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1
Rakhshandehroo, Maryam, Rinke Stienstra, Nicole J. de Wit, Marjolijn C. E. Bragt, Martin Haluzik, Ronald P. Mensink, Michael Müller, and Sander Kersten. "Plasma mannose-binding lectin is stimulated by PPARα in humans." American Journal of Physiology-Endocrinology and Metabolism 302, no. 5 (March 1, 2012): E595—E602. http://dx.doi.org/10.1152/ajpendo.00299.2011.
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The peroxisome proliferator activated receptor-α (PPARα) is a major transcriptional regulator of lipid metabolism in liver and represents the molecular target for hypolipidemic fibrate drugs. Effects of PPARα on lipid metabolism are partially mediated by circulating proteins such as FGF21 and ANGPTL4. The present study was undertaken to screen for and identify circulating proteins produced by human liver that are under the control of PPARα. Toward that aim, primary human hepatocytes were treated with the synthetic PPARα agonist Wy-14643 and whole genome expression data selected for secreted proteins. Expression of FGF21, ANGPTL4, and mannose-binding lectin (MBL), a soluble mediator of innate immunity and primary component of the lectin branch of the complement system, was markedly upregulated by Wy-14643 in primary human hepatocytes. Mice express two MBL isomers, Mbl1 and Mbl2. Mbl1 mRNA was weakly induced by Wy-14643 in primary mouse hepatocytes and remained unaltered by Wy-14643 in mouse liver. Mbl2 mRNA was unchanged by Wy-14643 in primary mouse hepatocytes and was strongly reduced by Wy-14643 in mouse liver. Remarkably, plasma Mbl1 levels were increased by chronic PPARα activation in lean and obese mice. Importantly, in two independent clinical trials, treatment with the PPARα agonist fenofibrate at 200 mg/day for 6 wk and 3 mo increased plasma MBL levels by 73 ( P = 0.0016) and 86% ( P = 0.017), respectively. It is concluded that hepatocyte gene expression and plasma levels of MBL are stimulated by PPARα and fenofibrate in humans, linking PPARα to regulation of innate immunity and complement activation in humans and suggesting a possible role of MBL in lipid metabolism.
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Mullighan, Charles G., Susan L. Heatley, Silke Danner, Melinda M. Dean, Kathleen Doherty, Uwe Hahn, Kenneth F. Bradstock, et al. "Mannose-binding lectin status is associated with risk of major infection following myeloablative sibling allogeneic hematopoietic stem cell transplantation." Blood 112, no. 5 (September 1, 2008): 2120–28. http://dx.doi.org/10.1182/blood-2007-07-100222.
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Abstract Mannose-binding lectin (MBL) is a mediator of innate immunity that influences the risk of infection in a range of clinical settings. We previously reported associations between MBL2 genotype and infection in a retrospective study of myeloablative allogeneic hematopoietic stem cell transplantation (allo-HCT). However, other studies have been inconclusive, and the role of MBL in reduced-intensity conditioning (RIC) transplantation is unknown. Here we report a prospective study examining MBL2 genotype, MBL levels, and risk of major infection following HLA-matched sibling myeloablative (n = 83) and RIC (n = 59) HCT. Baseline MBL levels were higher in recipients than donors (P < .001), and recipient MBL levels increased during the peritransplantation period (P = .001), most notably in MBL2 wild-type individuals receiving myeloablative total body irradiation (mTBI). MBL2 coding mutations were associated with major infection in recipients receiving mTBI. The cumulative incidence of major infection in recipient harboring an MBL2 mutation receiving mTBI was 70.6%, compared with 31.1% of those without mutations not receiving mTBI (P = .01). MBL status was not associated with infection in RIC transplants. These results confirm the association of MBL status with risk of infection in myeloablative, TBI-conditioned transplantation. Studies examining the role of MBL replacement therapy to prevent infection in this setting should be considered.
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Papanicolaou, G. A., C. Mihu, K. Kadeishvili, M. Doll, D. Stokar, A. Buchbinder, K. Hsu, R. O'Reilly, E. G. Pamer, and J. Satagopan. "Association of MBL2 genotypes wtih infections and outcome after allogeneic stem cell transplantation." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 7100. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7100.
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7100 Background: Low MBL2 concentration and MBL2 genotype variants have been associated with an increased risk of infection. Our objective was to correlate MBL2 genotypes with specific infections and outcome of HSCT. Methods: 125 non- consecutive, non-selected HSCT were examined. Patients were classified as high or low risk group based on status of underlying disease. Antifungal prophylaxis consisted of fluconazole 400 mg daily. Patients on steroids received mould prophylaxis. There was no routine antibacterial prophylaxis. Microbiologically confirmed infections were recorded. Genotype was determined by PR-Melting Curve Analysis on blood or buccal swab specimens. MBL genotype was classified as wild-type: A/A (MBL-sufficient, MBL-S) or variant-type: A/O, O/O (MBL deficient, MBL- D). Patients were followed for up to 2 years. Analyses of categorical variables were performed using the Fisher exact test and the Log-Rank test for time to event. Results: Seventy-one (58.2%) patients were homozygous for wild-type MBL2 (AA), 43 (35.3%) were heterozygous (A/0) and 8 (6.5%) were homozygous for variant genotypes (OO). MBL-D group had higher incidence of fungal infections (20% vs 7%, p=0.05), and in particular Aspergillosis (12% vs 3%, p=0.05). MBL-D was associated with a trend for higher rates of bacterial infections (63% vs 46%, p=0.10) and total number of bacterial infections (p=0.10). Rates of respiratory and enteric viral infections or CMV were similar in MBL-D and MBL-S groups (41% vs 38%, p=0.9 and 58% vs. 54% p=1.0 respectively). Patients with MBL-D genotype were at a disadvantage in relapse-free (RFS) and overall survival (OS), (p<0.01 and p=.08). This disadvantage was also observed when stratified by disease risk groups. The estimated 2-year relapse-free survival rate was 30% compared to 53% for MBL-D vs. MBL-S patients (p<0.01). Conclusions: 1) Patients with variant MBL genotype (MBL-D) had a trend for increased incidence and number of bacterial infections. 2) MBL-D genotype and graft versus host disease were risk factors for aspergillosis. 3) MBL-D genotype was associated with worse overall survival and relapse free survival post HSCT. These data suggest that MBL-D patients have impaired immune function compared with MBL-S patients and is consistent with animal data. [Table: see text]
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Kumari, Minal, Yogesh Kumar, and Parvinder Kaur. "Effectiveness of Module Based Learning regarding Facility Based Newborn Care in terms of knowledge and practices among nursing students." International Journal of Contemporary Pediatrics 6, no. 5 (August 23, 2019): 2184. http://dx.doi.org/10.18203/2349-3291.ijcp20193749.
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ABSTRACTBackground: Mobile Applications are being developed at a rapid speed and are intensively used by students. It can help to achieve better performance in organizing, managing, and monitoring classroom activities.Aims and objectives: Present study aimedto assess and compare the knowledge and practice regarding FBNC among nursing students in MBL group and MABL group before and after the administration of MBL and MABL. The conceptual framework of the study was based on CIPP model by Stufflebeam.Methods: A Quantitative research approach with quasi-experimental and non-equivalent controlgroup pre–test post–test design. The study was conducted at two nursing colleges of Ambala, Haryana. A total of 70 B.Sc. Nursing 3rd Year students, randomly allocated to 2 groups i.e. 35 in MBL and 35 in MABL. The tool used for the study consisted of structured knowledge questionnaire and observational check list was used to assess knowledge and practices by OSCE method of nursing students regarding FBNC. Data collection was done in January, 2017. The obtained data was analyzed and interpreted in terms of objectives and researchResults: Findingsof the study indicate that revealed that mean post- test knowledge and practices score in MBL group (21.4 ±0.89) and in MABL group (22.4 ± 0.54) was significantly higher than pre-test knowledge score in MBL group (14.6±15.0) and in MABL group (16.2±17.0). Also, the mean post-test practice score in MBL group (38.1±1.91) and in MABL group (38.9± 1.20) was significantly higher than pre-test practicescore in MBL (20.4 ± 3.70) as well as in MABL group (20.5 ± 4.26). Mild positive significant relationship (r=0.03) was found between post test score of knowledge and practicesConclusion: MABL was more effective in developing the practices of nursing students regarding FBNC than MBL.
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Chung, Dick, Lily Ding, Isabelle Amigues, Katuna Kadeishvili, Theresa Lo, Eric Pamer, Stacey Kalambakas, Aby Buchbinder, and Genovefa Papanicolaou. "Association of Mannose Binding Lectin (MBL-2) Deficiency with Pulmonary Infection after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)." Blood 112, no. 11 (November 16, 2008): 2209. http://dx.doi.org/10.1182/blood.v112.11.2209.2209.
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Abstract Background: Low MBL2 concentration and MBL2 genotype variants have been associated with an increased risk of infection in various clinical settings. Pulmonary infection is a major complication of HSCT. We examined the relationship of MBL genotypes with post-engraftment bacterial (B-PNA) and fungal (F-PNA) pneumonia Methods: Retrospective review of 236 non-consecutive, non-selected patients who underwent HSCT at MSKCC from 1/1/2000–4/30/2007. Microbiologically confirmed infections and pneumonias were recorded. Antifungal prophylaxis consisted of fluconazole 400 mg daily. Patients at high risk for mold infection received mold-active prophylaxis. After 1/1/2006 voriconazole was the first line anti-mold prophylaxis. Genotype was determined by PR-Melting Curve Analysis on blood or buccal swab specimens. MBL genotype was classified as wild-type: A/A (MBL-sufficient, MBL-S) or variant-type: A/O, O/O (MBL deficient, MBL-D). Patients were followed for up to 2 years. Statistical analysis: Fisher’s Exact test was used to compare the incidence rate between MBL-S and MBL-D patients. Multivariate logistical regression models were used to investigate the relationship between bacterial or fungal pneumonia and MBL genotype, matched related donor (MRD), myeloablative conditioning (MC) peripheral blood as stem cell source (PBSC), acute GVHD grade 2–4 (aGVHD). The results from Maximum Likelihood Estimates were summarized. Results: Transplant characteristics: 80% MC, 76% PBSC, 48.6% MRD. Incidence of aGVHD: 22.4%. MBL genotypes: One-hundred and forty-two (60%) patients were homozygous for wild-type MBL2 (AA), 85(36%) were heterozygous (A/0) and 9 (3.8%) were homozygous for variant genotypes (OO). Transplant characteristics, rates of GVHD, relapse-free and overall survival were similar between MBL-D and MBL-S. There was higher incidence of overall bacterial infections in MBL-D compared to MBL-S pts (47.87% vs 36.62%, p=0.1049). MBL-D had a higher incidence of B-PNA (12.7% vs 4.9%, p=0.048). In multivariate logistic regression analysis, MBL-D(p=0.04) and aGVHD(p=0.06) were likely associated with B-PNA. Rates of overall fungal infections and F-PNA were similar [among MBL-D and MBL-S pts (12.77% vs 9.86%, p=0.5277) and (8.51% vs 7.75%, p=0.1049) respectively]. In multivariate logistic regression analysis only aGVHD was statistically significantly associated with F-PNA p=0.0002. Conclusions: 1) MBL-D genotype was likely associated with increased risk of bacterial pneumonia. 2) MBL-D and aGVHD were risk factors for B-PNA. 3) Further analyses are in progress to evaluate the effect of MBL-D on fungal pneumonia in patients who received mold prophylaxis versus patients who did not receive mold prophylaxis. 4) Prospective studies are needed to assess the relative contribution of MBL-D genotype on the risk of pulmonary infection in HSCT.
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Kashiwagi, Yasuyo, Shinji Suzuki, Ryo Takahashi, Gaku Yamanaka, Yuji Hirai, and Hisashi Kawashima. "Association of the Mannose-Binding Lectin 2 BB Genotype with COVID-19-Related Mortality." Life 13, no. 2 (January 30, 2023): 382. http://dx.doi.org/10.3390/life13020382.
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Mannose-binding lectin (MBL) is crucial in first-line immune defenses. There are still many unknown factors regarding the mechanisms causing variability in the clinical course of coronavirus disease 2019 (COVID-19). In Japan, there have been few reports to date regarding the association between MBL and COVID-19. It has been demonstrated that the MBL2 gene B variant at codon 54 (rs1800450) is associated with variabilities in the clinical course of COVID-19. We aimed to investigate how the level of serum MBL and the codon 54 variant of MBL (rs1800450) affect the disease severity of COVID-19. A total of 59 patients from the fourth wave and 49 patients from the fifth wave in Japan were analyzed based on serum MBL levels using ELISA and the genotype of MBL2 codon 54 using PCR reaction. There was no significant association between serum MBL levels and age. MBL2 genotype was independent of age, there was no significant difference in different COVID-19 severities, MBL genotypes, and serum MBL levels. Binary logistic regression analysis to identify predisposing factors for severe COVID-19 symptoms demonstrated that patients with the BB genotype had a higher risk of death from COVID-19. Our results quantitatively demonstrated that the BB genotype might be a factor associated with death from COVID-19.
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Baioumy, Shereen A., Shaimaa H. Fouad, Shaimaa A. Abdalgeleel, Ahmed A. Baiomy, Dina E. Sallam, and Sara I. Taha. "Mannose-binding lectin serum levels and (Gly54asp) gene polymorphism in recurrent aphthous stomatitis: A case-control study." International Journal of Immunopathology and Pharmacology 35 (January 2021): 205873842110644. http://dx.doi.org/10.1177/20587384211064454.
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Objectives: Dysregulation of the immune response appears to play a significant role in recurrent aphthous stomatitis (RAS) development. The main objective of this case–control study is to investigate the blood levels of mannose-binding lectin (MBL) and the frequency of the MBL2 gene (gly54asp) polymorphism in RAS patients, including 40 RAS patients and 40 healthy controls. Methods: Serum MBL levels were determined by ELISA, while the PCR-restriction fragment length polymorphism was used in MBL2 genotyping. Results: The median serum MBL level was significantly lower in the RAS group than in the control group (975 ng/mL (545–1320) vs. 1760 ng/mL (1254–2134); p≤ 0.001). The MBL levels were significantly lower in the BB genotype, whereas they were significantly higher in the wild type AA with a median of 525 and 1340 ng/mL, respectively ( p =0.005). The B allele was expressed in significantly higher percentages of RAS patients than in controls. There was no significant association between MBL serum levels ( p=0.685) or MBL2 codon 54 genotypes ( p=0.382) with the type of ulcers. Conclusion: There was an association between low MBL serum levels and the variant allele B of the MBL2 (gly54asp) gene, and the susceptibility to RAS. As a result, potential novel therapeutic options for RAS patients with MBL deficiency should be investigated.
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Thio, Chloe L., Timothy Mosbruger, Jacquie Astemborski, Spencer Greer, Gregory D. Kirk, Stephen J. O'Brien, and David L. Thomas. "Mannose Binding Lectin Genotypes Influence Recovery from Hepatitis B Virus Infection." Journal of Virology 79, no. 14 (July 2005): 9192–96. http://dx.doi.org/10.1128/jvi.79.14.9192-9196.2005.
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ABSTRACT Mannose binding lectin (MBL) is a central component of the innate immune response and thus may be important for determining hepatitis B virus (HBV) persistence. Since single-nucleotide polymorphisms (SNPs) in the gene encoding MBL (mbl2) alter the level of functional MBL, we hypothesized that mbl2 genotypes are a determinant of HBV persistence or recovery from viral infection. We tested this hypothesis by using a nested case control design with 189 persons with HBV persistence matched to 338 individuals who had naturally recovered from HBV infection. We determined genotypes of two promoter and three exon 1 SNPs in mbl2 and grouped these genotypes according to the amount of functional MBL production. We found that the promoter SNP −221C, which leads to deficient MBL production, was more common in those subjects with viral persistence (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.01 to 1.89; P = 0.04). Those subjects homozygous for the combination of promoter and exon 1 genotypes associated with the highest amount of functional MBL had significantly increased odds of recovery from infection (OR, 0.55; 95% CI, 0.37 to 0.84; P = 0.005). Conversely, those homozygous for the combination of promoter and exon 1 genotypes which produce the lowest amount of functional MBL were more likely to have viral persistence (OR, 1.76; 95% CI, 1.02 to 3.01; P = 0.04). These data are consistent with the hypothesis that functional MBL plays a central role in the pathogenesis of acute hepatitis B.
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Mullighan, Charles G., Susan E. Heatley, Silke Danner, Melinda Dean, Kathleen V. Doherty, Uwe Hahn, Kenneth Bradstock, et al. "Mannose-Binding Lectin Status Is Associated with Risk of Major Infection Following Myeloablative Sibling Allogeneic Hematopoietic Stem Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 2928. http://dx.doi.org/10.1182/blood.v108.11.2928.2928.
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Abstract Infection is a leading cause of morbidity following allogeneic hematopoietic stem cell transplantation (allo-HCT). In a previous retrospective study of related, HLA-matched myeloablative transplants, we identified associations between common inherited polymorphisms in the MBL2 gene encoding the mediator of innate immunity, mannose-binding lectin (MBL), and risk of major infection. Missense mutations resulting in low circulating MBL levels were associated with increased infection, and high-producing promoter haplotypes were protective. However, subsequent studies have been conflicting, there are no data examining non-myeloablative transplants, and the relationship between MBL2 genotype and serum MBL levels peri-transplant has not been studied. This is important as MBL is an acute phase reactant primarily synthesized by the liver, and many conditioning regimens are hepatotoxic. Here we report a prospective study examining MBL2 genotype, MBL levels and risk of major infection following HLA-matched sibling myeloablative and non-myeloablative allo-HCT. Data is available for 138 transplants, 81 myeloablative and 57 non-myeloablative. 49 of the myeloablative transplants utilized total body irradiation (TBI) based conditioning regimens. Five promoter and missense MBL2 polymorphisms were genotyped, and plasma MBL mannan-binding and C4-deposition levels were measured pretransplant for donor and recipient, and at days 0, 14 and 28 post-transplant. Major infection was defined as invasive or systemic episodes of microbiologically confirmed sepsis. MBL levels were higher in recipients than donors at baseline (t test P<0.0001), reflecting an acute phase response induced by disease and prior treatment. Recipient MBL levels increased during the peritransplant period (ANOVA P=0.0002), most strikingly in individuals without MBL2 coding mutations undergoing TBI. 59 of 138 (42.8%) recipients experienced at least one episode of major infection (myeloablative 38/81, 46.9%, non-myeloablative 21/57 (36.8%), P=NS). The most significant clinical risk factor for infection was the use of myeloablative TBI (HR 2.8, CI 1.39–5.8, p=0.004). Analyzing all transplants, MBL2 genotype (recipient P=0.07, donor p=0.08), and recipient mannan-binding MBL levels (P=0.10) were weak risk factors for infection, however the association was highly dependent upon the type and intensity of conditioning. No association was observed in non-myeloablative transplants, but a significant interaction was observed between recipient MBL2 coding mutations and the use of TBI in myeloablative transplants (Cox P=0.002). For example, 70.6% of recipients with a coding MBL2 mutation receiving TBI developed major sepsis, compared with 20% of those without mutations not receiving TBI. Our results confirm the association of MBL status with risk of infection risk post allo-HCT. Importantly, the association is restricted to myeloablative, TBI-conditioned transplants. Further studies examining the role of MBL replacement in this setting are warranted.
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Friborg, Jeppe T., Ruth F. Jarrett, Anders Koch, Peter Garred, June M. L. Freeland, Andreas Andersen, and Mads Melbye. "Mannose-Binding Lectin Genotypes and Susceptibility to Epstein-Barr Virus Infection in Infancy." Clinical and Vaccine Immunology 17, no. 9 (July 7, 2010): 1484–87. http://dx.doi.org/10.1128/cvi.00527-09.
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ABSTRACT In a cohort study of children <4 years of age in Greenland, mannose-binding lectin (MBL2) genotypes and Epstein-Barr virus (EBV) antibody levels were determined. EBV seropositivity was significantly lower and time to seroconversion increased in MBL-insufficient compared with MBL-sufficient children, indicating that MBL may be involved in primary EBV infection in infancy.
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Smithson, Alex, Rafael Perello, Jesus Aibar, Gerard Espinosa, Dolors Tassies, Carolina Freire, Pedro Castro, Belen Suarez, Francisco Lozano, and Josep-Maria Nicolas. "Genotypes Coding for Low Serum Levels of Mannose-Binding Lectin Are Underrepresented among Individuals Suffering from Noninfectious Systemic Inflammatory Response Syndrome." Clinical and Vaccine Immunology 17, no. 3 (December 30, 2009): 447–53. http://dx.doi.org/10.1128/cvi.00375-09.
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ABSTRACT Gene polymorphisms, giving rise to low serum levels of mannose-binding lectin (MBL) or MBL-associated protease 2 (MASP2), have been associated with an increased risk of infections. The objective of this study was to assess the outcome of intensive care unit (ICU) patients with systemic inflammatory response syndrome (SIRS) regarding the existence of functionally relevant MBL2 and MASP2 gene polymorphisms. The study included 243 ICU patients with SIRS admitted to our hospital, as well as 104 healthy control subjects. MBL2 and MASP2 single nucleotide polymorphisms were genotyped using a sequence-based typing technique. No differences were observed regarding the frequencies of low-MBL genotypes (O/O and XA/O) and MASP2 polymorphisms between patients with SIRS and healthy controls. Interestingly, ICU patients with a noninfectious SIRS had a lower frequency for low-MBL genotypes and a higher frequency for high-MBL genotypes (A/A and A/XA) than either ICU patients with an infectious SIRS or healthy controls. The existence of low- or /high-MBL genotypes or a MASP2 polymorphism had no impact on the mortality rates of the included patients. The presence of high-MBL-producing genotypes in patients with a noninfectious insult is a risk factor for SIRS and ICU admission.
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Garred, Peter, Morten A. Nielsen, Jørgen A. L. Kurtzhals, Rajneesh Malhotra, Hans O. Madsen, Bamenla Q. Goka, Bartholomew D. Akanmori, Robert B. Sim, and Lars Hviid. "Mannose-Binding Lectin Is a Disease Modifier in Clinical Malaria and May Function as Opsonin for Plasmodium falciparum- Infected Erythrocytes." Infection and Immunity 71, no. 9 (September 2003): 5245–53. http://dx.doi.org/10.1128/iai.71.9.5245-5253.2003.
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ABSTRACT Variant alleles in the mannose-binding lectin (MBL) gene (mbl2) causing low levels of functional MBL are associated with susceptibility to different infections and are common in areas where malaria is endemic. Therefore, we investigated whether MBL variant alleles in 551 children from Ghana were associated with the occurrence and outcome parameters of Plasmodium falciparum malaria and asked whether MBL may function as an opsonin for P. falciparum. No difference in MBL genotype frequency was observed between infected and noninfected children or between children with cerebral malaria and/or severe malarial anemia and children with uncomplicated malaria. However, patients with complicated malaria who were homozygous for MBL variant alleles had significantly higher parasite counts and lower blood glucose levels than their MBL-competent counterparts. Distinct calcium-dependent binding of MBL to the membrane of P. falciparum-infected erythrocytes, which could be inhibited by mannose, was observed. Further characterization revealed that MBL reacted with a P. falciparum glycoprotein identical to the 78-kDa glucose-regulated stress protein of P. falciparum. MBL seems to be a disease modifier in clinical malaria and to function as an opsonin for erythrocytes invaded by P. falciparum and may thus be involved in sequestration of the parasite, which in turn may explain the association between homozygosity for MBL variant alleles and high parasite counts.
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Garred, Peter. "Mannose-binding lectin genetics: from A to Z." Biochemical Society Transactions 36, no. 6 (November 19, 2008): 1461–66. http://dx.doi.org/10.1042/bst0361461.
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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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Badawy, Magda, Doaa Saber, Hanan Madani, and Dalia Mosallam. "Use of Mannose-Binding Lectin Gene Polymorphisms and the Serum MBL Level for the Early Detection of Neonatal Sepsis." Journal of Pediatric Genetics 07, no. 04 (November 9, 2018): 150–57. http://dx.doi.org/10.1055/s-0038-1675801.
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Background Mannose-binding lectin (MBL) is a component of innate immunity and is particularly important in neonates, in whom adaptive immunity has not yet completely developed. MBL deficiency and MBL2 gene polymorphisms are associated with an opsonization defect and have been associated with neonatal sepsis. Aim The aim of our study was to assess serum MBL levels and genotype MBL2 genes to determine whether they can serve as markers for predicting neonatal sepsis in neonatal intensive care units. Patients and Methods A case-control study was conducted with 114 neonates classified into two groups: the septic group included 64 neonates (41 preterm and 23 full-term infants), and the non-septic control group included 50 neonates (29 preterm and 21 full-term infants). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used to genotype MBL2 gene exon 1 (rs1800450) and (rs1800451) SNPs. Enzyme-linked immunosorbent assay (ELISA) was used to measure MBL serum concentrations. Results The polymorphic genotypes BB and AC at codons 54 and 57, respectively, showed higher frequencies than the wild-type genotype (AA) (14.1% versus 12.9% and 28.1% versus 19.4% respectively) in both groups, and this difference was greater in the septic group than in the non-septic group; however, the differences did not reach statistical significance. The B and C allele frequencies were also higher in the septic group than in the non-septic group, but the differences did not reach statistical significance (p = 0.282 and 0.394, respectively). The serum levels of MBL were significantly lower in the septic group than in the non-septic group (p = 0.028). Conclusion This study found no association between MBL levels or MBL2 exon 1 genotypes or alleles and neonatal sepsis risk. Further studies with larger sample sizes are needed to determine the role of the MBL2 gene as a risk factor and early predictor of neonatal sepsis.
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GERGELY, PÉTER, BORBÁLA PAZÁR, ZSOLT B. NAGY, TÍMEA GOMBOS, KATALIN RAJCZY, ZSOLT BALOGH, ILONA ORBÁN, KRISZTINA SEVCIC, and GYULA POÓR. "Structural Polymorphisms in the Mannose-Binding Lectin Gene Are Associated with Juvenile Idiopathic Arthritis." Journal of Rheumatology 36, no. 4 (March 13, 2009): 843–47. http://dx.doi.org/10.3899/jrheum.080681.
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Objective.To investigate the possible association between polymorphisms of the mannose-binding lectin gene (MBL2) and susceptibility to juvenile idiopathic arthritis (JIA).Methods.We performed a case-control association study including 118 Hungarian patients with JIA and 118 sex-matched healthy controls. MBL genotyping for the 3 mutant structural alleles at codons 54 (B), 57 (C), and 52 (D) in exon 1 and the promoter polymorphisms at position −550 (HL) and −221 (YX) were carried out by real-time PCR allelic discrimination. Serum level of MBL was determined by ELISA.Results.Variant allele frequencies of both codon 52 and 57 polymorphisms in the MBL2 gene were significantly overrepresented in JIA (p = 0.001 and p = 0.004, respectively). The frequency of low MBL genotypes (XA/XA, YA/YO, XA/YO, and YO/YO) in JIA was higher than that in healthy controls (p = 0.001). Serum MBL concentrations were found to be significantly lower in JIA patients versus control subjects (p = 0.001). The 2 promoter polymorphisms and codon 54 SNP of the MBL2 gene were not associated with JIA.Conclusion.Our findings suggest that genetically determined low MBL levels may predispose children to JIA in a Hungarian population. These data warrant further research to investigate the role of the lectin-dependent complement system in the pathogenesis of JIA.
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Buchbinder, Aby, Thomas Basile, Cliff Ding, Jeff Hester, Jing Yu, Thomas Eckhardt, Charles Conover, and Ivan Horak. "Evaluation of Ethnic Differences in Mannose-Binding Lectin (MBL) Level or MBL Genotype." Blood 108, no. 11 (November 16, 2006): 3859. http://dx.doi.org/10.1182/blood.v108.11.3859.3859.
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Abstract Background: MBL is a natural human plasma protein that plays an important role in the humoral innate immune defense. MBL specifically recognizes a broad range of microorganisms, including bacteria, fungi, viruses, and parasites, by binding to common carbohydrate structures located on their surfaces and activating the lectin pathway of complement. The concentration of MBL in plasma is largely genetically determined and ranges from 5 to 10,000 ng/mL. Deficiency is caused by mutations within the mbl2 gene or its promoter region. Individuals heterozygous (A/O) and homozygous (O/O) for these mutations display a reduced level of MBL in plasma. Low levels of MBL have been associated with increased risk of serious infection in situations in which other components of the immune system are compromised. Studies in patients with hematologic malignancies undergoing chemotherapy suggest that low MBL levels or variant MBL genotypes (A/O or O/O) are correlated with infectious complications of chemotherapy and/or duration of febrile neutropenia. The effect of ethnicity on MBL level and genotype was examined as part of the development of recombinant human MBL (rhMBL), a novel molecule that is entering clinical trials. Methods: The plasma MBL level (protein concentration) and MBL genotype of 80 healthy volunteers were determined by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR), respectively. Results: No differences in MBL level or genotype were observed among the 3 ethnic groups (see table below). Overall, the plasma MBL level was <100 ng/mL for 10% of the volunteers and <300 ng/mL for 16%. Regarding MBL genotype, 4% had an O/O genotype and 34% had an A/O genotype. Conclusions: The MBL level and genotype data from 80 healthy volunteers of different ethnic backgrounds were observed to be generally concordant. Further analyses in individuals with other ethnicities are ongoing. MBL Level and MBL Genotype by Ethnicity White Black Hispanic Total (N=50) (N=15) (N=15) (N=80) n (%) n (%) n (%) n (%) MBL Level (ng/mL) <100 5 (10) 1 (7) 2 (13) 8 (10) 100 to <300 3 (6) 2 (13) 0 5 (6) ≥300 42 (84) 12 (80) 13 (87) 67 (84) MBL Genotype A/A 32 (64) 9 (60) 9 (60) 50 (63) A/O 16 (34) 6 (40) 5 (33) 27 (34) O/O 2 (4) 0 1 (7) 3 (4)
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Kalia, Namarta, Jatinder Singh, and Manpreet Kaur. "The ambiguous role of mannose-binding lectin (MBL) in human immunity." Open Medicine 16, no. 1 (January 1, 2021): 299–310. http://dx.doi.org/10.1515/med-2021-0239.
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Abstract Mannose-binding lectin (MBL) and lectin complement pathway have become targets of increasing clinical interest. Many aspects of MBL have been recently explored, including the structural properties that allow it to distinguish self from non-self/altered-self structures. Experimental evidences have declared the additional 5′- and 3′-variants that in amalgamation with well-known secretor polymorphisms change MBL function and concentration. Moreover, the current review highlights the differential behavior of MBL on exposure with extra/intracellular pathogens and in autoimmune diseases, stressing the fact that “high MBL levels can increase diseases susceptibility,” a paradox that needs justification. Attributable to these discrepancies, no absolute level of MBL deficiency could be defined so far and thus must be interpreted for specific diseases through case–control population-specific designs. Overall, it is evident that further research is needed about MBL and the lectin pathway of complement. Particularly, the transformative role of MBL over evolution is of interest and its role with regard to pathogenesis of different diseases and potential therapeutic targets within the respective pathways should be further explored. Apart from this, it is necessary to adopt an extensive locus-wide methodology to apprehend the clinical significance of MBL2 polymorphisms in a variety of infectious diseases by the future studies.
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Hammad, Noha M., Nissreen E. El Badawy, Ashraf M. Nasr, Hamed A. Ghramh, and Laila M. Al Kady. "Mannose-Binding Lectin Gene Polymorphism and Its Association with Susceptibility to Recurrent Vulvovaginal Candidiasis." BioMed Research International 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/7648152.
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Recurrent vulvovaginal candidiasis (RVVC) is a common illness influencing childbearing women worldwide. Most women suffering from RVVC develop infection without specified risk factors. Mannose-binding lectin (MBL) is an important component of innate immune defense against Candida infection. Innate immunity gene mutations and polymorphisms have been suggested to play a role in susceptibility to RVVC. This study aimed to investigate the association between MBL 2 gene exon 1 codon 54 polymorphism and susceptibility to RVVC in childbearing women. Whole blood and serum samples were obtained from 59 RVVC cases and 59 controls. MBL serum level was measured by enzyme-linked immune-sorbent assay (ELISA). MBL2 exon 1 codon 54 polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). It was shown that MBL serum level was nonsignificantly different between RVVC cases and controls. The risk of RVVC was 3 times higher in those carrying MBL2 exon 1 codon 54 variant allele (B). It could be concluded that the carrying of MBL2 exon 1 codon 54 variant allele (B) was shown to be a risk factor for RVVC in childbearing women.
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Birbian, Niti, Jagtar Singh, Surinder Kumar Jindal, Amit Joshi, Navneet Batra, and Neha Singla. "Association of the Wild-Type A/A Genotype of MBL2 Codon 54 with Asthma in a North Indian Population." Disease Markers 32, no. 5 (2012): 301–8. http://dx.doi.org/10.1155/2012/757302.
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Background: High serumMBL level as well as polymorphisms in the mannose-binding lectin 2 (MBL2) gene resulting in MBL deficiency are involved in the mechanism of a number of non-infectious diseases such as asthma, conferring either risk or protection in different population studies. MBL being the first reactant of the MBL pathway is also a major determinant of the fate of the anaphylatoxins such as C3a and C5a, which are also pro-inflammatory mediators. The MBL2 gene polymorphisms thus control the serum levels of MBL as well as C3a and C5a.Objective: This is the first case-control study conducted in India, investigating the role of MBL2 codon 54 A/B polymorphism in asthma pathogenesis.Methods: A case-control study was performed with a total of 992 adult subjects, including 410 adult asthmatics and 582 healthy controls from regions of North India. The MBL2 codon 54 A/B polymorphism was genotyped by PCR-RFLP.Results: Statistical analysis for the codon 54 polymorphism revealed that the wild (A) allele was significantly associated with asthma with OR = 1.9, 95% CI (1.4–2.4), and p < 0.001.Conclusion: The MBL2 codon 54 A/B polymorphism is significantly associated with asthma and its phenotypic traits as the wild (A/A) genotype confers a significant risk towards the disease in the studied North Indian population.
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Krupodorova, Tetiana, Victor Barshteyn, and Elena Pokas. "ANTIBACTERIAL ACTIVITY OF FOMITOPSIS BETULINA CULTURAL LIQUID." EUREKA: Life Sciences 6 (November 30, 2019): 10–16. http://dx.doi.org/10.21303/2504-5695.2019.001066.
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The antibacterial activity of Fomitopsis betulina cultural liquid (native, native concentrated, lyophilized, dried) against standard bacteria (Escherichia coli АТСС 25922, Pseudomonas aeruginosa АТСС 27853, Staphylococcus aureus АТСС 25923), and clinical isolates (Acinetobacter baumannii 50/1496 MBL, A. baumannii 88/2995 MBL, E. coli 116/3196 KPC, Klebsiella pneumoniae 6/509 ESBL, AmpC, KPC, P. aeruginosa 99/3066 MBL, P. aeruginosa 125/3343 MBL, S. haemoliticus 22/824 MRSA, S. aureus 134/3569 MRCNS) has been evaluated by the serial dilutions method. The antibacterial activity of F. betulina against S. haemoliticus and A. baumannii has been found for the first time. All samples of F. betulina cultural liquid demonstrated the inhibitory effect against standard bacterial strains at the minimum bactericidal concentration (MBC) ranging from >2.0 up to 18.75 mg/ml, and against multidrug-resistant clinical isolates with MBC from 7.8 up to 48.42 mg/ml. The dried F. betulina cultural liquid showed the highest antimicrobial activity against standard bacteria and clinical isolates, except A. baumannii 50/1496 MBL, while native concentrated cultural liquid was the most effective against this pathogen. The study showed that the antibacterial activity of the cultural liquid of F. betulina was improved by concentration and drying. The results obtained indicate that F. betulina cultural liquid contains alternative antimicrobial agents, useful for the treatment of bacterial diseases and might be a perspective substance for the pharmaceutical industries
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Bezerra, Marcos André Cavalcanti, Isabela Cristina Farias, Diego Arruda Falcão, Igor de Farias Domingos, Luana Laranjeira Prado, Mariana Rezende Bandeira Mello, Taciana Mendonça, et al. "Association of MBL2 polymorphism with Leg Ulcers Development in Sickle Cell Anemia Patients." Blood 124, no. 21 (December 6, 2014): 4912. http://dx.doi.org/10.1182/blood.v124.21.4912.4912.
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Abstract Leg ulcers are the most common clinical manifestations of sickle cell anemia (SCA), a monogenic disease with huge clinical diversity among patients. They affect 8% to 10% of SCA patients, reaching a percentage greater than 50% in patients residing in tropical areas. These ulcers occur due to vascular occlusion, tissue hypoxia, hemolysis and genetic factors, presenting a slow healing, high recurrence rate and huge susceptibility to infection. Recently, some studies have shown a positive relationship between the complement system and the development of some vascular diseases and injuries such as leg ulcers in non-SCA patients. Mannan-binding lectin (MBL) is an important component of the humoral innate immune system, and MBL possesses several characteristics indicating that it may play an essential role in wound healing; modulating inflammation and contributing to the clearance of microorganisms and apoptotic cells. In a recent study of chronic leg and foot ulcer patients, serum MBL levels were significantly different between wounds of different etiologies, with chronic venous leg ulcers patients having a higher frequency of MBL deficiency. Polymorphisms in the MBL2 are associated with a reduction in the MBL protein serum levels, increasing risk of developing leg ulcers and also the maintenance of these wounds, compromising the integrity of the immune defence and its response to potential invading pathogens. Here, we aimed to determine the frequency of polymorphisms in the promoter region -221 (Y / X) and -550 (H / L) and exon 1 of the MBL2 and assess the clinical impact of these variants in a northeastern Brazilian SCA population who presented leg ulcers. Two-hundred seventy-five unrelated SCA patients were included. According the leg ulcers presence, the total cohort was classified in patients presenting current or prior history of leg ulcers (n=100) and SCA patients above 18 years with no history of leg ulcers (n=175). Molecular analysis was performed by qPCR. Our population was in Hardy-Weinberg equilibrium. The allelic frequency of haplotypes associated with high MBL production (HYA, LYA) was 54.5% for cases and 62.9% in controls. The genotypes related to low MBL production (HYO, LYO) in cases and controls was 27.5% and 18.6%, respectively. The frequency of genotype related to intermediate MBL production (LXA) was 18% in cases and 18.5% in controls. We had no statistically significant results when we analyzed only the polymorphisms (P>0.05). However, the phenotypic analysis between high and low MBL production revealed that patients with leg ulcers have lower MBL protein levels (P=0.019). We focused specifically on a possible role of MBL deficiency on healing complications, based on the facts that MBL deficiency is the most common immune disorder, and that a common causality for prolonged healing of these ulcers is infection or colonization by bacteria. In our study, MBL deficiency appears to increase the risk of developing leg ulcers in SCA patients. Disclosures No relevant conflicts of interest to declare.
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Thévenon, Audrey D., Rose G. F. Leke, Amorsolo L. Suguitan, James A. Zhou, and Diane Wallace Taylor. "Genetic Polymorphisms of Mannose-Binding Lectin Do Not Influence Placental Malaria but Are Associated with Preterm Deliveries." Infection and Immunity 77, no. 4 (January 12, 2009): 1483–91. http://dx.doi.org/10.1128/iai.01069-08.
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ABSTRACT During pregnancy, Plasmodium falciparum-infected erythrocytes (IE) sequester in the placenta where they induce pathology and increase the risk of low-birth-weight (LBW) babies. The innate immune mediator, mannose-binding lectin (MBL), enhances phagocytosis of pathogens. Since MBL is reported to bind to IE, we hypothesized that it might aid in clearance of IE from the placenta, thereby reducing the risk of LBW babies. To test this hypothesis, molecular genotyping was used to detect polymorphisms at codon 57 (A/C) in exon 1 of MBL2 in 401 pregnant Cameroonian women, with or without placental malaria, who had LBW and normal-weight babies. Polymorphisms in the promoter region at positions −550 (H/L), −221 (X/Y), and +4 (P/Q) were also determined, and plasma MBL levels were measured during pregnancy and at delivery. The expected correlation between genotype and plasma MBL levels was confirmed. However, asymptomatic infections were not associated with an increase in MBL levels in the peripheral blood, and MBL levels were similar in the placental and cord blood of women with or without placental malaria at delivery. There was no evidence that MBL levels at delivery were associated with malaria-related poor pregnancy outcomes. Women with the LXPA haplotype, however, were more likely to have LBW babies, but the risk was not related to malaria. These results do not support the hypothesis that MBL aids in the clearance of parasites from the placenta but suggest that Cameroonian women with LXPA are at risk of having LBW babies due to other causes.
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Molle, Ingolf, Niels A. Peterslund, Rudi Steffensen, and Steffen Thiel. "Polymorphisms of MBL2, Encoding Mannan-Binding Lectin, Influences the Risk of Sepsis in Multiple Myeloma Patients during Autologous Stem Cell Transplantation (ASCT)." Blood 108, no. 11 (November 16, 2006): 5301. http://dx.doi.org/10.1182/blood.v108.11.5301.5301.
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Abstract Polymorphisms of various immune defence genes interfere with the risk of severe infections in critically ill patients. This includes studies on autologous and allogeneic stem cell transplantation (ASCT). Mannan-binding lectin (MBL) is a plasma protein which is able to recognize carbohydrate structures forming pathogen associated molecular patterns on the surface of bacteria and viruses. When binding to pathogens occur the complement system is activated leading killing of the microorganisms. Lack of MBL may lower the ability to resist infections. The gene MBL2, encoding mannan-binding lectin (MBL), contains three well-characterized single nucleotide polymorphisms B (G54D), C (G57E), and D (R52C) (collectively termed O in contrast to the wild-type A). The presence of O variants greatly reduces the effector functions of MBL. We examined the impact of the polymorphisms on the occurrence of severe infections related to ASCT in patients with multiple myeloma. Patients were genotyped with PCR techniques using aliquots of peripheral stem cells from apheresis. Infectious complications were recorded retrospectively from clinical records and database extractions from the Department of Microbiology. One hundred and thirteen consecutive patients were studied. During ASCT 71 patients (63%) had fever above 38.5°C despite prophylactic antibiotics. Eleven (10%) patients had proven sepsis. MBL2 analyses: 4/71 patients with AA genotype had sepsis versus 7/41 with AO/OO genotype (p=0.09). Two lethal cases of sepsis were seen in the AO/OO patients, none in the AA patients. In multivariate analyses the risk of sepsis was significantly lower in AA patients: OR 0.15 (95% CI: 0.03–0.74), p=0.02. Wild-type MBL2, associated with a high function of mannose-binding lectin, probably reduces the risk of sepsis in myeloma patients during ASCT. Myeloma patients with variant MBL2 may be candidates for future MBL replacement trials.
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Ramasawmy, Rajendranath, Guilherme S. Spina, Kellen C. Fae, Alexandre C. Pereira, Renato Nisihara, Iara Jose Messias Reason, Max Grinberg, Flavio Tarasoutchi, Jorge Kalil, and Luiza Guilherme. "Association of Mannose-Binding Lectin Gene Polymorphism but Not of Mannose-Binding Serine Protease 2 with Chronic Severe Aortic Regurgitation of Rheumatic Etiology." Clinical and Vaccine Immunology 15, no. 6 (April 9, 2008): 932–36. http://dx.doi.org/10.1128/cvi.00324-07.
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ABSTRACT N-Acetylglucosamine (GlcNAc) is the major immunoepitope of group A streptococcal cell wall carbohydrates. Antistreptococcal antibodies cross-reactive with anti-GlcNAc and laminin are present in sera of patients with rheumatic fever. The cross-reactivity of these antibodies with human heart valvular endothelium and the underlying basement membrane has been suggested to be a possible cause of immune-mediated valve lesion. Mannose-binding lectin (MBL) encoded by the MBL2 gene, a soluble pathogen recognition receptor, has high affinity for GlcNAc. We postulated that mutations in exon 1 of the MBL2 gene associated with a deficient serum level of MBL may contribute to chronic severe aortic regurgitation (AR) of rheumatic etiology. We studied 90 patients with severe chronic AR of rheumatic etiology and 281 healthy controls (HC) for the variants of the MBL2 gene at codons 52, 54, and 57 by using a PCR-restriction fragment length polymorphism-based method. We observed a significant difference in the prevalence of defective MBL2 alleles between patients with chronic severe AR and HC. Sixteen percent of patients with chronic severe AR were homozygotes or compound heterozygotes for defective MBL alleles in contrast to 5% for HC (P = 0.0022; odds ratio, 3.5 [95% confidence interval, 1.6 to 7.7]). No association was detected with the variant of the MASP2 gene. Our study suggests that MBL deficiency may contribute to the development of chronic severe AR of rheumatic etiology.
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TROELSEN, LONE N., PETER GARRED, BURIS CHRISTIANSEN, CHRISTIAN TORP-PEDERSEN, and SØREN JACOBSEN. "Genetically Determined Serum Levels of Mannose-Binding Lectin Correlate Negatively with Common Carotid Intima-Media Thickness in Systemic Lupus Erythematosus." Journal of Rheumatology 37, no. 9 (July 1, 2010): 1815–21. http://dx.doi.org/10.3899/jrheum.100158.
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Objective.Patients with systemic lupus erythematosus (SLE) have excess cardiovascular morbidity and mortality due to accelerated atherosclerosis that cannot be attributed to traditional cardiovascular risk factors alone. Variant alleles of the mannose-binding lectin gene (MBL2) causing low serum concentrations of functional mannose-binding lectin (MBL) are associated with SLE and development of atherosclerosis. Recent studies show that these variant alleles are associated with increased risk of arterial thrombosis and cardiovascular disease in patients with SLE. Intima-media thickness of the common carotid artery (ccIMT) is a validated noninvasive anatomic measure of subclinical atherosclerosis. In a cross-sectional study we examined the relation among ccIMT, MBL2 genotypes, and serum concentrations of MBL.Methods.The MBL2 extended genotypes (YA/YA, YA/XA, XA/XA, YA/YO, XA/YO, YO/YO) and serum concentrations of MBL were determined in 41 outpatients with SLE. ccIMT was measured by means of ultrasonography. Traditional and nontraditional cardiovascular risk modifiers were assessed and controlled for.Results.Using nonparametric Mann-Whitney tests we found a significant difference in ccIMT between low-expressing (XA/XA+YA/YO+XA/YO+YO/YO) and high-expressing (YA/YA+YA/XA) MBL2 genotypes (p = 0.034). The difference in ccIMT remained significant in multivariable analysis adjusting for traditional and nontraditional cardiovascular risk modifiers (p = 0.049). ccIMT was negatively correlated to serum concentrations of MBL (Spearman rho = −0.33, p = 0.037). This relation also remained significant in multivariable analysis (p = 0.042).Conclusion.In this group of SLE patients, MBL2 low-expressing genotypes and low serum levels of MBL were correlated with ccIMT, independent of the effects of traditional and nontraditional cardiovascular risk modifiers.
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Dommett, Rachel M., Mona Bajaj-Elliott, Julia Chisholm, and Nigel Klein. "Influence of Mannose Binding Lectin (MBL) Gene Polymorphisms on Infectious Complications during Treatment for Childhood Malignancy." Blood 108, no. 11 (November 16, 2006): 1260. http://dx.doi.org/10.1182/blood.v108.11.1260.1260.
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Abstract Infection remains a major cause of morbidity and hospitalisation in children receiving chemotherapy. At present clinical parameters provide a guide to risk of severe infection but it has become increasingly apparent that, among patients with the same diagnosis and treatment regimen, not all suffer equally from infectious complications. Mannose binding lectin is a pattern recognition molecule of the innate immune system which, upon binding to a wide range of microorganisms, activates the lectin pathway of complement. Polymorphisms in the MBL2 gene result in low levels of MBL protein and are frequently associated with increased susceptibility to infection. Studies investigating the role of MBL in defence against infection following chemotherapy have reported conflicting findings to date. MBL replacement therapy is a potential treatment option in the future and we consider it imperative that we clarify the role of MBL in this clinical setting. Clinical data from episodes of febrile neutropenia (FN) in children aged 0−16 receiving chemotherapy for childhood cancer was recorded prospectively from April 2004−March 2005, including clinical and microbiological evidence of infection, antibiotic days and duration of admission. MBL genotyping was performed using a reverse hybridisation technique and results were analysed against FN outcome. 269 children were recruited into the study. A total of 513 episodes of FN were captured over the study period from 211 patients. 58 patients had no recorded episodes of FN. There was no association between age, sex, ethnicity or diagnosis and MBL genotype. 75% of subjects had a haematological malignancy and of these 84% had acute lymphoblastic leukaemia (ALL). Overall, patients with MBL2 polymorphisms experienced more episodes of FN than wildtype individuals (median 2 and 1, respectively, p=0.074). Analysis of episodes with documented clinical/microbiological infection revealed that the proportion of patients with ≥ 3 episodes was 14.6% in those with polymorphisms and 8% in wildtype, p=0.045. This trend was also true for the supgroup of patients with ALL. The duration of inpatient stay for FN, used as a surrogate measure of severity, was influenced by MBL genotype in some groups of patients. Longer inpatient stays and antibiotic days were most apparent in the MBL deficient patients with high risk diagnoses e.g. AML and B NHL who spent up to 4.5 days longer/per episode in hospital than high risk wildtype patients. These results suggest that MBL deficiency influences both susceptibility to FN and outcome of FN episodes in this study cohort. The effect of MBL deficiency differs between diagnostic groups and may be most important in those patients who are at higher risk of severe FN by virtue of their underlying diagnosis and treatment regime.
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Bernig, Toralf, Willemijn Breunis, Nannette Brouwer, Dirk Roos, Taco W. Kuijpers, and Stephen J. Chanock. "Functional Consequences of Genetic Variation across the Entire MBL2 Locus: Possible Identification of 3′ SNPs That Could Modify Circulating Levels of MBL." Blood 104, no. 11 (November 16, 2004): 1330. http://dx.doi.org/10.1182/blood.v104.11.1330.1330.
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Abstract Mannose-binding protein (MBL) is a critical component of innate immunity and provides first-line protection against pathogens by binding to N-acetyl-glucosamine and mannose residues on the surface of microorganisms (bacteria, fungi and parasites). MBL can activate complement by the lectin pathway. Both circulating MBL serum levels and functional activity have been correlated with common genetic variants in the MBL2 gene; decreased levels and activity correlate with 3 nonsynonymous single nucleotide polymorphisms, SNPs, (known as B, C and D) in exon 1 and two linked promoter SNPs (−550 H/L and −221 Y/X) as well as a 5′UTR SNP (+4 P/Q) influence circulating levels. These components form the “secretor haplotypes”, which correlate with circulating levels. A number of studies have reported associations between MBL deficiency and recurrent or severe infections, especially in immuno-incompetent patients (i.e., BMT recipients, cancer patients, and infants) or in auto-immune disorders; however, measured MBL serum levels do not fully correlate with the “secretor haplotypes”. Based on data from a re-sequence analysis across the entire MBL2 locus, in which we revealed a probable recombination hotspot in the 3′ end of the gene dividing MBL2 into two haplotype blocks, we investigated whether the extended block structure might identify additional SNPs that contribute to MBL serum levels and activity. We analysed more than 20 common SNPs across the locus, including haplotype-tagging SNPs (htSNPs) with Taqman assays validated on the SNP500 website (http://snp500cancer.nci.nih.gov); we captured more than 95% of common haplotypes in both the 5′ and 3′ haplotype blocks. Our pilot analysis was performed in 235 DNA samples of healthy Dutch Caucasian blood donors with known MBL serum concentrations measured by ELISA. Haplotypes were deduced by maximization-estimation analysis of unphased genotypes; PHASE 2.0 (http://www.stat.washington.edu/stephens/software.html). The haplotype analysis of the results confirmed the haplotype block structure of MBL2 in the Dutch population. The additional 5′ variants tested in this study were in strong linkage to the elements of the “secretor haplotypes”; functional alleles B, C and D also lie on restricted haplotypes. As reported by others, in our study, the secretor haplotypes predicted levels in roughly 85%. Four variants in the 3′ block (Ex4–1483T>C, Ex4–1067G>A, Ex4–901G>A and Ex4–710G>A) lie in 3 common haplotypes (TAAA, CGGG and TGAA) that strongly correlate with MBL serum concentration (Kruskal-Wallis p < 0.0001); individuals with at least one TAAA allele have a higher serum concentration. Thus, it is also possible that both 5′ and the 3′ haplotypes could contribute to serum levels. This suggests that there could be a selective advantage for diversification of the 3′ region of the gene, perhaps altering expression or stability (to be analyzed in follow-up studies). Our data provide evidence that there are additional SNPs in regulatory elements of MBL2, which could influence circulating levels. These observations could improve the predictive value of locus-wide analysis of MBL2 in genetic association studies.
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Pozdnyakova-Filatova, I. Yu, A. A. Zagoskin, M. V. Zakharova, and Maxim O. Nagornykh. "Analysis of the genes encoding the MBL-fold metallohydrolase superfamily proteins of the Pseudomonas putida BS3701 petroleum component-degrading strain." Clinical Microbiology and Antimicrobial Chemotherapy 24, no. 3 (2022): 248–53. http://dx.doi.org/10.36488/cmac.2022.3.248-253.
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Objective. To determine whether the genes whose products are annotated as «MBL-fold metallohydrolase superfamily» are related to the proteins of the metallo-β-lactamase group. Materials and Methods. Sequences of the 7 genes annotated as «MBL-fold metallohydrolase superfamily» were analyzed using the following resources: ClustalW, IQ-TREE, iTOL. Selection of the oligonucleotides for real-time PCR was performed using the Primer-BLAST resource. The level of gene expression was assessed using real-time PCR. MIC and MBC measuring was performed using cefepime and meropenem. The double-disc method with EDTA was used to determine the presence of MBL in the strain. Results. Analysis of the nucleotide sequences of the studied genes revealed that all of them were not included in the clade containing sequences of metallo-β-lactamase. In the exponential growth phase, mRNAs corresponding to the studied proteins were found. Determination of MIC and MBC revealed a low level of resistance to antibiotics of the β-lactamase group. The phenotypic test was negative for MBL in P. putida strain BS3701. Conclusions. The investigated genes and corresponding proteins are not related to metallo-β-lactamases. They are not involved in the resistance of P. putida BS3701 to antibiotics of the metallo-β-lactamase group.
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Lops, Diego, Eugenio Romeo, Michele Stocchero, Antonino Palazzolo, Barbara Manfredi, and Luca Sbricoli. "Marginal Bone Maintenance and Different Prosthetic Emergence Angles: A 3-Year Retrospective Study." Journal of Clinical Medicine 11, no. 7 (April 4, 2022): 2014. http://dx.doi.org/10.3390/jcm11072014.
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The aim of the present retrospective study was to assess marginal bone changes around implants restored with different prosthetic emergence profile angles. Patients were treated with implants supporting fixed dentures and were followed for 3 years. Marginal bone levels (MBL) measured at the prosthesis installation (t0) and at the 3-year follow-up visit (t1) were considered. The MBL change from t0 to t1 was investigated. Two groups were considered: Group 1 for restorations with an angle between implant axis and prosthetic emergence profile >30°, and Group 2 for those with an angle ≤30°, respectively. Moreover, peri-implant soft tissue parameters, such as the modified bleeding index (MBI) and plaque index (PI) were assessed. Seventy-four patients were included in the analysis and a total of 312 implants were examined. The mean EA in groups 1 and 2 was 45 ± 4 and 22 ± 7 degrees, respectively. The mean marginal bone level change (MBL change) of 0.06 ± 0.09 mm and 0.06 ± 0.10 mm were, respectively, in groups 1 and 2. The difference in the MBL change between the two groups was not statistically significant (p = 0.969). The MBL change does not seem to be influenced by the emergence angle for implants with a stable internal conical connection and platform-switching of the abutment diameter.
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Coelho, Cidarley Grecco Fernandes. "MPL e MBL." Línguas e Instrumentos Línguísticos, no. 44 (December 9, 2019): 112–34. http://dx.doi.org/10.20396/lil.v44i0.8657789.
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Este artigo, filiado à teoria da Análise de Discurso, analisa duas imagens da ocupação da Avenida Paulista: a primeira, em 2013, pelo Movimento Passe Livre (MPL), e a segunda, em 2016, pelo Movimento Brasil Livre (MBL). Para essa análise, mobilizaremos alguns conceitos do campo da AD, como formação discursiva, memória discursiva, memória metálica, imagem, memória digital, para avançarmos teórica e analiticamente sobre aquilo que Dias (2011) nos explica ao afirmar que a cidade é modificada pelo digital. Para tal, mobilizaremos também a noção de condições de produção, trazida por Pêcheux em seu livro AAD-69, e que é essencial para pensarmos as questões aqui colocadas em jogo. Quando pensamos, hoje, em como o autor já se debruçava em interrogações que envolviam o discurso digital, acreditamos olhar para tais questões na tentativa de criar novos dispositivos de análise que auxiliem na compreensão dos avanços alcançados na área.
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Ziegler-Heitbrock, Loems. "MBL and MoBL." British Journal of Haematology 130, no. 5 (September 2005): 795. http://dx.doi.org/10.1111/j.1365-2141.2005.05675.x.
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Scarfò, Lydia, Claudia Fazi, and Paolo Ghia. "MBL Versus CLL." Hematology/Oncology Clinics of North America 27, no. 2 (April 2013): 251–65. http://dx.doi.org/10.1016/j.hoc.2013.01.004.
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Jensen, Pia Hønnerup, Inga Laursen, Finn Matthiesen, and Peter Højrup. "Posttranslational modifications in human plasma MBL and human recombinant MBL." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1774, no. 3 (March 2007): 335–44. http://dx.doi.org/10.1016/j.bbapap.2006.12.008.
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Neglia, Laura, Stefano Fumagalli, Franca Orsini, Adriana Zanetti, Carlo Perego, and Maria-Grazia De Simoni. "Mannose-binding lectin has a direct deleterious effect on ischemic brain microvascular endothelial cells." Journal of Cerebral Blood Flow & Metabolism 40, no. 8 (September 7, 2019): 1608–20. http://dx.doi.org/10.1177/0271678x19874509.
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Mannose-binding lectin (MBL), an initiator of the lectin pathway, is detrimental in ischemic stroke. MBL deposition on the ischemic endothelium indicates the beginning of its actions, but downstream mechanisms are not clear yet. We investigated MBL interactions with the ischemic endothelium by exposing human brain microvascular endothelial cells (hBMECs) to protocols of ischemia. Cells were exposed to hypoxia or oxygen–glucose deprivation (OGD), and re-oxygenated with human serum (HS) or recombinant MBL (rhMBL). Hypoxic hBMECs re-oxygenated with HS showed increased complement system activation (C3c deposition, +59%) and MBL deposition (+93%) than normoxic cells. Super-resolution microscopy showed MBL internalization in hypoxic cells and altered cytoskeletal organization, indicating a potential MBL action on the endothelial structure. To isolate MBL effect, hBMECs were re-oxygenated with rhMBL after hypoxia/OGD. In both conditions, MBL reduced viability (hypoxia: −25%, OGD: −34%) compared to conditions without MBL, showing a direct toxic effect. Ischemic cells also showed greater MBL deposition (hypoxia: +143%, OGD: +126%) than normoxic cells. These results were confirmed with primary hBMECs exposed to OGD (increased MBL-induced cell death: +226%, and MBL deposition: +104%). The present findings demonstrate that MBL can exert a direct deleterious effect on ischemic brain endothelial cells in vitro, independently from complement activation.
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Ghiran, Ionita, Sergi F. Barbashov, Lloyd B. Klickstein, Sander W. Tas, Jens C. Jensenius, and Anne Nicholson-Weller. "Complement Receptor 1/Cd35 Is a Receptor for Mannan-Binding Lectin." Journal of Experimental Medicine 192, no. 12 (December 18, 2000): 1797–808. http://dx.doi.org/10.1084/jem.192.12.1797.
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Mannan-binding lectin (MBL), a member of the collectin family, is known to have opsonic function, although identification of its cellular receptor has been elusive. Complement C1q, which is homologous to MBL, binds to complement receptor 1 (CR1/CD35), and thus we investigated whether CR1 also functions as the MBL receptor. Radioiodinated MBL bound to recombinant soluble CR1 (sCR1) that had been immobilized on plastic with an apparent equilibrium dissociation constant of 5 nM. N-acetyl-d-glucosamine did not inhibit sCR1–MBL binding, indicating that the carbohydrate binding site of MBL is not involved in binding CR1. C1q inhibited MBL binding to immobilized sCR1, suggesting that MBL and C1q might bind to the same or adjacent sites on CR1. MBL binding to polymorphonuclear leukocytes (PMNs) was associated positively with changes in CR1 expression induced by phorbol myristate acetate. Finally, CR1 mediated the adhesion of human erythrocytes to immobilized MBL and functioned as a phagocytic receptor on PMNs for MBL–immunoglobulin G opsonized bacteria. Thus, MBL binds to both recombinant sCR1 and cellular CR1, which supports the role of CR1 as a cellular receptor for the collectin MBL.
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Laursen, I. "Mannan-binding lectin (MBL) production from human plasma." Biochemical Society Transactions 31, no. 4 (August 1, 2003): 758–62. http://dx.doi.org/10.1042/bst0310758.
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Individuals with low levels of mannan-binding lectin (MBL) appear to be susceptible to infectious diseases. This suggests that substitution therapy with MBL might be a beneficial treatment of patients with MBL deficiency. A production process for an MBL product has been developed from a fraction II+III precipitate obtained by ethanol fractionation of plasma. The MBL process includes three chromatographic steps, where the first and key step is affinity chromatography on a cross-linked agarose matrix selecting for oligomeric, carbohydrate-binding MBL. The yield from the production process is about 25% of the plasma MBL content, and the purity is about 65%. The MBL product shows mannan-binding activity and complement-activating ability. A safety study has shown this plasma-derived MBL to be safe and well tolerated in adult MBL-deficient volunteers.
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Slager, Susan L., Mark C. Lanasa, Sallie D. Allgood, Sara J. Achenbach, Aaron Norman, Celine M. Vachon, Lynn Goldin, et al. "Prevalence of MBL Increases Over Time In Relatives of CLL Families,." Blood 118, no. 21 (November 18, 2011): 3881. http://dx.doi.org/10.1182/blood.v118.21.3881.3881.
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Abstract Abstract 3881 Background: Chronic lymphocytic leukemia (CLL) is largely incurable neoplasm of the blood and has one of the highest familial risks of disease among cancers. Monoclonal B-cell lymphocytosis (MBL) with a CLL immunophenotypic profile (i.e., CLL-like MBL) is a precursor state to CLL. In the general adult population, the prevalence rate of MBL is 5–9% and increases with age. This is in contrast to the 13–18% rate of MBL in first-degree relatives of CLL patients from high-risk families (defined here as families with at least two confirmed living cases of CLL). Few longitudinal studies of MBL incidence exists. One study evaluated MBL status over time in a cohort of individuals with MBL from a rural valley in Northern Italy. Our work herein will be the first to evaluate the status of MBL over time in relatives of CLL patients from high-risk families. Methods: Using a cohort of 41 high-risk CLL families, we evaluated the MBL status and clonal blood B-cell counts in 94 relatives of CLL patients at two time points at least 1 year a part. High sensitivity, multi-color flow cytometry was performed on fresh or previously frozen blood samples in three laboratories: Duke University, the US Food and Drug Administration, and Mayo Clinic. The number of cell events collected for flow cytometry evaluation varied from 1 to 5 x105 cells. To assure concordance across flow cytometry laboratories, 15 samples were evaluated at multiple labs. The concordance of MBL calling was a 100%. We defined three monotypic B-cell subsets as CLL-like MBL (CD5+ CD20dim), atypical MBL (CD5+ CD20+), and non-CLL like MBL (CD5−CD20+). Results: Of the 94 relatives, the median age at consent was 57 years (range 42–93) and 39% were male. At the initial MBL screening, 70 (74%) relatives had normal immunophenotype (NIPT) and 24 (26%) had MBL (1 atypical MBL, 3 non-CLL like MBL, and 20 CLL-like MBL). Seven of the 24 individuals with MBL had monoclonal B-cell counts available at baseline screening; median = 147.4 cells/uL (range 22.7–1663). The 94 relatives underwent repeat evaluation with a median follow up time of 1.8 years (range 1–6). At the second evaluation, we found an increase in the prevalence of MBL, with 11 of the 70 (12%) initially NIPT relatives developing a new MBL clone (10 CLL-like, 1 non-CLL like). These 11 incident MBL cases were from 9 families with 2 families each having 2 relatives changing MBL status. The median number of monoclonal B-cells in these 11 incident MBL cases was 0.58 cells/uL (range 0.38–60.3). The 23 out of the 24 relatives with baseline MBL (20 CLL-like MBL and 3 non-CLL like MBL) had a persistent MBL clone. Only 6 of these 23 individuals had monoclonal B-cell counts available at both time points, and among these 6, the clonal B-cell counts decreased at follow-up screening; median difference −64.1 cells/uL (range −1204.3– 10.5). The second evaluation of the initial atypical MBL relative had too few clonal cells for flow assessment. Conclusion: We found that our CLL-like MBL clones persisted over the period of observation in relatives from high-risk CLL families; this finding is similar to that previously reported using a population-based study conducted in Northern Italy. Notably, 12% of relatives from high-risk CLL families developed incident MBL during just 2 years of follow up. Although these MBL clones are all low count (< 1500 cells/uL), these data provide further evidence that MBL is a marker of inherited predisposition to CLL. It will be important to see how our rate of change of MBL status compares to that of the general population as we continue to follow our cohort of CLL families. Disclosures: No relevant conflicts of interest to declare.
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Yager, Phoebe H., Zerong You, Tao Qin, Hyung-Hwan Kim, Kazue Takahashi, Alan B. Ezekowitz, Gregory L. Stahl, Michael C. Carroll, and Michael J. Whalen. "Mannose Binding Lectin Gene Deficiency Increases Susceptibility to Traumatic Brain Injury in Mice." Journal of Cerebral Blood Flow & Metabolism 28, no. 5 (January 9, 2008): 1030–39. http://dx.doi.org/10.1038/sj.jcbfm.9600605.
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Mannose binding lectin (MBL) initiates complement activation and exacerbates tissue damage after systemic ischemia/reperfusion. We tested the hypothesis that MBL activates complement and worsens outcome using two levels of controlled cortical impact (CCI) in mice. After moderate CCI (0.6 mm depth), MBL immunostaining was detected on injured endothelial cells of wild-type (WT) mice and C3d was detected in MBL KO (deficient in MBL A/C) and WT mice, suggesting that MBL is dispensable for terminal complement activation after CCI. Brain neutrophils, edema, blood-brain barrier permeability, gross histopathology, and motor dysfunction were similar in injured MBL KO and WT mice. In mice subjected to mild CCI (0.2 mm), MBL KO mice had almost two-fold increased acute CA3 cell degeneration at 6 h ( P<0.01 versus WT). Naive MBL KO mice had decreased brain volume but performed similar to WT mice in two distinct Morris water maze (MWM) paradigms. However, injured MBL KO mice had impaired performance in cued platform trials (P<0.05 versus WT), suggesting a transient nonspatial learning deficit in injured MBL KO mice. The data suggest that MBL deficiency increases susceptibility to CCI through C3-independent mechanisms and that MBL-deficient patients may be at increased risk of poor outcome after traumatic brain injury.
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Káplár, Miklós, Shah Sweni, Julianna Kulcsár, Barbara Cogoi, Regina Esze, Sándor Somodi, Mária Papp, et al. "Mannose-Binding Lectin Levels and Carotid Intima-Media Thickness in Type 2 Diabetic Patients." Journal of Diabetes Research 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/8132925.
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Introduction. Mannose-binding lectin (MBL) activates complement system and has been suggested to play a role in vascular complications in diabetics. Carotid intima-media thickness (cIMT) detects subclinical atherosclerosis. We evaluated the association of MBL and IMT in type 2 diabetic (T2DM) patients.Methods. Serum MBL levels and cIMT were measured in a total of 103 diabetics and in 98 age-matched healthy controls.Results. There was no significant difference in MBL level in T2DM versus controls. As expected, IMT was significantly higher in T2DM patients than in controls (P=0.001). In T2DM, the lowest cIMT was seen in patients with normal MBL level (500–1000) while cIMT continuously increased with both high MBL and absolute MBL deficiency states. This was especially significant in high MBL versus normal MBL T2DM patients (P=0.002). According to multiple regression analysis the main predictors of IMT in T2DM are age (P<0.003), ApoA level (P=0.023), and the MBL (P=0.036).Conclusions. Our results suggest a dual role of MBL as a risk factor for cIMT in T2DM. MBL may also be used as a marker of macrovascular disease, as both low and high levels indicate the susceptibility for atherosclerosis in T2DM.
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Lanasa, Mark C., Sallie D. Allgood, Barbara K. Goodman, John F. Whitesides, Jon P. Gockerman, Joseph O. Moore, J. Brice Weinberg, and Marc C. Levesque. "Monoclonal B Cell Lymphocytosis Exhibits Biologic Diversity Similar to Chronic Lymphocytic Leukemia." Blood 110, no. 11 (November 16, 2007): 3084. http://dx.doi.org/10.1182/blood.v110.11.3084.3084.
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Abstract Background: Monoclonal B cell lymphocytosis (MBL) is a pre-clinical syndrome characterized by small accumulations of monoclonal B lymphocytes in the peripheral blood. MBL have an immunophenotype similar to CLL: CD5+, CD19+, CD20lo, CD23+, CD79blo, sIglo. The biologic characteristics and clinical implications of MBL remain unclear. We hypothesized that MBL have a biology similar to CLL and represent a pre-neoplastic state of CLL. Characterization and longitudinal evaluation of MBL may provide insight into mechanisms of CLL leukemogenesis. Methods: We defined MBL as a population of CD5+, CD20lo cells that were kappa/lambda restricted and comprised at least 2% of the CD19+ peripheral B cell compartment. Persons with MBL were ascertained by flow cytometric screening of peripheral blood from unaffected members of CLL kindreds. Flow cytometric analysis and fluorescence-activated cell sorting (FACS) were used to determine the surface immunophenotype and molecular characteristics of MBL. MBL cells were bulk-sorted and analyzed using FISH for loci associated with clinical CLL [13q14.3 (D13S319), 17p13.1 (TP53), 11q22.3 (ATM), and 12p11.1-q11 (enumeration probe)]. Single MBL cells were sorted and genomic DNA analyzed by PCR to determine immunoglobulin heavy and light chain sequences. Results: Twelve out of 113 (11%) unaffected family members were found to have MBL. Seven of these individuals provided additional blood for MBL characterization. All 7 MBL subjects had normal complete blood counts and leukocyte differentials. Six of the 7 MBL subjects had MBL counts less than 150 cells/μL. All MBL samples had immunophenotypes similar to CLL. One MBL sample was CD38+/Zap70+, one was CD38+/Zap70−, one was CD38−/Zap70+, and 4 samples were CD38−/Zap70−. The ratio of median fluorescence intensity of CD69:CD71 was low (<1.0) in 6 of the 7 MBL samples, but was 2.8 in the one CD38+/Zap70+ case, consistent with an activated membrane surface phenotype. Next, MBL cells were sorted as single cells and genomic DNA was amplified for direct sequencing of immunoglobulin heavy and light chains. This analysis has been completed in 4 of 7 individuals. Immunoglobulin heavy chain variable (IgVH) region gene usage mirrored that of typical CLL and included examples of IgVH mutated and unmutated sequences. Some MBL were monoclonal, some consisted of related antigen-driven oligoclonal populations, and others consisted of unrelated oligoclonal populations. For example, one person showed three unique clones: a mutated VH4-59 clone (38% of all MBL cells), a mutated VH4-34 clone (5%), and an unrelated unmutated VH4-34 clone (57%). FISH analyses showed mono- or biallelic deletion of 13q14 in four of seven samples. No other loci were deleted or amplified in these 7 MBL subjects. Four individuals provided a second sample of blood for longitudinal MBL analysis. The size of the MBL clone expanded in 3 of these subjects and was unchanged in the 4th subject. Conclusions: This cohort of familial MBL recapitulated much of the biologic diversity of clinical CLL. By several different phenotypic measures, the MBL phenotype was similar to typical CLL. To our knowledge, this is the first report of CD38+, Zap70+, and IgVH unmutated MBL. In contrast to most CLL, we found that many MBL consisted of more than one clonal population. Likewise, we identified evidence of ongoing antigen-driven intraclonal diversification in MBL.
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Valdimarsson, H. "Infusion of plasma-derived mannan-binding lectin (MBL) into MBL-deficient humans." Biochemical Society Transactions 31, no. 4 (August 1, 2003): 768–69. http://dx.doi.org/10.1042/bst0310768.
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Our first experience of mannan-binding lectin (MBL)-replacement therapy was with a patient experiencing recurrent erythema multiforme associated with reactivation of herpes simplex virus; his erythematous eruptions could be controlled with infusions of fresh frozen plasma containing MBL, but not with plasma lacking MBL. Some years later, we treated a young girl with recurrent, debilitating infections with purified MBL; this was also followed by a dramatic clinical improvement. We have now carried out a phase I clinical trial on 20 MBL-deficient, but healthy, adult volunteers. The MBL was prepared by the State Serum Institute in Copenhagen, Denmark, from blood donor plasma. Each volunteer received a total of 18 mg of MBL in three 6-mg doses given intravenously once a week over 3 weeks. The volunteers were monitored closely after each infusion and no adverse clinical or laboratory effects were observed. Laboratory parameters included C-reactive protein, various complement components, and antibodies to MBL, HIV and hepatitis viruses. C3a (the anaphylotoxin derived from complement component C3) was monitored for signs of complement activation, but no significant infusion-associated fluctuations were observed. Serum levels of MBL after each 6-mg infusion ranged between 1200 and 2500 ng/ml. The half-life of the infused MBL was about 70 h, or 3 days. It was concluded that infusion of purified MBL manufactured by the Danish State Serum Institute is a safe procedure. However, adults may have to be given 6 mg or more at least twice weekly to maintain protective plasma MBL levels in MBL-deficient individuals.
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Lanasa, Mark C., Sallie D. Allgood, Susan L. Slager, Nicola Camp, Logan Spector, Laura Rassenti, Neil E. Kay, et al. "Family-Associated Monoclonal B Lymphocytosis Is Commonly Oligoclonal and Expresses Markers Associated with Adverse Risk in CLL." Blood 112, no. 11 (November 16, 2008): 3144. http://dx.doi.org/10.1182/blood.v112.11.3144.3144.
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Abstract Background and Significance : Chronic lymphocytic leukemia (CLL) is the most heritable hematologic malignancy; however, no common CLL predisposition genes are known. Monoclonal B lymphocytosis (MBL) is a hematologic syndrome characterized by small accumulations of B lymphocytes in the peripheral blood. MBL has a CLL-like immunophenotype, may progress to overt CLL, and is over represented in CLL families. Therefore, MBL observed in the context of familial CLL may be a marker of inherited risk for development of CLL. Detailed characterization of family-associated MBL may also provide mechanistic insights into the pathogenesis of familial CLL. Our strategy was to detail the biologic characteristics of CLL in family-associated MBL. Methods : Persons with MBL were identified by flow cytometric screening of peripheral blood from unaffected members of CLL kindreds ascertained by Genetic Epidemiology of CLL Consortium (GEC) sites. Flow cytometry was used to determine the surface immunophenotype including CD38 and intracellular ZAP-70. We defined MBL as populations of CD19+, CD5+, CD20lo, CD23+ B cells that comprised at least 2% of the CD19+ peripheral B cell compartment and did not exceed 5.0 × 109 MBL cells/L. RNA and genomic DNA from single MBL cells isolated by flow cytometric sorting were analyzed using PCR to determine immunoglobulin heavy and light chain sequences. MBL cells were sorted in bulk for FISH for loci associated with clinical CLL. Results : Twenty-two out of 190 (12%) unaffected family members were found to have MBL. We observed significant variability in the size of the MBL clone as a percentage of the CD19+ B cell compartment (mean 32%; range 2%–97%). Nonetheless, the absolute size of the MBL clone was small, 15 of 17 individuals had < 200 × 106 MBL cells/L. CD38 expression (defined as CD38 surface expression in ≥30% of MBL cells) was observed in 8 of 18 subjects tested. ZAP-70 (defined as intracellular expression in ≥ 20% of MBL cells) was expressed in 4 of 12 participants. Among 12 subjects tested, 5 MBL expressed both surface IgD and IgM, 3 expressed IgD only, 2 expressed IgM only, and 2 did not express IgD or IgM. Analysis of immunoglobulin heavy and light chains has been completed in 8 individuals. Both immunoglobulin heavy chain variable (IgVH) region mutated (n = 12) and unmutated (n = 4) sequences were observed. Four of 8 individuals had 2 or more unrelated MBL clones (range 2–5), including one individual with both unmutated and mutated clones. Among the 16 MBL clones identified in these 8 subjects, VH3 or VH4 rearrangements were observed in all MBL clones. The most commonly rearranged IgVH genes were 3–07 (3 MBL clones), 3–15 (3), and 4–34 (3). No VH1 family gene rearrangements were observed. In one individual, a VH3–07 MBL clone showed intraclonal diversification suggestive of antigen driven immunoglobulin sequence changes. Twenty productive light chain rearrangements were identified among the 16 MBL clones, with 11 Vλ and 9 Vκ genes used. We observed 6 productive rearrangements of Vλ1–51. MBL cells were bulk sorted for FISH from 9 subjects. Mono or biallelic deletion of 13q14.3 was observed in 5 subjects, the other 4 were normal. Conclusions : Our findings confirm that MBL is commonly observed among the unaffected family members from CLL kindreds. We found that some MBL clones express ZAP-70, CD38 or have unmutated IgVH genes and thus are similar to clinical CLL. The clinical outcome of these MBL clones in relation to our baseline prognostic characterization will be of interest. Small MBL clones are commonly oligoclonal. Importantly, although the immunoglobulin heavy and light chain genes rearranged in these MBL clones are all commonly used in CLL, the absence of VH1 and abundance of Vλ1–51 rearrangements do suggests differences in BCR usage between CLL and MBL. Further investigation of family associated MBL may clarify the genetics and immunobiology of familial CLL.
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Radnay, Zita, Miklos Udvardy, Attila Kiss, Maria Papp, Laszlo Rejto, Jolan Harsfalvi, Tamas Masszi, et al. "A New Approach to Predict the Chance of Infectious Complications Following Autologous Hematopoietic Stem Cell Transplantation: Mannose-Binding Lectin ELISA." Blood 118, no. 21 (November 18, 2011): 4492. http://dx.doi.org/10.1182/blood.v118.21.4492.4492.
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Abstract Abstract 4492 Introduction: Haematopoietic stem cell transplantation associated immuncompromised state carries high risk of infectious complications. Gram-positive cocci are responsible for the majority of the post-transplant bloodstream infections. Viral and invasive fungal infections can be significant causes of morbidity. Mannose-binding lectin (MBL) is involved in innate immune response. MBL is an acute phase protein, synthesized in the liver. MBL binds microbial surface carbohydrates and mediates opsonophagocytosis directly and by activation of the lectin complement pathway. MBL also functions as co-receptor of Toll-like receptor. Serum MBL level is genetically determined and quite stable. MBL deficiency is a result of impaired assembly or stability of multimers. In patients who received high dose chemotherapy/transplantation, the innate immunodeficiency is an additive risk factor for infectious complications. According to literature, significant association was shown between low concentrations of MBL and serious infections. MBL is a potential modifier of susceptibility to infection in patients who have chemotherapy-induced neutropenia. Furthermore, infections might also compromise the engraftment of stem cells and the development of cell-lines might be prolonged. Patients and methods: The association between serum MBL level and frequency, severity and occurrence of infections has been studied in 127 patients following autologous stem cell transplantation (ASCT). Subgroups, i.e. multiple myeloma, non-Hodgkin and Hodgkin lymphoma were formed and the infectious complications have been compared. A double-monoclonal antibody sandwich ELISA system (BioPorto, Denmark) was used, which is a sensitive method for determining the MBL antigen levels in the sera. The range of MBL level in healthy population varies between 5 and 5000 ng/ml, <100 ng/ml is defined as MBL deficiency. MBL antigen levels were measured following transplantation, in a period without the presence of active infection. Results: 18 patients (out of 127) proved to be MBL deficient. The median time of the onset of first infection was day +5 in MBL deficient, while day +15 among non-MBL deficient patients following transplantation. More infections were found among MBL deficient patients (2.44 vs 2.28 infectious episodes/patient). When patients with more and less than 500 ng/ml serum MBL level were compared, similar trends were seen, but the difference was not significant. The occurrence of absolute MBL deficiency was not different between patients with malignant hematological diseases and the 294 healthy controls (14.5% vs 14%). Interestingly, MBL serum levels were significantly higher in the examined patients with malignant hematological diseases compared to healthy controls. Conclusions: MBL deficiency may predispose to infections. To our best knowledge, this is one of the first reports regarding MBL deficiency in bone marrow transplant settings. Our MBL deficient patients had a greater number of severe infections and experienced their first severe infection earlier, compared to nondeficient patients following ASCT. The measuring of MBL may be helpful in antibiotic treatment, in case of MBL deficiency earlier and more intensive treatment may be indicated. Disclosures: No relevant conflicts of interest to declare.
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Lambourne, Jonathan, Dan Agranoff, Aby Buchbinder, Peter F. Troke, Raoul Herbrecht, Jodi Lindsay, and Thomas Harrison. "Mannose-Binding Lectin Deficiency - a Risk Factor for Invasive Aspergillosis in Immunocompromised Patients." Blood 112, no. 11 (November 16, 2008): 1465. http://dx.doi.org/10.1182/blood.v112.11.1465.1465.
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Abstract Invasive aspergillosis is a devastating infection with 30–40% mortality. Immune mechanisms involved in recognition and elimination of aspergillus are incompletely understood. Mannose-binding lectin (MBL) deficiency occurs in 10–15% of the population and has been identified as a susceptibility factor in animal models of aspergillosis. We hypothesise there is an association between human MBL deficiency and invasive aspergillosis. In this multi-centre case-control study, serum MBL concentrations were measured in 65 patients with probable or proven invasive aspergillosis (as defined by the 2002 EORTC/NIH-MSG criteria) and in 79 immunocompromised controls with fever not due to aspergillosis. MBL concentrations were measured using a commercially available, technically straightforward solid phase ELISA (Hycult Biotechnology, The Netherlands). Median MBL concentrations and the frequency of MBL deficiency were compared using the Mann-Whitney and Fisher’s exact tests. Cases and controls were well matched in terms of age, gender, ethnicity and cause of immunocompromise. The assay performed well with a mean coefficient of variation of 7%. Patients with invasive aspergillosis had significantly lower MBL concentrations and a greater frequency of MBL deficiency than controls (65% vs. 33%, p = 0.0002, MBL deficiency cut-off 500ng/ml). MBL deficiency was significantly more frequent in cases than in controls at all MBL concentrations ≤500ng/ml. This is the first study to identify a strong association between MBL deficiency and invasive aspergillosis in immunocompromised patients. Because MBL concentrations do not consistently change during acute infection we conclude that MBL deficiency predisposes to invasive aspergillosis. Routine measurement of MBL levels is within the capability of most diagnostic laboratories. These data suggest that replacement therapy with recombinant human MBL may be an opportunity to prevent or mitigate the poor outcome of invasive aspergillosis.
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Matos, Daniel Mazza, and Roberto Passetto Falcão. "Monoclonal B-cell lymphocytosis: a brief review for general clinicians." Sao Paulo Medical Journal 129, no. 3 (May 2011): 171–75. http://dx.doi.org/10.1590/s1516-31802011000300008.
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Monoclonal B-cell lymphocytosis (MBL) is a recently described medical condition that displays biological similarities to the most common subtype of adult leukemia in the Western world, i.e. chronic lymphocytic leukemia (CLL). Diagnostic criteria have been published with the aim of differentiating between these two entities. The overall prevalence of MBL is at least 100 times higher than that of CLL, which indirectly suggests that MBL is not necessarily a pre-leukemic condition, although in some circumstances, CLL cases can really be preceded by MBL. In view of this high prevalence rate, general clinicians and even non-hematological specialists have a high chance of being faced with individuals with MBL in their routine clinical practice. MBL is classified as "clinical MBL", "population-screening MBL" and "atypical MBL" and the clinical management of affected individuals depends greatly on this differentiation. The present review provides a guide to diagnosing and following up MBL patients.
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De Pascale, Gennaro, Salvatore Lucio Cutuli, Mariano Alberto Pennisi, and Massimo Antonelli. "The Role of Mannose-Binding Lectin in Severe Sepsis and Septic Shock." Mediators of Inflammation 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/625803.
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Severe sepsis and septic shock are a primary cause of death in patients in intensive care unit (ICU). Investigations upon genetic susceptibility profile to systemic complications during severe infections are a field of increasing scientific interest. Particularly when adaptive immune system is compromised or immature, innate immunity plays a key role in the immediate defense against invasive pathogens. Mannose-binding lectin (MBL) is a serum protein that recognizes a wide range of pathogenic microorganisms and activates complement cascade via the antibody-independent pathway. More than 30% of humans harbor mutations in MBL gene (MBL2) resulting in reduced plasmatic levels and activity. Increased risk of infection acquisition has been largely documented in MBL-deficient patients, but the real impact of this form of innate immunosuppression upon clinical outcome is not clear. In critically ill patients higher incidence and worse prognosis of severe sepsis/septic shock appear to be associated with low-producers haplotypes. However an excess of MBL activation might be also harmful due to the possibility of an unbalanced proinflammatory response and an additional host injury. Strategies of replacement therapies in critically ill patients with severe infections are under investigation but still far to be applied in clinical practice.
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Tereshchenko, S. Yu, and M. V. Smolnikova. "Polymorphism of the mannose-binding lectin gene in the Arctic indigenous populations of the Russian Federation." Vavilov Journal of Genetics and Breeding 24, no. 8 (December 31, 2020): 868–75. http://dx.doi.org/10.18699/vj20.685.
Full textAbstract:
Mannose-binding lectin (MBL) is a pattern recognizing acute-phase protein of the innate immunity system actively involved in the elimination of a wide range of pathogenic microorganisms by activating the lectin pathway of the complement system. A significant part of the human population has a congenitally low production level and/or low MBL activity due to the carriage of various MBL2 variants, which can modify the course of a wide range of infectious diseases. The genotype and haplotype frequencies of the MBL2 polymorphisms have significant population differences. So far, data on the prevalence of the MBL2 genotypes in indigenous populations of the Russian Arctic regions have not been available. The aim of the study was to analyze the frequency and ethnic specificity of the distribution of allelic variants of the MBL2 polymorphisms rs11003125, rs7096206, rs7095891, rs5030737, rs1800450 and rs1800451 and their haplotypes in the populations of the Taimyr Dolgans-Nenets region of the Krasnoyarsk territory (Nenets, Dolgans-Nganasans, Russians). Data on the genotype and haplotype frequencies of the MBL2 gene among indigenous peoples of the Russian Arctic territories was first obtained in the study. The HYPA haplotype prevalence associated with a high concentration of MBL amounted to 35.4 % for Russian newborns in Eastern Siberia, corresponding to the one for European populations (27–33 %). In newborns of the Arctic populations, the prevalence of HYPA haplotype was significantly higher than in Russians and amounted to 64 % for Nenets and 56 % for the DolgansNganasans, which is close to the one detected for the Eskimos and North American Indians (64–81 %). Populations of Nenets and Dolgans-Nganasans demonstrated a significantly lower prevalence of MBL-deficient haplotypes compared with Caucasians of Eastern Siberia (3.9, 6.4 and 21.3 % respectively). Isolated Arctic populations were suggested to experience some intracellular infections (tuberculosis, leprosy) historically later and, unlike Caucasoid populations, to retain the high activity of the lectin complement activation pathway formed in the early stages of human evolution.
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Summerfield, J. A. "Clinical potential of mannose-binding lectin-replacement therapy." Biochemical Society Transactions 31, no. 4 (August 1, 2003): 770–73. http://dx.doi.org/10.1042/bst0310770.
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Mannose-binding lectin (MBL; also known as mannan-binding lectin) is an important component of innate immunity. MBL levels are mainly genetically determined. Low serum MBL levels and their cognate haplotypes have been associated with a wide range of infections. However, most subjects with MBL deficiency remain healthy. MBL deficiency is also associated with non-infectious diseases including systemic lupus erythematosus, rheumatoid arthritis, cystic fibrosis and common variable immunodeficiency. MBL deficiency may affect susceptibility to (e.g. meningococcal disease), or alter the natural history of (e.g. rheumatoid arthritis, cystic fibrosis), a disease. MBL (plasma-derived or recombinant) therapy has yet to be shown to be safe and effective. Potentially it may be useful in MBL-deficient patients to reduce susceptibility to, or enhance recovery from, bacterial infection or to alter the natural history of a disease (disease-modifying drug). In practise the place of MBL therapy may be as a disease-modifying drug to reduce the severity of rheumatoid arthritis and to preserve lung and liver function in cystic fibrosis. MBL therapy may also ameliorate various immunodeficiency syndromes. A potential hazard of MBL therapy is enhanced complement-mediated host damage. The place of MBL therapy will await results of randomized controlled clinical trials.
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Østergaard, Jakob Appel, Mette Bjerre, Satish Posettihalli RamachandraRao, Kumar Sharma, Jens Randel Nyengaard, Troels Krarup Hansen, Steffen Thiel, and Allan Flyvbjerg. "Mannan-Binding Lectin in Diabetic Kidney Disease: The Impact of Mouse Genetics in a Type 1 Diabetes Model." Experimental Diabetes Research 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/678381.
Full textAbstract:
Background. Mannan-binding lectin (MBL) is involved in the development of diabetic nephropathy. MBL is a part of the innate immune system where it can activate the complement system. Serum MBL level predicts later renal impairment in diabetes patients. Direct involvement of MBL in the development of diabetic kidney disease is observed in one animal strain. However, this involvement may differ among the animal strains. We thus examined the impact of the genetic background on the role of MBL in diabetic nephropathy.Materials/Methods. C57BL/6JBomTac and 129S6/SvEvTac mice were compared. In both strains, experimental type 1 diabetes was induced in wild-type (WT) and MBL-knockout (MBL-KO) mice by streptozotocin. Nondiabetic WT and MBL-KO mice were used as controls. We tested if MBL modified the diabetes-induced kidney changes by two-way ANOVA allowing for interaction.Results. MBL aggravated diabetes-induced kidney growth and glomerulus enlargement in C57BL/6JBomTac mice. MBL did not modify diabetes effects on glomerular basement membrane thickness or mesangial volume in any strain. Diabetes-induced changes in renal gene transcription of growth factors and matrix components were unaffected by MBL.Conclusions. Strain-specific MBL effects were found on downstream diabetic kidney changes. This emphasizes the importance of genetic background in this model of diabetic complications.
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Ansari, Ahmed Nadeem, Sara J. Achenbach, Sameer A. Parikh, Geffen Kleinstern, Aaron D. Norman, Kari G. Rabe, Connie E. Lesnick, et al. "Abstract 5256: Incidence of squamous cell carcinoma (SCC) in a large screening cohort of monoclonal B-cell lymphocytosis (MBL)." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5256. http://dx.doi.org/10.1158/1538-7445.am2022-5256.
Full textAbstract:
Abstract MBL is a common pre-malignant condition characterized by circulating clonal B-cells with an absolute B-cell count <5x109/L and no lymphadenopathy, organomegaly, or cytopenias. MBL is the precursor to CLL. The incidence of cutaneous SCC in CLL is significantly higher compared to controls. The incidence of SCC in MBLs has not yet been determined. Study participants from the Mayo Clinic Biobank who had no prior history of hematologic malignancy, were 40 years or older, and were Olmsted County residents completed a health questionnaire and provided blood samples between 7/2009 and 12/2020. Stored peripheral blood mononuclear cells were screened for MBL using flow cytometry. We defined three MBL immunophenotypes: CLL-like MBL (CD5+, CD20dim), atypical MBL (CD5+, CD20+), and non-CLL-like MBL (CD5-, CD20+). MBL individuals were also classified by cell count into low-count MBL (LC-MBL) and high-count MBL (HC-MBL), with HC-MBL having a percent clonal B-cell count ≥85%. Data on newly diagnosed SCC was abstracted from the medical records, and prior history of skin cancer before sample collection was ascertained from patient questionnaires. Individuals were followed from sample date to the earliest of SCC, death, loss to follow-up, progression, or 12/31/2020. Cumulative SCC incidence was adjusted for competing risk of death. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) adjusted for age and sex. A total of 5,470 participants were screened for MBL and included 949 (17%) with LC-MBL, 63 (1%) with HC-MBL, and 4,458 (81%) controls (negative for MBL). Individuals with HC-MBL (median age 75 years) or LC-MBL (median age 73 years) were significantly older (P<0.001) than controls (median age 66 years). There were 41 (65%) males among HC-MBL, 447 (47%) among LC-MBL, and 1,551 (35%) among controls. Prior skin cancer history was highest among HC-MBLs (N=17, 27%) or LC-MBLs (N=236, 25%) compared to controls (N=767, 17%). After a median follow-up of 18 months (range 0-138), 154 of the 5,470 individuals were identified to have incident SCC following MBL screening. At least one SCC was observed in 3 individuals with HC-MBL, 33 individuals with LC-MBL, and 118 controls. The 5- and 10-year cumulative incidence of SCC in individuals with MBLs was 7% and 16%, respectively; control estimates were 4% and 8%, respectively. However, after adjusting for age and sex, we observed no evidence of an association between MBL and risk of incident SCC (HR=0.95, CI=0.65-1.40, P=0.80), nor when we stratified individuals by age or by sex (all P>0.05). In the largest MBL screening cohort to date, individuals with MBL do not have an increased risk of incident SCC compared to controls. In contrast to individuals with CLL, these individuals with screening MBL do not need increased dermatologic examination for skin cancer, which is important given the high prevalence of MBL (18% of the population above age 40). Citation Format: Ahmed Nadeem Ansari, Sara J. Achenbach, Sameer A. Parikh, Geffen Kleinstern, Aaron D. Norman, Kari G. Rabe, Connie E. Lesnick, Timothy G. Call, Janet E. Olson, James R. Cerhan, Neil E. Kay, Celine M. Vachon, Esteban Braggio, Curtis A. Hanson, Tait D. Shanafelt, Christian L. Baum, Susan L. Slager. Incidence of squamous cell carcinoma (SCC) in a large screening cohort of monoclonal B-cell lymphocytosis (MBL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5256.