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Kazue Takahashi - One of the best experts on this subject based on the ideXlab platform.
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Mannose Binding Lectin regulates host resistance and pathology during experimental infection with trypanosoma cruzi
PLOS ONE, 2012Co-Authors: Ester Roffe, Amanda K Gibson, Kazue Takahashi, Mario Steindel, Antonio Gigliotti Rothfuchs, Allen W Cheever, Alan Sher, Alan R B Ezekowitz, Andre BaficaAbstract:Mannose-Binding Lectin (MBL) is a humoral pattern-recognition molecule important for host defense. Although recent genetic studies suggest an involvement of MBL/MASP2-associated pathways in Chagas’ disease, it is currently unknown whether MBL plays a role in host resistance to the intracellular protozoan Trypanosoma cruzi, the causative agent of Chagas’ disease. In this study we employed MBL−/− mice to assess the role of MBL in resistance to experimental infection with T. cruzi. T. cruzi infection enhanced tissue expression of MBL both at the mRNA and protein level. Similarly, symptomatic acute Chagas’ disease patients displayed increased serum concentrations of MBL compared to patients with indeterminate, asymptomatic forms of the disease. Furthermore, increased parasite loads in the blood and/or tissue were observed in MBL−/− mice compared to WT controls. This was associated with reduced systemic levels of IL-12/23p40 in MBL−/− mice. Importantly, MBL−/− mice infected with a cardiotropic strain of T. cruzi displayed increased myocarditis and cardiac fibrosis compared to WT controls. The latter was accompanied by elevated hydroxyproline content and mRNA levels of collagen-1 and -6 in the heart. These observations point to a previously unappreciated role for MBL in regulating host resistance and cardiac inflammation during infection with a major human pathogen.
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Mannose Binding Lectin binds to amyloid β protein and modulates inflammation
BioMed Research International, 2012Co-Authors: Mykol Larvie, Gregory L Stahl, Weichuan Chang, Mitchell R White, Kevan L Hartshorn, Timothy M Shoup, Lorencia Chigweshe, David R Elmaleh, Kazue TakahashiAbstract:Mannose-Binding Lectin (MBL), a soluble factor of the innate immune system, is a pattern recognition molecule with a number of known ligands, including viruses, bacteria, and molecules from abnormal self tissues. In addition to its role in immunity, MBL also functions in the maintenance of tissue homeostasis. We present evidence here that MBL binds to amyloid β peptides. MBL Binding to other known carbohydrate ligands is calcium-dependent and has been attributed to the carbohydrate-recognition domain, a common feature of other C-type Lectins. In contrast, we find that the features of MBL Binding to Aβ are more similar to the reported Binding characteristics of the cysteine-rich domain of the unrelated Mannose receptor and therefore may involve the MBL cysteine-rich domain. Differences in MBL ligand Binding may contribute to modulation of inflammatory response and may correlate with the function of MBL in processes such as coagulation and tissue homeostasis.
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recombinant chimeric Lectins consisting of Mannose Binding Lectin and l ficolin are potent inhibitors of influenza a virus compared with Mannose Binding Lectin
Biochemical Pharmacology, 2011Co-Authors: Weichuan Chang, Teizo Fujita, Ian C Michelow, Mitchell R White, Patience Moyo, Kevan L Hartshorn, Henry Koziel, Bernard Kinane, Emmett V Schmidt, Kazue TakahashiAbstract:MBL structurally contains a type II-like collagenous domain and a carbohydrate recognition domain (CRD). We have recently generated three novel recombinant chimeric Lectins (RCL), in which varying length of collagenous domain of Mannose-Binding Lectin (MBL) is replaced with that of L-ficolin (L-FCN). CRD of MBL is used for target recognition because it has a broad spectrum in pathogen recognition compared with L-FCN. Results of our study demonstrate that these RCLs are potent inhibitors of influenza A virus (IAV). RCLs, against IAV, show dose-dependent activation of the Lectin complement pathway, which is significantly higher than that of recombinant human MBL (rMBL). This activity is observed even without MBL-associated serine proteases (MASPs, provided by MBL deficient mouse sera), which have been thought to mediate complement activation. These observations suggest that RCLs are more efficient in associating with MASP-2, which predominantly mediates the activity. Yet, additional serum further increases the activity while RCL-mediated coagulation-like enzyme activities are diminished compared with rMBL, suggesting reduced association with MASP-1, which has been shown to mediate coagulation-like activity. These data suggest that RCLs may interfere less with host coagulation, which is advantageous to be a therapeutic drug. Importantly, these RCLs have surpassed rMBL for anti-viral activities, such as viral aggregation, reduction of viral hemagglutination (HA) and inhibition of virus-mediated HA and neuraminidase (NA) activities. These results are encouraging that novel RCLs could be used as anti-IAV agents with less side effect and that RCLs would be suitable candidates in developing a new anti-IAV therapy.
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high dose Mannose Binding Lectin therapy for ebola virus infection
The Journal of Infectious Diseases, 2011Co-Authors: Ian C Michelow, Calli Lear, Corinne Scully, Laura I Prugar, Clifford Longley, Michael L Yantosca, Xin Ji, Marshall Karpel, Matthew Brudner, Kazue TakahashiAbstract:Mannose-Binding Lectin (MBL) targets diverse microorganisms for phagocytosis and complement-mediated lysis by Binding specific surface glycans. Although recombinant human MBL (rhMBL) trials have focused on reconstitution therapy, safety studies have identified no barriers to its use at higher levels. Ebola viruses cause fatal hemorrhagic fevers for which no treatment exists and that are feared as potential biothreat agents. We found that mice whose rhMBL serum concentrations were increased >7fold above average human levels survived otherwise fatal Ebola virus infections and became immune to virus rechallenge. Because Ebola glycoproteins potentially model other glycosylated viruses, rhMBL may offer a novel broadspectrum antiviral approach.
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lack of the pattern recognition molecule Mannose Binding Lectin increases susceptibility to influenza a virus infection
BMC Immunology, 2010Co-Authors: Weichuan Chang, Steffen Thiel, Mitchell R White, Patience Moyo, Sheree Mcclear, Kevan L Hartshorn, Kazue TakahashiAbstract:Background Mannose-Binding Lectin (MBL), a pattern recognition innate immune molecule, inhibits influenza A virus infection in vitro. MBL deficiency due to gene polymorphism in humans has been associated with infection susceptibility. These clinical observations were confirmed by animal model studies, in which mice genetically lacking MBL were susceptible to certain pathogens, including herpes simplex virus 2.
Peter Garred - One of the best experts on this subject based on the ideXlab platform.
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association between Mannose Binding Lectin polymorphisms and wuchereria bancrofti infection in two communities in north eastern tanzania
American Journal of Tropical Medicine and Hygiene, 2010Co-Authors: Dan W Meyrowitsch, Peter Garred, Paul E Simonsen, Michael B Dalgaard, Stephen M Magesa, Michael AlifrangisAbstract:The association between selected Mannose-Binding Lectin (MBL) genotype polymorphisms and Wuchereria bancrofti infection status was assessed among individuals whose infection status had been monitored for three decades. Blood samples were collected in 2006 and examined for polymorphisms in the mbl-2 gene and for W. bancrofti-specific circulating filarial antigen (CFA) status. Logistic regression analysis showed a significant association between MBL genotype and CFA status, with low-expression MBL genotype individuals being almost three times more likely to be CFA positive than high-expression MBL genotype individuals (odds ratio [OR] = 2.90). When individuals' filarial infection (microfilaria) status in 1975 was included in the analyses, the gain of new infections between the two examination points was almost 10 times higher among individuals with low than among those with high MBL expression genotype (OR = 9.51). The susceptibility to W. bancrofti infection thus appears to be significantly affected by the MBL expression genotype of the host.
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Mannose Binding Lectin genetics from a to z
Biochemical Society Transactions, 2008Co-Authors: Peter GarredAbstract:MBL (Mannose-Binding Lectin) is primarily a liver-derived collagen-like serum protein. It binds sugar structures on micro-organisms and on dying host cells and is one of the four known mediators that initiate activation of the complement system via the Lectin pathway. Common variant alleles situated both in promoter and structural regions of the human MBL gene ( MBL2 ) influence the stability and the serum concentration of the protein. Epidemiological studies have suggested that genetically determined variations in MBL serum concentrations influence the susceptibility to and the course of different types of infectious, autoimmune, neoplastic, metabolic and cardiovascular diseases, but this is still a subject under discussion. The fact that these genetic variations are very frequent, indicates a dual role of MBL. This overview summarizes the current molecular understanding of human MBL2 genetics.
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ficolins and Mannose Binding Lectin in danish patients with sarcoidosis
Respiratory Medicine, 2008Co-Authors: Claus Bo Svendsen, Tina Hummelshøj, Peter Garred, Lea Munthefog, Nils Milman, Inga Laursen, Michael Christiansen, Karen A. KrogfeltAbstract:Mannose-Binding Lectin (MBL) is a prognostic marker in pulmonary diseases. Ficolins, sharing many structural and functional similarities with MBL, may also be involved in the pathogenesis of pulmonary diseases. The objectives of the study were to establish whether plasma concentrations of Ficolin-2, -3, and MBL in Danish patients with sarcoidosis and control persons differed and whether they were of prognostic significance. We retrospectively included 46 consecutive patients (26 male, 20 female) and 51 age- and sex-matched healthy control persons (28 male, 23 female). Information about the patients was obtained from their medical records. We measured plasma concentrations of Ficolin-2, -3, and MBL using ELISA. There was a significant difference in the patients' mean Ficolin-3 plasma level (14.9 microg/ml; +/-2SD: 6.7-23.1) compared with the control persons' (21.6 microg/ml; +/-2SD: 12.7-30.5). The difference was 6.7 microg/ml (95% CI: 5.0-8.4 microg/ml; p<0.001). In the patients, Ficolin-3 correlated inversely with the CD4(+)/CD8(+)-ratio (Spearman's Rho=-0.37; p=0.021; n=39). There were no significant differences in plasma concentrations of Ficolin-2 or MBL between the two groups. Ficolin-3 concentrations were lower in plasma from patients with sarcoidosis. This suggests a possible involvement of Ficolin-3 in the complex pathophysiology of sarcoidosis. However, we could not show the applicability of Ficolin plasma level measurement as a marker of disease activity or of prognostic significance in sarcoidosis.
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antibody mediated activation of the classical pathway of complement may compensate for Mannose Binding Lectin deficiency
European Journal of Immunology, 2004Co-Authors: Anja Roos, Peter Garred, Manon E. Wildenberg, Nicholas J. Lynch, Jeric R. Munoz, Tahlita C.m. Zuiverloon, Lee H. Bouwman, Nicole Schlagwein, Francien Fallauxvan Den C Houten, Maria C FaberkrolAbstract:Deficiency of Mannose-Binding Lectin (MBL), a recognition molecule of the Lectin pathway of complement, is associated with increased susceptibility to infections. The high frequency of MBL deficiency suggests that defective MBL-mediated innate immunity can be compensated by alternative defense strategies. To examine this hypothesis, complement activation by MBL-Binding ligands was studied. The results show that the prototypic MBL ligand mannan can induce complement activation via both the Lectin pathway and the classical pathway. Furthermore, antibody Binding to mannan restored complement activation in MBL-deficient serum in a C1q-dependent manner. Cooperation between the classical pathway and the Lectin pathway was also observed for complement activation by protein 60 from Listeria monocytogenes. MBL pathway analysis at the levels of C4 and C5b-9 in the presence of classical pathway inhibition revealed a large variation of MBL pathway activity, depending on mbl2 gene polymorphisms. MBL pathway dysfunction in variant allele carriers is associated with reduced MBL ligand Binding and a relative increase of low-molecular-mass MBL. These findings indicate that antibody-mediated classical pathway activation can compensate for impaired target opsonization via the MBL pathway in MBL-deficient individuals, and imply that MBL deficiency may become clinically relevant in absence of a concomitant adaptive immune response.
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Mannose Binding Lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus
The New England Journal of Medicine, 2004Co-Authors: Tommy Ohlenschlaeger, Peter Garred, Hans O Madsen, Soren JacobsenAbstract:Background Cardiovascular disease is an important complication in patients with systemic lupus erythematosus (SLE). Variant alleles of the Mannose-Binding Lectin gene are associated with SLE as well as with severe atherosclerosis. We determined whether Mannose-Binding Lectin variant alleles were associated with an increased risk of arterial thrombosis among patients with SLE. Methods Mannose-Binding Lectin alleles were genotyped by means of a polymerase-chain-reaction assay in 91 Danish patients with SLE. Arterial and venous thromboses occurring after the diagnosis of SLE were assessed in a prospective study. Arterial and venous thromboses were confirmed by appropriate diagnostic methods. Results Fifty-four patients had no Mannose-Binding Lectin variant alleles (A/A genotype), 30 were heterozygous (A/O genotype), and 7 were homozygous (O/O genotype). During a median follow-up of 9.1 years, arterial thromboses (cerebral or myocardial infarction or leg embolus) developed in 6 of the 7 patients with the O/O ...
Alan R B Ezekowitz - One of the best experts on this subject based on the ideXlab platform.
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Mannose Binding Lectin regulates host resistance and pathology during experimental infection with trypanosoma cruzi
PLOS ONE, 2012Co-Authors: Ester Roffe, Amanda K Gibson, Kazue Takahashi, Mario Steindel, Antonio Gigliotti Rothfuchs, Allen W Cheever, Alan Sher, Alan R B Ezekowitz, Andre BaficaAbstract:Mannose-Binding Lectin (MBL) is a humoral pattern-recognition molecule important for host defense. Although recent genetic studies suggest an involvement of MBL/MASP2-associated pathways in Chagas’ disease, it is currently unknown whether MBL plays a role in host resistance to the intracellular protozoan Trypanosoma cruzi, the causative agent of Chagas’ disease. In this study we employed MBL−/− mice to assess the role of MBL in resistance to experimental infection with T. cruzi. T. cruzi infection enhanced tissue expression of MBL both at the mRNA and protein level. Similarly, symptomatic acute Chagas’ disease patients displayed increased serum concentrations of MBL compared to patients with indeterminate, asymptomatic forms of the disease. Furthermore, increased parasite loads in the blood and/or tissue were observed in MBL−/− mice compared to WT controls. This was associated with reduced systemic levels of IL-12/23p40 in MBL−/− mice. Importantly, MBL−/− mice infected with a cardiotropic strain of T. cruzi displayed increased myocarditis and cardiac fibrosis compared to WT controls. The latter was accompanied by elevated hydroxyproline content and mRNA levels of collagen-1 and -6 in the heart. These observations point to a previously unappreciated role for MBL in regulating host resistance and cardiac inflammation during infection with a major human pathogen.
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Mannose Binding Lectin and innate immunity
Immunological Reviews, 2009Co-Authors: W Eddie K Ip, Alan R B Ezekowitz, Kazue Takahashi, Lynda M StuartAbstract:Summary: Innate immunity is the earliest response to invading microbes and acts to contain infection in the first minutes to hours of challenge. Unlike adaptive immunity that relies upon clonal expansion of cells that emerge days after antigenic challenge, the innate immune response is immediate. Soluble mediators, including complement components and the Mannose Binding Lectin (MBL) make an important contribution to innate immune protection and work along with epithelial barriers, cellular defenses such as phagocytosis, and pattern-recognition receptors that trigger pro-inflammatory signaling cascades. These four aspects of the innate immune system act in concert to protect from pathogen invasion. Our work has focused on understanding the protection provided by this complex defense system and, as discussed in this review, the particular contribution of soluble mediators such as MBL and phagocytic cells. Over the past two decades both human epidemiological data and mouse models have indicated that MBL plays a critical role in innate immune protection against a number of pathogens. As demonstrated by our recent in vitro work, we show that MBL and the innate immune signaling triggered by the canonical pattern-recognition receptors (PRRs), the Toll-like receptors (TLRs), are linked by their spatial localization to the phagosome. These observations demonstrated a novel role for MBL as a TLR co-receptor and establishes a new paradigm for the role of opsonins, which we propose to function not only to increase microbial uptake but also to spatially coordinate, amplify, and synchronize innate immune defenses mechanism. In this review we discuss both the attributes of MBL that make it a unique soluble pattern recognition molecule and also highlight its broader role in coordinating innate immune activation.
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Mannose Binding Lectin enhances toll like receptors 2 and 6 signaling from the phagosome
Journal of Experimental Medicine, 2008Co-Authors: W Eddie K Ip, Lynda M Stuart, Kazue Takahashi, Kathryn J Moore, Alan R B EzekowitzAbstract:Innate immunity is the first-line defense against pathogens and relies on phagocytes, soluble components, and cell-surface and cytosolic pattern recognition receptors. Despite using hard-wired receptors and signaling pathways, the innate immune response demonstrates surprising specificity to different pathogens. We determined how combinatorial use of innate immune defense mechanisms defines the response. We describe a novel cooperation between a soluble component of the innate immune system, the Mannose-Binding Lectin, and Toll-like receptor 2 that both specifies and amplifies the host response to Staphylococcus aureus. Furthermore, we demonstrate that this cooperation occurs within the phagosome, emphasizing the importance of engulfment in providing the appropriate cellular environment to facilitate the synergy between these defense pathways.
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Mannose Binding Lectin is a regulator of inflammation that accompanies myocardial ischemia and reperfusion injury
Journal of Immunology, 2005Co-Authors: Mary C Walsh, Kazue Takahashi, Alan R B Ezekowitz, Todd Bourcier, Marc N Busche, Russell P Rother, Scott D Solomon, Gregory L StahlAbstract:The Mannose-Binding Lectin (MBL), a circulating pattern recognition molecule, recognizes a wide range of infectious agents with resultant initiation of the complement cascade in an Ab-independent manner. MBL recognizes infectious non-self and altered self in the guise of apoptotic and necrotic cells. In this study, we demonstrate that mice lacking MBL, and hence are devoid of MBL-dependent Lectin pathway activation but have fully active alternative and classical complement pathways, are protected from cardiac reperfusion injury with resultant preservation of cardiac function. Significantly, mice that lack a major component of the classical complement pathway initiation complex (C1q) but have an intact MBL complement pathway, are not protected from injury. These results suggest that the MBL-dependent pathway of complement activation is a key regulator of myocardial reperfusion ischemic injury. MBL is an example of a pattern recognition molecule that plays a dual role in modifying inflammatory responses to sterile and infectious injury.
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Mannose Binding Lectin deficient mice display defective apoptotic cell clearance but no autoimmune phenotype
Journal of Immunology, 2005Co-Authors: Lynda M Stuart, John Savill, Kazue Takahashi, Alan R B EzekowitzAbstract:Mannose-Binding Lectin (MBL) is a circulating serum protein that is sequestered to sites of inflammation and infection. MBL is a member of the colLectin family with structural similarities to the lung colLectins and functional similarities to C1q. Both MBL and C1q activate complement; C1q activates the classical pathway and MBL the Lectin pathway. Here we demonstrate that MBL binds apoptotic cells in vitro and confirm a role for MBL in clearance of apoptotic cells in vivo. Despite MBL null mice demonstrating defective apoptotic cell clearance they did not develop spontaneous autoimmunity, lymphoproliferation, or germinal center expansion although increased numbers of peritoneal B1 cells were detected. These data demonstrate an important in vivo role for MBL in clearance of dying cells and adds the MBL null animals to the few animals with demonstrable in vivo apoptotic cell clearance defects. Moreover, it demonstrates that failure of apoptotic cell clearance can be dissociated from autoimmunity.
Hans O Madsen - One of the best experts on this subject based on the ideXlab platform.
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Mannose Binding Lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus
The New England Journal of Medicine, 2004Co-Authors: Tommy Ohlenschlaeger, Peter Garred, Hans O Madsen, Soren JacobsenAbstract:Background Cardiovascular disease is an important complication in patients with systemic lupus erythematosus (SLE). Variant alleles of the Mannose-Binding Lectin gene are associated with SLE as well as with severe atherosclerosis. We determined whether Mannose-Binding Lectin variant alleles were associated with an increased risk of arterial thrombosis among patients with SLE. Methods Mannose-Binding Lectin alleles were genotyped by means of a polymerase-chain-reaction assay in 91 Danish patients with SLE. Arterial and venous thromboses occurring after the diagnosis of SLE were assessed in a prospective study. Arterial and venous thromboses were confirmed by appropriate diagnostic methods. Results Fifty-four patients had no Mannose-Binding Lectin variant alleles (A/A genotype), 30 were heterozygous (A/O genotype), and 7 were homozygous (O/O genotype). During a median follow-up of 9.1 years, arterial thromboses (cerebral or myocardial infarction or leg embolus) developed in 6 of the 7 patients with the O/O ...
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disease associated mutations in human Mannose Binding Lectin compromise oligomerization and activity of the final protein
Journal of Biological Chemistry, 2004Co-Authors: Flemming H Larsen, Claus Koch, Hans O Madsen, Peter GarredAbstract:Abstract Deficiency of human Mannose-Binding Lectin (MBL) caused by mutations in the coding part of the MBL2 gene is associated with increased risk and severity of infections and autoimmunity. To study the biological consequences of MBL mutations, we expressed wild type MBL and mutated MBL in Chinese hamster ovary cells. The normal MBL cDNA (WT MBL-A) was cloned, and the three known natural and two artificial variants were expressed in Chinese hamster ovary cells. When analyzed, WT MBL-A formed covalently linked higher oligomers with a molecular mass of about 300-450 kDa, corresponding to 12-18 single chains or 4-6 structural units. By contrast, all MBL variants formed a dominant band of about 50 kDa, with increasingly weaker bands at 75, 100, and 125 kDa corresponding to two, three, four, and five chains, respectively. In contrast to WT MBL-A, variant MBL formed noncovalent oligomers containing up to six chains (two structural units). MBL variants bound ligands with a markedly reduced capacity compared with WT MBL-A. Mutations in the collagenous region of human MBL compromise assembly of higher order oligomers, resulting in reduced ligand Binding capacity and thus reduced capability to activate complement.
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association of Mannose Binding Lectin polymorphisms with sepsis and fatal outcome in patients with systemic inflammatory response syndrome
Critical Care, 2004Co-Authors: Peter Garred, Jens J Strom, Lars Quist, Ellen Taaning, Hans O MadsenAbstract:Genetic factors may predispose to increased risk for sepsis in critically ill patients. Mannose-Binding Lectin (MBL) is an important factor in innate immune defence. Accordingly, we investigated whether MBL gene polymorphisms causing low levels of functional MBL in the the blood are associated with the development and progression of sepsis in adult intensive care patients. In 272 patients with systemic inflammatory response syndrome followed prospectively, different MBL genotypes were compared with respect to microbiology, sepsis development, and survival. The presence of MBL variant alleles was highly significantly associated with development of sepsis, severe sepsis and septic shock in a gene dose-dependent fashion. An increased risk of death was observed in variant allele carriers. These data show that a genetic factor such as MBL insufficiency plays an important role in the susceptibility of critically ill patients for development and progression of sepsis, and confer a substantial risk for fatal outcome.
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association of Mannose Binding Lectin polymorphisms with sepsis and fatal outcome in patients with systemic inflammatory response syndrome
The Journal of Infectious Diseases, 2003Co-Authors: Peter Garred, Jens J Strom, Lars Quist, Ellen Taaning, Hans O MadsenAbstract:Genetic factors may predispose critically ill patients to increased risk of developing sepsis. Mannose-Binding Lectin (MBL) is an important factor in innate immune defense. We investigated whether MBL gene polymorphisms causing low levels of MBL are associated with the development and progression of sepsis in adult patients in intensive care units. In 272 prospectively monitored patients with systemic inflammatory response syndrome, different MBL genotypes were compared, with respect to microbiology, sepsis development, and survival. The presence of MBL variant alleles was associated with the development of sepsis, severe sepsis, and septic shock. An increased risk of fatal outcome was observed in patients carrying variant alleles. These data show that MBL insufficiency plays an important role in the susceptibility of critically ill patients to the development and progression of sepsis and confers a substantial risk of fatal outcome.
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Mannose Binding Lectin engagement with late apoptotic and necrotic cells
European Journal of Immunology, 2003Co-Authors: Alma J Nauta, Hans O Madsen, Anja Roos, Mohamed R Daha, Claus Koch, Nicoline Raaschoujensen, Maria C Borriasessers, Lars P Ryder, Peter GarredAbstract:The serum opsonin Mannose-Binding Lectin (MBL) has been shown to be involved in the handling of apoptotic cells. However, at what stage in the process this happens and whether this mediates activation of complement is unknown. Cells rendered apoptotic or necrotic were incubated with purified MBL/MBL-associated serine protease (MASP) complexes and assessed by flow cytometry and fluorescence microscopy. MBL bound specifically to late apoptotic cells, as well as to apoptotic blebs and to necrotic cells, but not to early apoptotic cells. Binding of MBL could be inhibited by EDTA as well as with an antibody against the CRD region. Addition of C1q, another serum opsonin involved in the handling of apoptotic cells, prior to MBL partly inhibited MBL Binding to apoptotic cells and vice versa. MBL/MASP could initiate deposition of purified complement C4 on the target cells. However, addition of MBL/MASP to whole serum deficient for both C1q and MBL did not enhance deposition of C4, but MBL enhanced phagocytosis of apoptotic cells by macrophages. These results demonstrate that MBL interacts with structures exposed on cells rendered late apoptotic or necrotic and facilitates uptake by macrophages. Thus, MBL may promote non-inflammatory sequestration of dying host cells.
Damon P Eisen - One of the best experts on this subject based on the ideXlab platform.
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Mannose Binding Lectin deficiency and respiratory tract infection
Journal of Innate Immunity, 2010Co-Authors: Damon P EisenAbstract:Mannose-Binding Lectin (MBL) is an innate immune system pattern recognition protein that kills a wide range of pathogenic microbes through complement activation. A substantial proportion of all human
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Mannose Binding Lectin deficiency and respiratory tract infection
Journal of Innate Immunity, 2010Co-Authors: Damon P EisenAbstract:Mannose-Binding Lectin (MBL) is an innate immune system pattern recognition protein that kills a wide range of pathogenic microbes through complement activation. A substantial proportion of all human populations studied to date have MBL deficiency due to MBL2 polymorphisms, which potentially increases susceptibility to infectious disease. MBL binds numerous respiratory pathogens but the capsule of Streptococcus pneumoniae abrogates its efficient Binding. Clinical studies in humans have shown that MBL deficiency appears to predispose to severe respiratory tract infection. A recent meta-analysis shows that MBL deficiency was associated with death in patients with pneumococcal infection after adjusting for bacteraemia and comorbidities. Human clinical studies have also shown associations between MBL deficiency and various less common respiratory infections. Intracellular infections like tuberculosis may be less common with MBL deficiency because of reduced opsonophagocytosis. Lung secretions contain small amounts of MBL that are potentially sufficient to activate complement, but their measurement is confounded by dilution inherent in collection techniques. Therefore, if this protein does play a role in pulmonary immunity it is presumably through prevention of haematogenous dissemination of respiratory pathogens while adding to mucosal defences. Ficolins are colLectins that are structurally and functionally related to MBL and are either present in serum or expressed in tissues including the lung. Limited variation in serum levels of L- and H-ficolin result from the presence of FCN2 and FCN3 polymorphisms. Initial studies on the impact of FCN2 polymorphisms or low L-ficolin levels do not seem to show major associations with respiratory infection. MBL is being developed as a new immunotherapeutic agent for prevention of infection in immunocompromised hosts. The available literature suggests that it may also be of benefit in MBL deficient patients with severe pneumonia. This review concentrates on clinical associations between MBL deficiency and susceptibility to respiratory tract infection.
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impact of Mannose Binding Lectin on susceptibility to infectious diseases
Clinical Infectious Diseases, 2003Co-Authors: Damon P Eisen, R M MinchintonAbstract:When the adaptive immune response is either immature or compromised, the innate immune system constitutes the principle defense against infection. Mannose-Binding Lectin (MBL) is a C-type serum Lectin that plays a central role in the innate immune response. MBL binds microbial surface carbohydrates and mediates opsonophagocytosis directly and by activation of the Lectin complement pathway. A wide variety of clinical isolates of bacteria, fungi, viruses, and parasites are bound by MBL. Three polymorphisms in the structural gene MBL2) and 2 promoter gene polymorphisms are commonly found that result in production of low serum levels of MBL. Clinical studies have shown that MBL insufficiency is associated with bacterial infection in patients with neutropenia and meningococcal sepsis. Low MBL levels appear to predispose persons to HIV infection. Numerous other potential infectious disease associations have been described. Therapy to supplement low MBL levels is being explored using either plasma-derived or recombinant material.