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Lectins Offer New Perspectives in the Development of Macrophage-Targeted Therapies for COPD/Emphysema  [PDF]
Violet R. Mukaro, Johan Bylund, Greg Hodge, Mark Holmes, Hubertus Jersmann, Paul N. Reynolds, Sandra Hodge
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056147
Abstract: We have previously shown that the defective ability of alveolar macrophages (AM) to phagocytose apoptotic cells (‘efferocytosis’) in chronic obstructive pulmonary disease/emphysema (COPD) could be therapeutically improved using the C-type lectin, mannose binding lectin (MBL), although the exact mechanisms underlying this effect are unknown. An S-type lectin, galectin-3, is also known to regulate macrophage phenotype and function, via interaction with its receptor CD98. We hypothesized that defective expression of galectin/CD98 would be associated with defective efferocytosis in COPD and that mechanisms would include effects on cytoskeletal remodeling and macrophage phenotype and glutathione (GSH) availability. Galectin-3 was measured by ELISA in BAL from controls, smokers and current/ex-smokers with COPD. CD98 was measured on AM using flow cytometry. We assessed the effects of galectin-3 on efferocytosis, CD98, GSH, actin polymerisation, rac activation, and the involvement of PI3K (using β-actin probing and wortmannin inhibition) in vitro using human AM and/or MH-S macrophage cell line. Significant decreases in BAL galectin-3 and AM CD98 were observed in BAL from both current- and ex-smoker COPD subjects vs controls. Galectin 3 increased efferocytosis via an increase in active GTP bound Rac1. This was confirmed with β-actin probing and the role of PI3K was confirmed using wortmannin inhibition. The increased efferocytosis was associated with increases in available glutathione and expression of CD98. We provide evidence for a role of airway lectins in the failed efferocytosis in COPD, supporting their further investigation as potential macrophage-targeted therapies.
Mannose-binding lectin deficiency and acute exacerbations of chronic obstructive pulmonary disease  [cached]
Albert RK,Connett J,Curtis JL,Martinez FJ
International Journal of COPD , 2012,
Abstract: Richard K Albert,1 John Connett,2 Jeffrey L Curtis,3,4 Fernando J Martinez,3 MeiLan K Han,3 Stephen C Lazarus,5 Prescott G Woodruff51Medicine Service, Denver Health and Department of Medicine, University of Colorado Denver, Denver, CO, 2Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, 3Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan, Ann Arbor, MI, 4Pulmonary and Critical Care Medicine, VA Medical Center, Ann Arbor, MI, 5Pulmonary and Critical Care Medicine, Department of Medicine, and Cardiovascular Research Institute, University of California, San Francisco, CA, USABackground: Mannose-binding lectin is a collectin involved in host defense against infection. Whether mannose-binding lectin deficiency is associated with acute exacerbations of chronic obstructive pulmonary disease is debated.Methods: Participants in a study designed to determine if azithromycin taken daily for one year decreased acute exacerbations had serum mannose-binding lectin concentrations measured at the time of enrollment.Results: Samples were obtained from 1037 subjects (91%) in the trial. The prevalence of mannose-binding lectin deficiency ranged from 0.5% to 52.2%, depending on how deficiency was defined. No differences in the prevalence of deficiency were observed with respect to any demographic variable assessed, and no differences were observed in time to first exacerbation, rate of exacerbations, or percentage of subjects requiring hospitalization for exacerbations in those with deficiency versus those without, regardless of how deficiency was defined.Conclusion: In a large sample of subjects with chronic obstructive pulmonary disease selected for having an increased risk of experiencing an acute exacerbation of chronic obstructive pulmonary disease, only 1.9% had mannose-binding lectin concentrations below the normal range and we found no association between mannose-binding lectin concentrations and time to first acute exacerbation or frequency of acute exacerbations during one year of prospective follow-up.Keywords: COPD, acute exacerbations, mannose-binding lectin
Mannose-binding lectin deficiency and acute exacerbations of chronic obstructive pulmonary disease
Albert RK, Connett J, Curtis JL, Martinez FJ, Han MK, Lazarus SC, Woodruff PG
International Journal of Chronic Obstructive Pulmonary Disease , 2012, DOI: http://dx.doi.org/10.2147/COPD.S33714
Abstract: nnose-binding lectin deficiency and acute exacerbations of chronic obstructive pulmonary disease Original Research (852) Total Article Views Authors: Albert RK, Connett J, Curtis JL, Martinez FJ, Han MK, Lazarus SC, Woodruff PG Published Date November 2012 Volume 2012:7 Pages 767 - 777 DOI: http://dx.doi.org/10.2147/COPD.S33714 Received: 09 May 2012 Accepted: 09 July 2012 Published: 23 November 2012 Richard K Albert,1 John Connett,2 Jeffrey L Curtis,3,4 Fernando J Martinez,3 MeiLan K Han,3 Stephen C Lazarus,5 Prescott G Woodruff5 1Medicine Service, Denver Health and Department of Medicine, University of Colorado Denver, Denver, CO, 2Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, 3Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan, Ann Arbor, MI, 4Pulmonary and Critical Care Medicine, VA Medical Center, Ann Arbor, MI, 5Pulmonary and Critical Care Medicine, Department of Medicine, and Cardiovascular Research Institute, University of California, San Francisco, CA, USA Background: Mannose-binding lectin is a collectin involved in host defense against infection. Whether mannose-binding lectin deficiency is associated with acute exacerbations of chronic obstructive pulmonary disease is debated. Methods: Participants in a study designed to determine if azithromycin taken daily for one year decreased acute exacerbations had serum mannose-binding lectin concentrations measured at the time of enrollment. Results: Samples were obtained from 1037 subjects (91%) in the trial. The prevalence of mannose-binding lectin deficiency ranged from 0.5% to 52.2%, depending on how deficiency was defined. No differences in the prevalence of deficiency were observed with respect to any demographic variable assessed, and no differences were observed in time to first exacerbation, rate of exacerbations, or percentage of subjects requiring hospitalization for exacerbations in those with deficiency versus those without, regardless of how deficiency was defined. Conclusion: In a large sample of subjects with chronic obstructive pulmonary disease selected for having an increased risk of experiencing an acute exacerbation of chronic obstructive pulmonary disease, only 1.9% had mannose-binding lectin concentrations below the normal range and we found no association between mannose-binding lectin concentrations and time to first acute exacerbation or frequency of acute exacerbations during one year of prospective follow-up.
Mannose Binding Lectin Deficiency and Clinical Features
Ertugrul Erken
Arsiv Kaynak Tarama Dergisi , 2013,
Abstract: Innate immunity consists of macrophages, neutrophils, natural killer cells, mucosal immunuglobulins and the comlement system. Mannose binding lectin (MBL) takes part in innate immunity through opsonisation and complement activation. MBL deficiency is associated with some infections and autoimmune disorders. However some studies indicate that MBL deficiency alone is not essential for immunity but it may intensify the clinic picture of an immune deficiency that already exists. This article refers to clincal studies related to MBL and brings up the clinical importance of MBL deficiency. [Archives Medical Review Journal 2013; 22(4.000): 565-574]
Association of Mannose Binding Lectin Polymorphism with Hepatitis C Infection in Northwest of Iran
Mohammad H. Somi,Mohammad Asgharzadeh,Sara Farhang,Rasoul Estakhry
Hepatitis Monthly , 2006,
Abstract: Background and Aims: Persistent infection with hepatitis C virus leads to liver cirrhosis and often to liver cancer. Mannose binding lectin is a C-type serum lectin, which plays an important role in innate immunity by activating the classical complement pathway. Variants of the mannose binding lectin have been shown to be associated with low serum concentrations of the protein and to predispose the subjects to bacterial, fungal and viral infections. This study was undertaken to investigate the association between hepatitis C virus infection and polymorphisms of mannose binding lectin gene.Methods: We assessed the single nucleotide polymorphism of mannose binding lectin in exon 1, at codon 52, codon 54 and codon 57 in 100 patients infected with hepatitis C virus and 100 controls in Iranian population. Mannose binding lectin gene mutations were determined by means of polymerase chain reaction and restriction fragment length polymorphism analyses.Results: The occurrence of the codon 54 mutation was significantly higher in patients (OR 3.53, CI 95%: 1.94-6.44, p<0.005). No significant difference in the frequency of codon 52 and 57 mutations was observed between patient and control groups.Conclusions: Mannose binding lectin may be one of the factors that influence the course of HCV infection. Our results suggest that heterozygous carriage of the variant allele of codon 54 of mannose binding lectin is associated with hepatitis C virus infection in our cases. This may not be true about codons 52 and 57 mutations.
Comparing mannose binding lectin genetic diversity in intracellular and extracellular pathogens
M Asgharzadeh, HS Kafil
African Journal of Biotechnology , 2007,
Abstract: One of the important immunological factors in diseases is mannose binding lectin (MBL). The aim of present study is to determine the distribution of the alleles of mannose-binding lectin gene codon 52, 54, 57 and promoter variants H/L, X/Y, P and Q in confirmed VL patients as an intracellular pathogen while compares with extracellular pathogens (in renal infection) and seek correlation between these variants and intracellular and extracellular infections. Fifty eight confirmed VL patients’ blood samples were compared with fifty eight blood samples of patients received renal in results of renal infections. MBL genotypes were investigated by polymerase chain reaction and restriction fragment length polymorphism. Frequency of defective allele B in extracellular pathogens was more than intracellular pathogens (P = 0.0001), and in contrary prevalence of wild type allele A in intracellular pathogens was more than extracellular pathogens (P = 0.0001), and in other alleles and variants there was not any significant difference. In conclusion, there was more prevalence of alleles with low mannose binding lectin serum level in extrallelular pathogens which can be consider as a risk factor for these infections. In other hand prevalence of high concentration alleles in intracellular pathogens indicate the role of mannose binding lectin level for susceptibility to intracellular pathogens.
Mannose-Binding Lectin 2 Gene and Risk of Adult Glioma  [PDF]
Dominique S. Michaud, Afshan Siddiq, David G. Cox, Danielle M. Backes, Federico C. F. Calboli, Michael E. Sughrue, J. Michael Gaziano, Jing Ma, Meir Stampfer, Shelley S. Tworoger, David J. Hunter, Carlos A. Camargo, Andrew T. Parsa
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061117
Abstract: Background and Aims The immune system is likely to play a key role in the etiology of gliomas. Genetic polymorphisms in the mannose-binding lectin gene, a key activator in the lectin complement pathway, have been associated with risk of several cancers. Methods To examine the role of the lectin complement pathway, we combined data from prospectively collected cohorts with available DNA specimens. Using a nested case-control design, we genotyped 85 single nucleotide polymorphisms (SNPs) in 9 genes in the lectin complement pathway and 3 additional SNPs in MBL2 were tested post hoc). Initial SNPs were selected using tagging SNPs for haplotypes; the second group of SNPs for MBL2 was selected based on functional SNPs related to phenotype. Associations were examined using logistic regression analysis. All statistical tests were two-sided. Nominal p-values are presented and are not corrected for multiple comparisons. Results A total of 143 glioma cases and 419 controls were available for this analysis. Statistically significant associations were observed for two SNPs in the mannose-binding lectin 2 (ML2) gene and risk of glioma (rs1982266 and rs1800450, test for trend p = 0.003 and p = 0.04, respectively, using the additive model). One of these SNPs, rs1800450, was associated with a 58% increase in glioma risk among those carrying one or two mutated alleles (odds ratio = 1.58, 95% confidence interval = 0.99–2.54), compared to those homozygous for the wild type allele. Conclusions Overall, our findings suggest that MBL may play a role in the etiology of glioma. Future studies are needed to confirm these findings which may be due to chance, and if reproduced, to determine mechanisms that link glioma pathogenesis with the MBL complement pathway.
Mannose binding lectin (MBL) levels predict lung function decline in severe asthma
Ilonka. H. van Veen,Pieter. S. Hiemstra,Anneke ten Brinke,Anja Roos
European Respiratory Review , 2006,
Abstract: There is increasing evidence that activation of the complement system in asthma contributes to ongoing inflammation, tissue damage and airway remodeling. Mannose binding lectin (MBL) is a pattern recognition molecule that serves as the key mediator of the lectin pathway of complement activation. MBL levels are genetically determined and vary widely amongst individuals. In the present study we hypothesized that high MBL levels in asthma are associated with increased loss of lung function over time, as a consequence of inflammatory tissue damage. We measured serum MBL levels by ELISA in 68 patients with severe asthma and prospectively determined the change in post-bronchodilator (pb) FEV1 over a mean period of 5.7 years. The relationship between MBL and change in pbFEV1 (FEV1) was analysed using (multiple) regression analysis and corrected for possible confounders (age, sex, age of onset, asthma duration, and pbFEV1). The median (range) MBL level was 332 (10.8-3587) ng·ml–1. MBL was significantly associated with FEV1 (p<0.04). Patients with a high MBL level (332 ng·ml–1) had an increased risk of lung function decline compared to those with low MBL levels (OR (CI): 3.16 (1.14-8.79), p = 0.027); the excess decline being 42 ml·yr–1 (p = 0.01). We conclude that a high MBL level is associated with an increased decline in lung function in patients with severe asthma. MBL might provide a clue towards better understanding of the pathophysiology of ongoing inflammation and subsequent decline in lung function of patients with severe asthma.
Mannose-Binding Lectin Binds to Amyloid Protein and Modulates Inflammation
Mykol Larvie,Timothy Shoup,Wei-Chuan Chang,Lorencia Chigweshe,Kevan Hartshorn,Mitchell R. White,Gregory L. Stahl,David R. Elmaleh,Kazue Takahashi
Journal of Biomedicine and Biotechnology , 2012, DOI: 10.1155/2012/929803
Abstract: Mannose-binding lectin (MBL), a soluble factor of the innate immune system, is a pattern recognition molecule with a number of known ligands, including viruses, bacteria, and molecules from abnormal self tissues. In addition to its role in immunity, MBL also functions in the maintenance of tissue homeostasis. We present evidence here that MBL binds to amyloid β peptides. MBL binding to other known carbohydrate ligands is calcium-dependent and has been attributed to the carbohydrate-recognition domain, a common feature of other C-type lectins. In contrast, we find that the features of MBL binding to Aβ are more similar to the reported binding characteristics of the cysteine-rich domain of the unrelated mannose receptor and therefore may involve the MBL cysteine-rich domain. Differences in MBL ligand binding may contribute to modulation of inflammatory response and may correlate with the function of MBL in processes such as coagulation and tissue homeostasis.
Mannose Binding Lectin Gene Polymorphism in Azarian Population of Iran
M. Asgharzadeh,G. Hanifi,A.A. Roudsary,G. Habibi,H.S. Kafil,M.A. Akhavizadegan
Research Journal of Biological Sciences , 2012,
Abstract: Mannose-Binding Lectin (MBL) is involved in first line defense by binding to pathogens through a pattern-recognition mode of detection and then initiating a range of host responses. In present study we analyzed MBL gene and promoter polymorphism in Azarian population and compare them with previous reports in other populations. Blood samples were obtained from 144 Azarian populations from Tabriz and surrounding areas from March 2004-July 2005. MBL genotypes were investigated by polymerase chain reaction and restriction fragment length polymorphism. Present study showed prevalence of Allele B and LXPA haplotype in Azarian population which can conclude to protection against intracellular pathogens such as leishmania or tuberculosis but in the contrary it can conclude to susceptibility to Extracellular pathogen and SLE and rheumatoid arthritis. Also, present finding showed genetic relation of Azarian population with other Eurasian population.
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