brogaard Larsen, Steffen Thiel, Anita Sylvest Andersen, Christine Lodberg Hvas, Michael R Lassen, Annemette Hvas, Anette Tarp Hansen
    Abstract:

    PROBLEM The Lectin Pathway of the complement system may be involved in the pathogenesis of pre-eclampsia. We aimed to investigate changes in serum concentrations of a broad range of Lectin Pathway proteins during normal pregnancy and their association with pre-eclampsia, placental infarctions and intrauterine growth restriction (IUGR). METHOD OF STUDY We included 51 women with normotensive pregnancies and 54 women with pregnancies complicated by pre-eclampsia. Blood samples were obtained at gestational weeks 16, 33, 37, and after delivery for the normotensive pregnant women and before and after delivery for women with pre-eclampsia. Mannose-binding Lectin (MBL), H- and M-ficolin, colLectin liver-1 (CL-L1), MBL-associated serine protease (MASP)-1, MASP-2 and MASP-3 and MBL-associated proteins of 19 (MAp19) and 44 (MAp44) kDa were analysed. Clinical information was obtained from medical records. The placentae were examined by two experienced perinatal pathologists. RESULTS Lectin Pathway protein concentrations generally increased during normal pregnancy and decreased after delivery in both normotensive pregnant women and women with pre-eclampsia. Exceptions were MASP-3 which increased after delivery in both groups (P < 0.0001) and H-ficolin which increased after delivery in pre-eclampsia (P < 0.0001). H-ficolin (P < 0.0001), M-ficolin (P = 0.005) and MASP-3 (P = 0.03) concentrations were lower in women with pre-eclampsia than in normotensive pregnant women. Low MASP-3 concentrations were associated with placental infarction (P = 0.03) and IUGR (P = 0.04). Low H-ficolin concentrations were associated with IUGR (P < 0.01). CONCLUSION In general, Lectin Pathway protein serum concentrations increased during normal pregnancy. H-ficolin and MASP-3 may be involved in the pathophysiology of pre-eclampsia and IUGR and could be potential future pre-eclampsia biomarkers.

  • the Lectin Pathway of complement activation in patients with systemic lupus erythematosus
    The Journal of Rheumatology, 2018
    Co-Authors: Anne Troldborg, Steffen Thiel, Marten Trendelenburg, Justa Friebuskardash, Josephine Nehring, Rudi Steffensen, Soren Hansen, Magdalena Janina Laska, Bent Deleuran
    Abstract:

    Objective The pathogenesis of systemic lupus erythematosus (SLE) involves complement activation. Activation of complement through the classical Pathway (CP) is well established. However, complement activation through pattern recognition not only happens through the CP, but also through the Lectin Pathway (LP). We investigated the hypothesis that the LP is activated in SLE and involved in the pathogenesis of the disease. Methods Using immunoassays developed in-house, we measured concentrations of LP proteins in a cohort of 372 patients with SLE and 170 controls. We estimated complement activation measuring total C3, and investigated whether LP protein concentrations were associated with complement activation and disease activity. Protein changes and disease activity over time were assessed in a cohort of 52 patients with SLE followed with repeated samples over a 5-year period. Results Concentrations of LP proteins in SLE were altered compared with controls. The differences observed in LP proteins associated with complement activation were reflected by a decrease in total C3. The pattern recognition molecules (M-ficolin, CL-L1, and CL-K1), the serine protease (MASP-3), and the associated protein (MAp19) displayed a negative correlation with disease activity. Changes in MASP-2 concentrations over time correlated significantly with increased disease activity. Association between active proteinuria and serum concentration was observed for MASP-3 and MAp19. Conclusion In patients with SLE, we measured specific changes in LP proteins that are associated with complement activation and disease activity, indicating that the LP is activated in patients with SLE. These novel findings substantiate the involvement of the LP in SLE.

  • extensive basal level activation of complement mannose binding Lectin associated serine protease 3 kinetic modeling of Lectin Pathway activation provides possible mechanism
    Frontiers in Immunology, 2017
    Co-Authors: Gabor Oroszlan, Steffen Thiel, Péter Gál, Peter Zavodszky, Rahel Dani, Andras Szilagyi, József Dobó
    Abstract:

    Serine proteases (SPs) are typically synthesized as precursors, termed proenzymes or zymogens, and the fully active form is produced via limited proteolysis by another protease or by autoactivation. The Lectin Pathway of the complement system is initiated by mannose-binding Lectin (MBL)-associated SPs (MASP)-1, and MASP-2, which are known to be present as proenzymes in blood. The third SP of the Lectin Pathway, MASP-3, was recently shown to be the major activator, and the exclusive "resting blood" activator of profactor D, producing factor D, the initiator protease of the alternative Pathway. Because only activated MASP-3 is capable of carrying out this cleavage, it was presumed that a significant fraction of MASP-3 must be present in the active form in resting blood. Here, we aimed to detect active MASP-3 in the blood by a more direct technique and to quantitate the active to zymogen ratio. First, MASPs were partially purified (enriched) from human plasma samples by affinity chromatography using immobilized MBL in the presence of inhibitors. Using this MASP pool, only the zymogen form of MASP-1 was detected by Western blot, whereas over 70% MASP-3 was in an activated form in the same samples. Furthermore, the active to zymogen ratio of MASP-3 showed little individual variation. It is enigmatic how MASP-3, which is not able to autoactivate, is present mostly as an active enzyme, whereas MASP-1, which has a potent autoactivation capability, is predominantly proenzymic in resting blood. In an attempt to explain this phenomenon, we modeled the basal level fluid-phase activation of Lectin Pathway proteases and their subsequent inactivation by C1 inhibitor and antithrombin using available and newly determined kinetic constants. The model can explain extensive MASP-3 activation only if we assume efficient intracomplex activation of MASP-3 by zymogen MASP-1. On the other hand, the model is in good agreement with the fact that MASP-1 and -2 are predominantly proenzymic and some of them is present in the form of inactive serpin-protease complexes. As an alternative hypothesis, MASP-3 activation by proprotein convertases is also discussed.

Wilhelm J. Schwaeble - One of the best experts on this subject based on the ideXlab platform.

  • Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins
    'Frontiers Media SA', 2021
    Co-Authors: Nicholas J Lynch, Sadam Yaseen, Gregory A Demopulos, Thomas Dudler, Youssif M Ali, Matteo Ferrari, Sasha Gragerov, Jonathan L. Heeney, Wilhelm J. Schwaeble
    Abstract:

    Early and persistent activation of complement is considered to play a key role in the pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory environment that might be critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of infection and shifting their state of activation towards an inflammatory phenotype. It precedes pathophysiological milestone events like the cytokine storm, progressive endothelial injury triggering microangiopathy, and further complement activation, and causes an acute respiratory distress syndrome (ARDS). To date, the application of antiviral drugs and corticosteroids have shown efficacy in the early stages of SARS-CoV-2 infection, but failed to ameliorate disease severity in patients who progressed to severe COVID-19 pathology. This report demonstrates that Lectin Pathway (LP) recognition molecules of the complement system, such as MBL, FCN-2 and CL-11, bind to SARS-CoV-2 S- and N-proteins, with subsequent activation of LP-mediated C3b and C4b deposition. In addition, our results confirm and underline that the N-protein of SARS-CoV-2 binds directly to the LP- effector enzyme MASP-2 and activates complement. Inhibition of the LP using an inhibitory monoclonal antibody against MASP-2 effectively blocks LP-mediated complement activation. FACS analyses using transfected HEK-293 cells expressing SARS-CoV-2 S protein confirm a robust LP-dependent C3b deposition on the cell surface which is inhibited by the MASP-2 inhibitory antibody. In light of our present results, and the encouraging performance of our clinical candidate MASP-2 inhibitor Narsoplimab in recently published clinical trials, we suggest that the targeting of MASP-2 provides an unsurpassed window of therapeutic efficacy for the treatment of severe COVID-19

  • Targeted deletions of complement Lectin Pathway genes improve outcome in traumatic brain injury, with MASP-2 playing a major role
    Acta Neuropathologica Communications, 2020
    Co-Authors: Domenico Mercurio, Silke Roscher, Marco Oggioni, Stefano Fumagalli, Denise Minuta, Carlo Perego, Stefania Ippati, Russell Wallis, N. J. Lynch, Wilhelm J. Schwaeble
    Abstract:

    The Lectin Pathway (LP) of complement activation is believed to contribute to brain inflammation. The study aims to identify the key components of the LP contributing to TBI outcome as possible novel pharmacological targets. We compared the long-term neurological deficits and neuropathology of wild-type mice (WT) to that of mice carrying gene deletions of key LP components after experimental TBI. WT or MASP-2 (Masp2^−/−), ficolin-A (Fcna^−/−), CL-11 (Colec11^−/−), MASP-1/3 (Masp1^−/−), MBL-C (Mbl2^−/−), MBL-A (Mbl1^−/−) or MBL^−/− (Mbl1^−/−/Mbl2^−/−) deficient male C57BL/6J mice were used. Mice underwent sham surgery or TBI by controlled cortical impact. The sensorimotor response was evaluated by neuroscore and beam walk tests weekly for 4 weeks. To obtain a comparative analysis of the functional outcome each transgenic line was rated according to a health score calculated on sensorimotor performance. For selected genotypes, brains were harvested 6 weeks after injury for histopathological analysis. MASP-2^−/−, MBL^−/− and FCN-A^−/− mice had better outcome scores compared to WT. Of these, MASP-2^−/− mice had the best recovery after TBI, showing reduced sensorimotor deficits (by 33% at 3 weeks and by 36% at 4 weeks). They also showed higher neuronal density in the lesioned cortex with a 31.5% increase compared to WT. Measurement of LP functional activity in plasma from MASP-2^−/− mice revealed the absence of LP functional activity using a C4b deposition assay. The LP critically contributes to the post-traumatic inflammatory pathology following TBI with the highest degree of protection achieved through the absence of the LP key enzyme MASP-2, underlining a therapeutic utility of MASP-2 targeting in TBI.

  • Deficiency in Mannose-Binding Lectin-Associated Serine Protease-2 Does Not Increase Susceptibility to Trypanosoma cruzi Infection
    2016
    Co-Authors: Carolina H. Ribeiro, Wilhelm J. Schwaeble, Nicholas J Lynch, Youssif M Ali, Cordula M. Stover, Carolina Valck, Francisca Noya-leal, Arturo Ferreira
    Abstract:

    Abstract. Trypanosoma cruzi is the causative agent of Chagas ’ disease, a chronic illness affecting 10 million people around the world. The complement system plays an important role in fighting microbial infections. The recognition molecules of the Lectin Pathway of complement activation, mannose-binding Lectin (MBL), ficolins, and CL-11, bind to specific carbohydrates on pathogens, triggering complement activation through MBL-associated serine protease-2 (MASP-2). Previous in vitro work showed that human MBL and ficolins contribute to T. cruzi lysis. However, MBL-deficient mice are only moderately compromised in their defense against the parasite, as they may still activate the Lectin Pathway through ficolins and CL-11. Here, we assessed MASP-2-deficient mice, the only presently available mouse line with total Lectin Pathway deficiency, for a phenotype in T. cruzi infection. Total absence of Lectin Pathway functional activity did not confer higher susceptibility to T. cruzi infection, suggesting that it plays a minor role in the immune response against this parasite. Chagas ’ disease (American Trypanosomiasis) is an endemic and chronic illness1 that affects around 10 million people in Latin America2 and ~400,000 people in North America, Europe, and Asia.3 Its causative agent, the flagellated protozoan Trypanosoma cruzi, is transmitted through blood-feedin

  • targeting of mannan binding Lectin associated serine protease 2 confers protection from myocardial and gastrointestinal ischemia reperfusion injury
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Wilhelm J. Schwaeble, Nicholas J Lynch, Russell Wallis, Thomas Dudler, James Clark, Michael S Marber, Nilesh J Samani, Brian Parent, Karl Lhotta, Conrad A Farrar
    Abstract:

    Complement research experienced a renaissance with the discovery of a third activation route, the Lectin Pathway. We developed a unique model of total Lectin Pathway deficiency, a mouse strain lacking mannan-binding Lectin-associated serine protease-2 (MASP-2), and analyzed the role of MASP-2 in two models of postischemic reperfusion injury (IRI). In a model of transient myocardial IRI, MASP-2–deficient mice had significantly smaller infarct volumes than their wild-type littermates. Mice deficient in the downstream complement component C4 were not protected, suggesting the existence of a previously undescribed Lectin Pathway-dependent C4-bypass. Lectin Pathway-mediated activation of C3 in the absence of C4 was demonstrated in vitro and shown to require MASP-2, C2, and MASP-1/3. MASP-2 deficiency also protects mice from gastrointestinal IRI, as do mAb-based inhibitors of MASP-2. The therapeutic effects of MASP-2 inhibition in this experimental model suggest the utility of anti–MASP-2 antibody therapy in reperfusion injury and other Lectin Pathway-mediated disorders.

  • the Lectin Pathway of complement activation contributes to protection from west nile virus infection
    Virology, 2011
    Co-Authors: Anja Fuchs, Wilhelm J. Schwaeble, Amelia K Pinto, Michael S Diamond
    Abstract:

    Abstract The function of the Lectin Pathway of complement activation in vivo against West Nile virus (WNV) or many other pathogenic viruses has not been defined. Mice deficient in Lectin Pathway recognition molecules (mannose binding Lectin-A (MBL-A) and mannose binding Lectin-C (MBL-C)) or the effector enzyme mannan-binding Lectin-associated serine protease-2 (MASP-2), were more vulnerable to WNV infection than wild type mice. Compared with studies of mice deficient in factors of the classical or alternative Pathway, MBL-A −/− × MBL-C −/− or MASP-2 −/− mice showed a less severe course of WNV infection. Indeed, a deficiency in Lectin Pathway activation did not significantly affect the kinetics of viral spread to the central nervous system (CNS) nor did it profoundly alter generation of adaptive B and T cell immune responses. We conclude that MBL-mediated recognition and Lectin Pathway activation have important yet subordinate functions in protecting against WNV infection and disease.

Michael Osthoff - One of the best experts on this subject based on the ideXlab platform.

  • role of Lectin Pathway complement proteins and genetic variants in organ damage and disease severity of systemic sclerosis a cross sectional study
    Arthritis Research & Therapy, 2019
    Co-Authors: Michael Osthoff, Marten Trendelenburg, Veronika K. Jaeger, Suzana Jordan, Oliver Distler, Ingmar Heijnen, Ulrich A. Walker
    Abstract:

    Background The role of the complement system in the pathogenesis of systemic sclerosis (SSc) is controversial. This study investigated the role of the Lectin Pathway of complement as a mediator of ischemia/reperfusion injury in SSc.

  • Role of Lectin Pathway complement proteins and genetic variants in organ damage and disease severity of systemic sclerosis: a cross-sectional study
    BMC, 2019
    Co-Authors: Michael Osthoff, Marten Trendelenburg, Veronika K. Jaeger, Ingmar A. F. M. Heijnen, Suzana Jordan, Oliver Distler, Ulrich A. Walker
    Abstract:

    Abstract Background The role of the complement system in the pathogenesis of systemic sclerosis (SSc) is controversial. This study investigated the role of the Lectin Pathway of complement as a mediator of ischemia/reperfusion injury in SSc. Methods This is a prospective observational cross-sectional study of 211 SSc patients and 29 patients with Raynaud’s phenomenon in undifferentiated connective tissue disease (UCTD) at risk of developing SSc from two outpatient clinics. Serum levels of Lectin Pathway proteins (FCN-2, FCN-3, MBL, and MASP-2) and eight MBL2 and FCN2 single-nucleotide polymorphisms (SNP) were analyzed by sandwich-type immunoassays and genotyping and examined for their association with disease manifestations. Results Lectin Pathway protein levels and SNPs were similar between SSc and UCTD patients. FCN-2 levels were however higher in SSc patients with present evidence of digital ulcers (mean 1.4 vs. 1.0 μg/mL, p = 0.05), pitting scars (mean 1.3 vs. 1.0 μg/mL, p = 0.01), and puffy fingers (mean 1.2 vs. 1.0 μg/mL, p = 0.04). Similarly, higher FCN-2 levels were observed in SSc patients with Scl-70 autoantibodies (mean 1.5 vs. 1.0 μg/mL, p = 0.001), interstitial lung disease (mean 1.2 vs. 0.9 μg/mL, p = 0.02), and a forced vital capacity (FVC) below 80% (mean 1.4 vs. 1.0 μg/mL, p = 0.02). In line, variant alleles in the FCN-2 SNP at position + 6359 were associated with a significantly reduced FVC and diffusion capacity. Furthermore, patients with SSc renal crisis harbored higher MBL levels (mean 2.7 vs. 1.5 μg/mL, p = 0.04). No other Lectin Pathway protein levels or polymorphisms were associated with disease manifestations, low complement C3 and/or C4 levels, or inflammatory markers. Conclusions This study does not support a relevant role for several Lectin Pathway complement proteins in the pathogenesis of SSc. Higher FCN-2 levels were however associated with Scl-70 autoantibody positivity, interstitial lung involvement, and digital vasculopathy. Elevated MBL levels were associated with renal crisis

  • the Lectin Pathway of complement in myocardial ischemia reperfusion injury review of its significance and the potential impact of therapeutic interference by c1 esterase inhibitor
    Frontiers in Immunology, 2018
    Co-Authors: Anneza Panagiotou, Marten Trendelenburg, Michael Osthoff
    Abstract:

    Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality in modern medicine. Early reperfusion accomplished by primary percutaneous coronary intervention is pivotal for reducing myocardial damage in ST elevation AMI. However, restoration of coronary blood flow may paradoxically trigger cardiomyocyte death secondary to a reperfusion-induced inflammatory process, which may account for a significant proportion of the final infarct size. Unfortunately, recent human trials targeting myocardial ischemia/reperfusion (I/R) injury have yielded disappointing results. In experimental models of myocardial I/R injury, the complement system, and in particular the Lectin Pathway, have been identified as major contributors. In line with this, C1 esterase inhibitor (C1INH), the natural inhibitor of the Lectin Pathway, was shown to significantly ameliorate myocardial I/R injury. However, the hypothesis of a considerable augmentation of myocardial I/R injury by activation of the Lectin Pathway has not yet been confirmed in humans, which questions the efficacy of a therapeutic strategy solely aimed at the inhibition of the Lectin Pathway after human AMI. Thus, as C1INH is a multiple-action inhibitor targeting several Pathways and mediators simultaneously in addition to the Lectin Pathway, such as the contact and coagulation system and tissue leukocyte infiltration, this may be considered as being advantageous over exclusive inhibition of the Lectin Pathway. In the present review, we summarize current concepts and evidence addressing the role of the Lectin Pathway as a potent mediator/modulator of myocardial I/R injury in animal models and in patients. In addition, we focus on the evidence and the potential advantages of using the natural inhibitor of the Lectin Pathway, C1INH, as a future therapeutic approach in AMI given its ability to interfere with several plasmatic cascades. Ameliorating myocardial I/R injury by targeting the complement system and other plasmatic cascades remains a valid option for future therapeutic interventions.

  • The Lectin Pathway of Complement in Myocardial Ischemia/Reperfusion Injury—Review of Its Significance and the Potential Impact of Therapeutic Interference by C1 Esterase Inhibitor
    Frontiers Media S.A., 2018
    Co-Authors: Anneza Panagiotou, Marten Trendelenburg, Michael Osthoff
    Abstract:

    Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality in modern medicine. Early reperfusion accomplished by primary percutaneous coronary intervention is pivotal for reducing myocardial damage in ST elevation AMI. However, restoration of coronary blood flow may paradoxically trigger cardiomyocyte death secondary to a reperfusion-induced inflammatory process, which may account for a significant proportion of the final infarct size. Unfortunately, recent human trials targeting myocardial ischemia/reperfusion (I/R) injury have yielded disappointing results. In experimental models of myocardial I/R injury, the complement system, and in particular the Lectin Pathway, have been identified as major contributors. In line with this, C1 esterase inhibitor (C1INH), the natural inhibitor of the Lectin Pathway, was shown to significantly ameliorate myocardial I/R injury. However, the hypothesis of a considerable augmentation of myocardial I/R injury by activation of the Lectin Pathway has not yet been confirmed in humans, which questions the efficacy of a therapeutic strategy solely aimed at the inhibition of the Lectin Pathway after human AMI. Thus, as C1INH is a multiple-action inhibitor targeting several Pathways and mediators simultaneously in addition to the Lectin Pathway, such as the contact and coagulation system and tissue leukocyte infiltration, this may be considered as being advantageous over exclusive inhibition of the Lectin Pathway. In this review, we summarize current concepts and evidence addressing the role of the Lectin Pathway as a potent mediator/modulator of myocardial I/R injury in animal models and in patients. In addition, we focus on the evidence and the potential advantages of using the natural inhibitor of the Lectin Pathway, C1INH, as a future therapeutic approach in AMI given its ability to interfere with several plasmatic cascades. Ameliorating myocardial I/R injury by targeting the complement system and other plasmatic cascades remains a valid option for future therapeutic interventions

  • potential role of the Lectin Pathway of complement in the pathogenesis and disease manifestations of systemic sclerosis a case control and cohort study
    Arthritis Research & Therapy, 2014
    Co-Authors: Michael Osthoff, Genesiew Ngian, Melinda M Dean, Mandana Nikpour, Wendy Stevens, Susanna M Proudman
    Abstract:

    Introduction Repetitive episodes of ischemia and reperfusion (I/R) are a cardinal feature of the pathogenesis of systemic sclerosis (SSc), which precedes tissue fibrosis. The complement system is a key mediator of tissue damage after I/R, primarily by activation of the Lectin Pathway. This study investigated whether serum levels and polymorphisms of mannose-binding Lectin (MBL) and ficolin-2 (FCN2), two pattern recognition receptors of the Lectin Pathway, are associated with the predisposition to and clinical features of SSc.

József Dobó - One of the best experts on this subject based on the ideXlab platform.

  • key components of the complement Lectin Pathway are not only required for the development of inflammatory arthritis but also regulate the transcription of factor d
    Frontiers in Immunology, 2020
    Co-Authors: Michael V Holers, Annette G. Hansen, József Dobó, Anna Borodovsky, Robert I Scheinman, Nhu Ho, Joseline Ramos Ramirez, Jared J Lindenberger, Dhruv Desai, Rasmus Pihl
    Abstract:

    The complement system plays an important role in the pathogenesis of rheumatoid arthritis (RA). Besides driving Lectin Pathway (LP) activation, the mannan-binding Lectin (MBL)-associated serine proteases (MASPs) also play a key role in regulating the alternative Pathway (AP). We evaluated the effects of N-acetylgalactosamine (GalNAc)-conjugated MASP-1 and MASP-2 duplexes in vitro and in mice with and without arthritis to examine whether knockdown of MASP-1 and MASP-2 expression affects the development of arthritis. GalNAc-siRNAs for MASP-1 and MASP-2 demonstrated robust silencing of MASP-1 or MASP-2 at pM concentrations in vitro. To evaluate the impact of silencing in arthritic mice, we used the collagen antibody-induced arthritis (CAIA) mouse model of RA. Mice were injected a 10 mg/kg dose of GalNAc-siRNAs 3x s.q. prior to the induction of CAIA. Liver gene expression was examined using qRT-PCR, and protein levels were confirmed in the circulation by sandwich immunoassays and Western blot. At day 10, CAIA mice separately treated with MASP-1 and MASP-2 duplexes had a specific reduction in expression of liver MASP-1 (70-95%, p < 0.05) and MASP-2 (90%, p < 0.05) mRNA, respectively. MASP-1-siRNA treatment resulted in a 95% reduction in levels of MASP-1 protein in circulation with no effect on MASP-2 levels and clinical disease activity (CDA). In mice injected with MASP-2 duplex, there was a significant (p < 0.05) 90% decrease in ex vivo C4b deposition on mannan, with nearly complete elimination of MASP-2 in the circulation. MASP-2 silencing initially significantly decreased CDA by 60% but subsequently changed to a 40% decrease vs. control. Unexpectedly, GalNAc-siRNA-mediated knockdown of MASP-1 and MASP-2 revealed a marked effect of these proteins on the transcription of FD under normal physiological conditions, whereas LPS-induced inflammatory conditions reversed this effect on FD levels. LPS is recognized by Toll-like receptor 4 (TLR4), we found MBL not only binds to TLR4 an interaction with a Kd of 907 nM but also upregulated FD expression in differentiated adipocytes. We show that MASP-2 knockdown impairs the development of RA and that the interrelationship between proteins of the LP and the AP may extend to the transcriptional modulation of the FD gene.

  • extensive basal level activation of complement mannose binding Lectin associated serine protease 3 kinetic modeling of Lectin Pathway activation provides possible mechanism
    Frontiers in Immunology, 2017
    Co-Authors: Gabor Oroszlan, Steffen Thiel, Péter Gál, Peter Zavodszky, Rahel Dani, Andras Szilagyi, József Dobó
    Abstract:

    Serine proteases (SPs) are typically synthesized as precursors, termed proenzymes or zymogens, and the fully active form is produced via limited proteolysis by another protease or by autoactivation. The Lectin Pathway of the complement system is initiated by mannose-binding Lectin (MBL)-associated SPs (MASP)-1, and MASP-2, which are known to be present as proenzymes in blood. The third SP of the Lectin Pathway, MASP-3, was recently shown to be the major activator, and the exclusive "resting blood" activator of profactor D, producing factor D, the initiator protease of the alternative Pathway. Because only activated MASP-3 is capable of carrying out this cleavage, it was presumed that a significant fraction of MASP-3 must be present in the active form in resting blood. Here, we aimed to detect active MASP-3 in the blood by a more direct technique and to quantitate the active to zymogen ratio. First, MASPs were partially purified (enriched) from human plasma samples by affinity chromatography using immobilized MBL in the presence of inhibitors. Using this MASP pool, only the zymogen form of MASP-1 was detected by Western blot, whereas over 70% MASP-3 was in an activated form in the same samples. Furthermore, the active to zymogen ratio of MASP-3 showed little individual variation. It is enigmatic how MASP-3, which is not able to autoactivate, is present mostly as an active enzyme, whereas MASP-1, which has a potent autoactivation capability, is predominantly proenzymic in resting blood. In an attempt to explain this phenomenon, we modeled the basal level fluid-phase activation of Lectin Pathway proteases and their subsequent inactivation by C1 inhibitor and antithrombin using available and newly determined kinetic constants. The model can explain extensive MASP-3 activation only if we assume efficient intracomplex activation of MASP-3 by zymogen MASP-1. On the other hand, the model is in good agreement with the fact that MASP-1 and -2 are predominantly proenzymic and some of them is present in the form of inactive serpin-protease complexes. As an alternative hypothesis, MASP-3 activation by proprotein convertases is also discussed.

  • the emerging roles of mannose binding Lectin associated serine proteases masps in the Lectin Pathway of complement and beyond
    Immunological Reviews, 2016
    Co-Authors: József Dobó, Gabor Pal, Laszlo Cervenak, Péter Gál
    Abstract:

    Mannose-binding Lectin (MBL)-associated serine proteases (MASPs) are the enzymatic constituents of the Lectin Pathway of the complement system. They are complexed with large pattern recognition molecules (PRMs) such as MBL, other colLectins, and ficolins. The main function of two of the three MASPs has crystallized lately: MASP-1 autoactivates first, then it activates MASP-2, and finally both participate in the formation of the C4b2a convertase. In addition to this, both enzymes are involved in several other processes which are subject to intense research nowadays. Notably, MASP-1, as a promiscuous enzyme, has been implicated in the coagulation cascade, in the kinin generating contact system, and in cellular activation through protease-activated receptor (PAR) cleavage on endothelial cells. The third protease MASP-3 has emerged recently as the protease responsible for pro-factor D activation in resting blood, providing a fundamental link between two complement Pathways. At present all three MASPs have at least one well-defined role and several other possible functions were implicated. Defect or more likely over-activation of MASPs may culminate into diseases such as ischemia-reperfusion injury (IRI); hence, MASPs are all potential targets of drug development.

  • The control of the complement Lectin Pathway activation revisited: both C1-inhibitor and antithrombin are likely physiological inhibitors, while α2-macroglobulin is not
    Molecular Immunology, 2013
    Co-Authors: Katalin Paréj, József Dobó, Peter Zavodszky, Péter Gál
    Abstract:

    The Lectin Pathway of complement is an important effector arm of innate immunity. It forms a first line of defense against invading pathogens and dangerously altered self structures. Pattern recognition molecules (mannose-binding Lectin (MBL), ficolins) bind to the dangerous particles, which is followed by activation of MBL-associated serine proteases, MASP-1 and MASP-2, resulting in the initiation of the complement cascade. The activation of the Lectin Pathway is strictly controlled by natural inhibitors, since uncontrolled activation can lead to serious self-tissue damage. Recently we have shown that inhibition of either MASP-1 or MASP-2 by in vitro evolved specific inhibitors completely blocks the Lectin Pathway in human serum. In this study, we examined the inhibitory action of C1-inhibitor (C1-inh), antithrombin (AT) and α2-macroglobulin (α2M) on MASP-1 and MASP-2, and studied the inhibition of the Lectin Pathway in normal human serum in the presence and absence of heparin using C3 and C4 deposition assays. We measured the association rate constants for the serpin/protease reactions. We found that in the presence of heparin both C1-inh and AT are equally efficient inhibitors of the Lectin Pathway. Although α2M formed complex with MASP-1 in fluid phase, it could not abolish Lectin Pathway activation on activator surfaces.

  • revised mechanism of complement Lectin Pathway activation revealing the role of serine protease masp 1 as the exclusive activator of masp 2
    Proceedings of the National Academy of Sciences of the United States of America, 2012
    Co-Authors: David Heja, Katalin Szilagyi, József Dobó, Andrea Kocsis, Robert Szasz, Peter Zavodszky
    Abstract:

    The Lectin Pathway of complement activation is an important component of the innate immune defense. The initiation complexes of the Lectin Pathway consist of a recognition molecule and associated serine proteases. Until now the autoactivating mannose-binding Lectin-associated serine protease (MASP)-2 has been considered the autonomous initiator of the proteolytic cascade. The role of the much more abundant MASP-1 protease was controversial. Using unique, monospecific inhibitors against MASP-1 and MASP-2, we corrected the mechanism of Lectin-Pathway activation. In normal human serum, MASP-2 activation strictly depends on MASP-1. MASP-1 activates MASP-2 and, moreover, inhibition of MASP-1 prevents autoactivation of MASP-2. Furthermore we demonstrated that MASP-1 produces 60% of C2a responsible for C3 convertase formation.

Teizo Fujita - One of the best experts on this subject based on the ideXlab platform.

  • deconstructing the Lectin Pathway in the pathogenesis of experimental inflammatory arthritis essential role of the Lectin ficolin b and mannose binding protein associated serine protease 2
    Journal of Immunology, 2017
    Co-Authors: Nirmal K Banda, Yuichi Endo, Robert I Scheinman, Steven H Sacks, Minoru Takahashi, Gaurav Mehta, Conrad A Farrar, Sumitra Acharya, Wuding Zhou, Teizo Fujita
    Abstract:

    Complement plays an important role in the pathogenesis of rheumatoid arthritis. Although the alternative Pathway (AP) is known to play a key pathogenic role in models of rheumatoid arthritis, the importance of the Lectin Pathway (LP) pattern recognition molecules such as ficolin (FCN) A, FCN B, and colLectin (CL)-11, as well as the activating enzyme mannose-binding Lectin-associated serine protease-2 (MASP-2), are less well understood. We show in this article that FCN A-/- and CL-11-/- mice are fully susceptible to collagen Ab-induced arthritis (CAIA). In contrast, FCN B-/- and MASP-2-/-/sMAp-/- mice are substantially protected, with clinical disease activity decreased significantly (p < 0.05) by 47 and 70%, respectively. Histopathology scores, C3, factor D, FCN B deposition, and infiltration of synovial macrophages and neutrophils were similarly decreased in FCN B-/- and MASP-2-/-/sMAp-/- mice. Our data support that FCN B plays an important role in the development of CAIA, likely through ligand recognition in the joint and MASP activation, and that MASP-2 also contributes to the development of CAIA, likely in a C4-independent manner. Decreased AP activity in the sera from FCN B-/- and MASP-2-/-/sMAp-/- mice with arthritis on adherent anti-collagen Abs also support the hypothesis that pathogenic Abs, as well as additional inflammation-related ligands, are recognized by the LP and operate in vivo to activate complement. Finally, we also speculate that the residual disease seen in our studies is driven by the AP and/or the C2/C4 bypass Pathway via the direct cleavage of C3 through an LP-dependent mechanism.

  • Lectin Pathway effector enzyme mannan binding Lectin associated serine protease 2 can activate native complement c3 in absence of c4 and or c2
    The FASEB Journal, 2017
    Co-Authors: Sadam Yaseen, Teizo Fujita, Gregory A Demopulos, Thomas Dudler, Munehisa Yabuki, Christi L Wood, Jason W Cummings, Larry W Tjoelker, Steven H Sacks, Peter Garred
    Abstract:

    All 3 activation Pathways of complement-the classic Pathway (CP), the alternative Pathway, and the Lectin Pathway (LP)- converge into a common central event: the cleavage and activation of the abundant third complement component, C3, via formation of C3-activating enzymes (C3 convertases). The fourth complement component, C4, and the second component, C2, are indispensable constituents of the C3 convertase complex, C4bC2a, which is formed by both the CP and the LP. Whereas in the absence of C4, CP can no longer activate C3, LP retains a residual but physiologically critical capacity to convert native C3 into its activation fragments, C3a and C3b. This residual C4 and/or C2 bypass route is dependent on LP-specific mannan-binding Lectin-associated serine protease-2. By using various serum sources with defined complement deficiencies, we demonstrate that, under physiologic conditions LP-specific C4 and/or C2 bypass activation of C3 is mediated by direct cleavage of native C3 by mannan-binding Lectin-associated serine protease-2 bound to LP-activation complexes captured on ligand-coated surfaces.-Yaseen, S., Demopulos, G., Dudler, T., Yabuki, M., Wood, C. L., Cummings, W. J., Tjoelker, L. W., Fujita, T., Sacks, S., Garred, P., Andrew, P., Sim, R. B., Lachmann, P. J., Wallis, R., Lynch, N., Schwaeble, W. J. Lectin Pathway effector enzyme mannan-binding Lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2.

  • New insights into the role of ficolins in the Lectin Pathway of innate immunity.
    International review of cell and molecular biology, 2015
    Co-Authors: Yuichi Endo, Misao Matsushita, Teizo Fujita
    Abstract:

    In the innate immune system, a variety of recognition molecules provide the first-line host defense to prevent infection and maintain endogenous homeostasis. Ficolin is a soluble recognition molecule, which senses pathogen-associated molecular patterns on microbes and aberrant sugar structures on self-cells. It consists of a collagen-like stalk and a globular fibrinogen-like domain, the latter binding to carbohydrates such as N-acetylglucosamine. Ficolins have been widely identified in animals from higher invertebrates to mammals. In mammals, ficolins form complexes with mannose-binding Lectin-associated serine proteases (MASPs), and ficolin-MASP complexes trigger complement activation via the Lectin Pathway. Once activated, complement mediates many immune responses including opsonization, phagocytosis, and cytokine production. Although the precise function of each ficolin is still under investigation, accumulating information suggests that ficolins have a crucial role in host defense by recognizing a variety of microorganisms and interacting with effector proteins.

  • lessons learned from mice deficient in Lectin complement Pathway molecules
    Molecular Immunology, 2014
    Co-Authors: Ninette Genster, Peter Garred, Yuichi Endo, Minoru Takahashi, Hideharu Sekine, Teizo Fujita
    Abstract:

    The Lectin Pathway of the complement system is initiated when the pattern-recognition molecules, mannose-binding Lectin (MBL), ficolins or colLectin-11, bind to invading pathogens or damaged host cells. This leads to activation of MBL/ficolin/colLectin-11 associated serine proteases (MASPs), which in turn activate downstream complement components, ultimately leading to elimination of the pathogen. Mice deficient in the key molecules of Lectin Pathway of complement have been generated in order to build knowledge of the molecular mechanisms of the Lectin Pathway in health and disease. Despite differences in the genetic arrangements of murine and human orthologues of Lectin Pathway molecules, the knockout mice have proven to be valuable models to explore the effect of deficiency states in humans. In addition, new insight and unexpected findings on the diverse roles of Lectin Pathway molecules in complement activation, pathogen infection, coagulation, host tissue injury and developmental biology have been revealed by in vivo investigations. This review provides an overview of the mice deficient in Lectin Pathway molecules and highlights some of the most important findings that have resulted from studies of these.

  • Structural and Functional Overview of the Lectin Complement Pathway: Its Molecular Basis and Physiological Implication
    Archivum Immunologiae et Therapiae Experimentalis, 2013
    Co-Authors: Misao Matsushita, Yuichi Endo, Teizo Fujita
    Abstract:

    The complement system is an effector mechanism in immunity. It is activated in three ways, the classical, alternative and Lectin Pathways. The Lectin Pathway is initiated by the binding of mannose-binding Lectin (MBL) or ficolins to carbohydrates on the surfaces of pathogens. In humans, MBL and three types of ficolins (L-ficolin, H-ficolin, and M-ficolin) are present in plasma. Of these Lectins, at least, MBL, L-ficolin, and H-ficolin are complexed with three types of MBL-associated serine proteases (MASPs), MASP-1, MASP-2, and MASP-3 and their truncated proteins (MAp44 and sMAP). In the Lectin Pathway, the Lectin–MASP complex (i.e., a complex of Lectin, MASPs and their truncated proteins) binds to pathogens, resulting in the activation of C4 and C2 to generate a C3 convertase capable of activating C3. MASP-2 is involved in the activation of C4 and C2. MASP-1 activates C2 and MASP-2. The functions of MASP-3, sMAP, and MAp44 in the Lectin Pathway remain unknown. MASP-1 and MASP-3 also have a role in the alternative Pathway. MBL and ficolins are able to bind to a variety of pathogens depending on their carbohydrate binding specificity, resulting in the activation of the Lectin Pathway. Deficiencies of the components of the Lectin Pathway are associated to susceptibility to infection, indicating an important role of the Lectin Pathway in innate immunity. The Lectin-MASP complex is also involved in innate immunity by activating the coagulation system. Recent findings suggest a crucial role of MASP-3 in development.