Effect Of Mannose-binding Lectin Research Articles

Mannan-Binding Lectin Regulates Inflammatory Cytokine Production, Proliferation, and Cytotoxicity of Human Peripheral Natural Killer Cells.

Natural killer (NK) cells represent the founding members of innate lymphoid cells (ILC) and play critical roles in inflammation and the immune response. NK cell effector functions are regulated and fine-tuned by various immune modulators. Mannan (or mannose)-binding lectin (MBL), a soluble C-type lectin, is traditionally recognized as an initiator of the complement pathway. Recently, it is also considered as an immunomodulator by its interaction with kinds of immune cells. However, the effect of MBL on NK cell function remains unexplored. In this study, we found that human plasma MBL could interact directly with peripheral NK cells partially via its collagen-like region (CLR). This MBL binding markedly suppressed the interleukin-2- (IL-2-) induced inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) production but increased the IL-10 production in NK cells. In addition, the expression of activation surface markers such as CD25 and CD69 declined after MBL treatment. Also, MBL impaired the proliferation and lymphokine-activated killing (LAK) of NK cells. Moreover, we demonstrated that MBL inhibited IL-2-induced signal transducers and activators of transcription 5 (STAT5) activation in NK cells. In conclusion, we have uncovered a far unknown regulatory role of MBL on NK cells, a new clue that could be important in the immunomodulatory networks of immune responses.

Functional characterization of a mannose-binding lectin (MBL) from Nile tilapia (Oreochromis niloticus) in non-specific cell immunity and apoptosis in monocytes/macrophages

Mannose-binding lectin (MBL), a soluble pattern recognition receptor, is able to recognize antigen and participate in non-specific cell immunity, such as regulation of inflammation, migration, opsonization, phagocytosis and killing, which plays an important role in innate immunity. In this study, we have investigated the contributing mechanisms and effects of MBL on the cell immunity of Nile tilapia (Oreochromis niloticus) monocytes/macrophages. The mRNA expression level of OnMBL was significantly up-regulated in monocytes/macrophages after in vitro bacterial infection (Streptococcus agalactiae and Aeromonas hydrophila). Recombinant OnMBL ((r)OnMBL) protein could participate in the regulation of inflammation, migration, and enhancement of phagocytosis and respiratory burst activity in monocytes/macrophages. Moreover, the (r)OnMBL could induce the apoptosis of monocytes/macrophages. Taken together, the results of this study indicated that OnMBL is likely to involve in immune regulation, which may play an important role in host defense of innate immunity in Nile tilapia.

Genetic and Phenotypic Screening of Mannose-Binding Lectin in Relation to Risk of Recurrent Vulvovaginal Infections in Women of North India: A Prospective Cohort Study.

Recurrent Vulvovaginal Infections (RVVI) is common problem associated with women of reproductive age. The function and deleterious effect of Mannose Binding Lectin 2 (MBL2) common polymorphisms are reported to be associated with various diseases. However, the role of MBL2 promoter gene polymorphisms and their combined effect with structural variant along with Serum Mannose Binding Lectin (sMBL) levels in RVVI has not been investigated. The study included 258 RVVI cases and 203 age matched healthy controls. These were investigated for the distribution of MBL2 codon 54 and promoter polymorphisms by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). sMBL levels were quantified by Enzyme Linked Immnosorbent Assay (ELISA). The frequency of X allele and its genotypes was significantly high in cases than controls conferring risk toward RVVI and its types (p < 0.05). The HXPA (OR; 2.0), LXQB (OR; 1.43) haplotypes were associated with susceptibility to RVVI cases while haplotype LYQB significantly protected against RVVI (OR; 0.58), Bacterial Vaginosis (BV) (OR; 0.27) and Mixed Infections (MI) cases (OR; 0.62) with high frequency observed in controls (p < 0.05). Mean sMBL levels were significantly low in RVVI, BV, Vulvovaginal Candidiasis (VVC), and MI cases compared to controls (p < 0.05). VVC patient showed significantly low sMBL levels than RVVI and MI cases (p < 0.05). The mean sMBL levels segregated based on MBL2 genotypes and haplotypes showed significant difference in different cases groups with controls. The findings of the present study suggested that MBL2 Y/X polymorphism and low sMBL levels were associated with susceptibility to RVVI either it is BV, VVC, or MI. Thus MBL deficiency in women with RVVI may contribute to decreased efficiency in clearing of pathogens. Hence, specific measures like administration of purified or recombinant MBL might decrease the incidence of vaginal infections recurrences and more-effective treatment.

Effects of mannose-binding lectin on pulmonary gene expression and innate immune inflammatory response to ozone.

Ozone is a common, potent oxidant pollutant in industrialized nations. Ozone exposure causes airway hyperreactivity, lung hyperpermeability, inflammation, and cell damage in humans and laboratory animals, and exposure to ozone has been associated with exacerbation of asthma, altered lung function, and mortality. The mechanisms of ozone-induced lung injury and differential susceptibility are not fully understood. Ozone-induced lung inflammation is mediated, in part, by the innate immune system. We hypothesized that mannose-binding lectin (MBL), an innate immunity serum protein, contributes to the proinflammatory events caused by ozone-mediated activation of the innate immune system. Wild-type (Mbl(+/+)) and MBL-deficient (Mbl(-/-)) mice were exposed to ozone (0.3 ppm) for up to 72 h, and bronchoalveolar lavage fluid was examined for inflammatory markers. Mean numbers of eosinophils and neutrophils and levels of the neutrophil attractants C-X-C motif chemokines 2 [Cxcl2 (major intrinsic protein 2)] and 5 [Cxcl5 (limb expression, LIX)] in the bronchoalveolar lavage fluid were significantly lower in Mbl(-/-) than Mbl(+/+) mice exposed to ozone. Using genome-wide mRNA microarray analyses, we identified significant differences in transcript response profiles and networks at baseline [e.g., nuclear factor erythroid-related factor 2 (NRF2)-mediated oxidative stress response] and after exposure (e.g., humoral immune response) between Mbl(+/+) and Mbl(-/-) mice. The microarray data were further analyzed to discover several informative differential response patterns and subsequent gene sets, including the antimicrobial response and the inflammatory response. We also used the lists of gene transcripts to search the LINCS L1000CDS(2) data sets to identify agents that are predicted to perturb ozone-induced changes in gene transcripts and inflammation. These novel findings demonstrate that targeted deletion of Mbl caused differential levels of inflammation-related gene sets at baseline and after exposure to ozone and significantly reduced pulmonary inflammation, thus indicating an important innate immunomodulatory role of the gene in this model.

Regulating effect of mannose-binding lectin on monocyte inflammatory factors in gestational diabetes mellitus women

目的 探讨甘露糖结合凝集素（mannose-binding lectin，MBL）在妊娠期糖尿病（gestational diabetes mellitus，GDM）炎症损伤中的作用。 方法 2014年9月14日至2015年1月10日，在安徽医科大学第一附属医院产前保健、且无GDM高危因素的孕妇中，随机选取GDM孕妇50例，对照组为同期口服葡萄糖耐量正常的孕妇37例。检测GDM组与对照组血浆脂多糖、MBL以及炎症因子[白细胞介素（interleukin，IL）-1、IL-10、肿瘤坏死因子（tumor necrosis factor，TNF）-α]水平。抽取孕妇空腹外周静脉血，分离单个核细胞，进行细胞培养，GDM组采用1μg/ml脂多糖和重组MBL处理，分为6个亚组：A组（未处理），B组（仅脂多糖处理），C、D、E和F组采用脂多糖及浓度分别为0.1、0.5、1.0和2.0μg/ml的重组MBL处理，检测各亚组炎症因子（IL-1、IL-10、TNF-α）水平，以及Toll样受体（Toll-like receptor，TLR）4和核转录因子（nuclear-factor，NF）-κB蛋白表达。统计学分析采用独立样本t检验、方差分析、LSD法、Pearson相关分析。 结果 GDM组血浆脂多糖水平高于对照组[（0.92±0.41）与（0.57±0.22）EU/ml，t=3.21]，MBL水平低于对照组[（254.4±123.4）与（424.8±150.4） μg/ml，t=－1.96]，IL-1和TNF-α水平均高于对照组[分别为（14.5±2.1）与（10.5±4.0）pg/ml，（5.72±0.99）与（2.79±0.87）pg/ml，t值分别为－3.46和3.77]，差异均有统计学意义（P值均<0.05）。GDM组中，炎症因子水平与脂多糖水平呈正相关，与MBL水平呈负相关（P值<0.05）；脂多糖与MBL水平呈负相关（r=－0.51，P<0.05）。细胞培养结果显示，GDM组外周血单个核细胞TLR4和NF-κB蛋白表达水平均高于对照组（分别为1.85±0.41与1.27±0.72，1.20±0.62与0.84±0.31，t值分别为－13.57和－7.19，P值均<0.05）。采用脂多糖及不同浓度的重组MBL干预后，与B组IL-1、IL-10、TNF-α水平及TLR4、NF-κB蛋白表达量[分别为（15.44±2.29）、（4.77±1.84）、（5.83±1.08）pg/ml及2.01±0.15、1.47±0.04]比较，随着重组MBL浓度增加，D组[分别为（13.37±1.34）、（3.13±1.71）、（4.23±1.71）pg/ml及1.58±0.69、1.20±0.16]、E组[分别为（12.18±1.38）、（2.72±0.69）、（3.15±0.78）pg/ml及0.85±0.02、0.89±0.02]、F组[分别为（10.59±1.20）、（2.03±0.92）、（2.71±0.96）pg/ml及0.56±0.44、0.61±0.21]逐渐降低，差异均有统计学意义（LSD检验，P值均<0.05）。 结论 GDM孕妇血浆中MBL水平降低，可能导致对TLR4/NF-κB通路的抑制作用减弱，从而形成慢性持续性炎症损伤，参与GDM发病。

Mannose-binding lectin in chronic hepatitis C in children

Objective. To investigate effect of mannose-binding lectin (MBL) genetic polymorphisms and phenotype in chronic hepatitis C and its impact on response to antiviral therapy in children. Methods. Fifty four children with chronic hepatitis C, aged 2.5–18 years were enrolled. Forty-five children were treated with interferon-α (IFN-α) alone (n = 2) or IFN-α and ribavirin (n = 43). Twenty-one children who responded to antiviral therapy were defined as sustained responders to therapy (IFN-SR). Before therapy, MBL genotypes and serum MBL levels (by ELISA) were determined. MBL genotype distribution and levels were correlated to disease characteristics and response to therapy. Results. Children with chronic hepatitis C who did not respond to antiviral therapy (IFN-NR) presented more frequently MBL2 polymorphisms, although this did not reach significance (p = 0.08). MBL levels were significantly lower in children classified as IFN-NR when compared to children defined as IFN-SR (1.623 ng/ml vs. 3.699 ng/ml), (p = 0.04). Serum activity levels of ALT and AST were higher in children with A/O MBL genotype when compared to group with A/A genotype (p < 0.05). Conclusions. Our findings suggest negative effect of MBL deficiency (defined by genotype and phenotype) on progression of chronic hepatitis C in children and response to antiviral therapy.

Effects of mannose-binding lectin and mannose-binding lectin polymorphisms on treatment response in patients with chronic hepatitis C.

The natural course and clinical outcome of hepatitis C virus (HCV) infection is related to the interaction between HCV and the immune response of the host. Only a limited number of studies have investigated the role of mannose-binding lectin (MBL) levels in HCV infection. The aim of the present study was to explore the relationship between MBL levels and gene polymorphisms on treatment response in patients with chronic hepatitis C (CHC). Serum MBL levels from 50 CHC patients who completed treatment at least 24 weeks before the present study and 75 healthy HCV-negative controls were measured. In addition, the presence of codon 54 mutations was investigated. Correlational analyses were performed to determine relationships between MBL levels and treatment response. In patients, mean serum MBL levels were lower and the rate of codon 54 mutations was higher. However, these differences were not statically significant. In both patients and controls, serum MBL levels were significantly lower in individuals with codon 54 mutations. Moreover, serum MBL levels and the rate of the codon 54 mutation were similar in patients regardless of treatment response. Our findings suggest that low MBL levels do not increase the susceptibility for HCV infection. Furthermore, MBL levels were not found to have a significant effect on the course of the disease or treatment response.

Mannose-Binding Lectin Inhibits Monocyte Proliferation through Transforming Growth Factor-β1 and p38 Signaling Pathways

Mannose-binding lectin (MBL), a plasma C-type lectin, plays an important role in innate immunity. However, the interaction, and the consequences of it, between MBL and the immune system remain ill defined. We have investigated the contributing mechanisms and effects of MBL on the proliferation of human monocytes. At lower concentrations (≤4 μg/ml) MBL was shown to partially enhance monocyte proliferation. By contrast, at higher concentrations (8–20 μg/ml) of MBL, cell proliferation was markedly attenuated. MBL-induced growth inhibition was associated with G0/G1 arrest, down-regulation of cyclin D1/D3, cyclin-dependent kinase (Cdk) 2/Cdk4 and up-regulation of the Cdk inhibitory protein Cip1/p21. Additionally, MBL induced apoptosis, and did so through caspase-3 activation and poly ADP-ribose polymerase (PARP) cleavage. Moreover, transforming growth factor (TGF)-β1 levels increased in the supernatants of MBL-stimulated monocyte cultures. We also found that MBL-dependent inhibition of monocyte proliferation could be reversed by the TGF-β receptor antagonist SB-431542, or by anti-TGF-β1 antibody, or by the mitogen-activated protein kinase (MAPK) inhibitors specific for p38 (SB203580), but not ERK (U0126) or JNK (SP600125). Thus, at high concentrations, MBL can affect the immune system by inhibiting monocyte proliferation, which suggests that MBL may exhibit anti-inflammatory effects.

Association of mannose‐binding lectin gene polymorphism with tuberculosis susceptibility and sputum conversion time

Mannose-binding lectin (MBL) plays an important role in innate immunity. The effect of low MBL levels producing variants of MBL2 gene on tuberculosis (TB) has been controversial with some studies reporting it to confer protection against the disease, whereas others estimating a susceptibility relation. Other than conducting a case-control study to evaluate the role of MBL A/B polymorphism on TB, we conducted a longitudinal study to check whether this MBL variant can influence the host response to Mycobacterium tuberculosis infection. A total of 357 TB patients (286 pulmonary TB, 71 extrapulmonary (EP) TB) and 392 healthy controls belonging to same ethnicity were included in the study. We found the mutant allele 'B' allele confers a protective role against TB in our study population. This effect was absent in EP patients. On stratification on the basis of sex, the protective role of the 'B' allele was found to be limited to females only and males reported no significant difference. No effect of MBL A/B polymorphism on sputum conversion time was reported. We conclude that MBL 'B' allele is associated with protection against TB, but no influence was found on sputum conversion rate.

Mannose-Binding Lectin (MBL) Facilitates Opsonophagocytosis of Yeasts but Not of Bacteria despite MBL Binding

Mannose-binding lectin (MBL) is a serum protein of the innate immune system. After binding to a microorganism, MBL in complex with MBL-associated serine proteases activates the complement system, resulting in cleavage of complement factor C3. Cleaved C3 on the surface of the microorganism mediates opsonization for clearance, but the impact of MBL on subsequent phagocytosis has not been widely studied. We investigated the role of MBL in complement activation and phagocytosis of various bacteria and yeast species by flow cytometry. We measured both the C3 deposition during serum opsonization of fluorescent-labeled microorganisms as well as subsequent uptake of these microorganisms by human neutrophils. In MBL-deficient sera, a consistently decreased C3 deposition on both zymosan and Candida albicans was found and a reduced phagocytosis by neutrophils that was restored by exogenous MBL. This indicates that the lectin pathway of complement activation is important for the opsonophagocytosis of yeasts. In contrast, the C1q-dependent classical pathway dominated in the opsonization and phagocytosis of Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli, whereas no effect of MBL was found. Both the lectin and the classical pathway of complement activation were highly amplified by the alternative route for opsonophagocytosis by neutrophils of yeast as well as microbial species. In summary, our data demonstrate that yeast species are preferentially opsonized and subsequently phagocytosed via activation of the lectin pathway of complement, whereas the uptake of bacterial strains was found to be largely MBL independent.

Modulatory effect of mannose‐binding lectin on cytokine responses: possible roles in HIV infection

Mannose-binding lectin (MBL) is a soluble receptor of the innate immune system, probably contributing to antimicrobial defence. The possible role of MBL in HIV infection is unclear. Peripheral blood mononuclear cells (PBMCs) from 28 HIV-infected patients and 13 healthy controls were stimulated with MBL and costimulated with HIV-1 gp120 or mannan from Saccharomyces cerevisiae before inflammatory responses in PBMC cultures were examined by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. HIV-1 RNA replication in vitro was assessed by quantitative reverse transcription polymerase chain reaction (RT-PCR) in supernatants from patients with measurable HIV-1 RNA levels. (i) Enhanced TNF-alpha responses were observed when PBMCs from healthy controls and HIV-infected patients were stimulated with MBL and costimulated with HIV-1 gp120 or mannan. (ii) MBL stimulation induced increased HIV RNA replication in culture supernatants when costimulated with mannan. The present study suggests a modulatory role of MBL on cytokine responses, and HIV replication after stimulation with microbial products. These effects of MBL on inflammatory responses and viral replication may be clinically relevant for HIV infection.

Mannose binding lectin (MBL) and HIV

The envelope protein (gp120/gp41) of HIV-1 is highly glycosylated with about half of the molecular mass of gp120 consisting of N-linked carbohydrates. While glycosylation of HIV gp120/gp41 provides a formidable barrier for development of strong antibody responses to the virus, it also provides a potential site of attack by the innate immune system through the C-type lectin mannose binding lectin (MBL) (also called mannan binding lectin or mannan binding protein). A number of studies have clearly shown that MBL binds to HIV. Binding of MBL to HIV is dependent on the high-mannose glycans on gp120 while host cell glycans incorporated into virions do not contribute substantially to this interaction. It is notable that MBL, due to its specificity for the types of glycans that are abundant on gp120, has been shown to interact with all tested HIV strains. While direct neutralization of HIV produced in T cell lines by MBL has been reported, neutralization is relatively low for HIV primary isolates. However, drugs that alter processing of carbohydrates enhance neutralization of HIV primary isolates by MBL. Complement activation on gp120 and opsonization of HIV due to MBL binding have also been observed but these immune mechanisms have not been studied in detail. MBL has also been shown to block the interaction between HIV and DC-SIGN. Clinical studies show that levels of MBL, an acute-phase protein, increase during HIV disease. The effects of MBL on HIV disease progression and transmission are equivocal with some studies showing positive effects and other showing no effect or negative effects. Because of apparently universal reactivity with HIV strains, MBL clearly represents an important mechanism for recognition of HIV by the immune system. However, further studies are needed to define the in vivo contribution of MBL to clearance and destruction of HIV, the reasons for low neutralization by MBL and ways that MBL anti-viral effects can be augmented.

Mannose binding lectin enhances IL-1β and IL-10 induction by non-lipopolysaccharide (LPS) components of Neisseria meningitidis

Mannose binding lectin (MBL) is a key molecule in the lectin pathway of complement activation, and likely of importance in our innate defence against meningococcal infection. We evaluated the role of MBL in cytokine induction by LPS or non-LPS components of Neisseria meningitidis, using a meningococcal mutant deficient for LPS. Binding experiments showed that MBL exhibited low, but significant binding to encapsulated LPS + meningococci (H44/76) and LPS-deficient (LPS −) meningococci (H44/76 lpxA). Experiments with human mononuclear cells (PBMCs) showed that MBL significantly augmented IL-1β production after stimulation with LPS + and LPS − meningococci, in a dose-dependent fashion. In addition, IL-10 production was enhanced after stimulation with LPS − meningococci. In contrast, TNFα, IL-6 and IFNγ productions were unaffected. No effect of MBL was observed on cytokine induction by meningococcal LPS. MBL enhanced cytokine production at concentrations >10 7 meningococci. It is concluded that MBL interacts with non-LPS components of N. meningitidis and in this way modulates the cytokine response.

The effect of mannose-binding lectin on phagocytic cell responses to Neisseria meningitidis

The effect of mannose-binding lectin on phagocytic cell responses to Neisseria meningitidis