Mannose-binding Protein Levels Research Articles

Mannose-binding protein in preterm infants: developmental profile and clinical significance.

The aim of this study was to determine the developmental profile of mannose-binding protein (MBP) in preterm infants. MBP was measured in 885 longitudinally collected serum samples from 168 preterm infants, and 63 were genotyped with respect to the codon 54 mutation in the MBP gene. MBP level/codon 54 genotyping were also determined on the cord blood of 146/123 term infants and 138/123 adults, respectively. The best cut-off values of MBP for dividing preterm, term infants and adults into 'low' and 'high' MBP groups were 400 ng/ml (55 low, 113 high), 700 ng/ml (35 low, 111 high) and 750 ng/ml (33 low, 105 high), respectively, by achieving the least number of misclassifications according to the codon 54 mutation. The relative risk of the 'low' groups for presence of the codon 54 mutation compared with 'high' groups were 42.4, 67.9 and 22.9 for preterm, term infants and adults, respectively (P < 0.00001). The gestational age and birth weight of the 'low' (n = 55) and 'high' (n = 113) MBP groups of the 168 preterm infants were 29.5 +/- 2.8 weeks, 30.5 +/- 2.8 weeks (P = 0.03) and 1230 +/- 317 g, 1277 +/- 289 g (P = 0.35), respectively. The mean MBP levels of these two groups of preterm infants were different (P < 0.001) at all ages measured. As a whole group, the MBP level rose from a mean of 500 ng/ml at 25 weeks gestation to 1700 ng/ml at 20 weeks post full-term. The mortality rates of 'low' and 'high' MBP groups of preterm infants were 22% and 12%, respectively (P = 0.113). This difference in mortality was due to gestational age and birth weight standard deviation score (SDS) after adjusting for length of gestation and gender (P = 0.0001) rather than to low MBP levels (P = 0.65). MBP levels were not related to birthweight SDS score (P = 0.26). The mean +/- s.d. MBP levels for preterm, term infants and adults without the codon 54 mutation were 1225 +/- 701 ng/ml (n = 45), 2064 +/- 829 ng/ml (n = 88) and 2473 +/- 1395 ng/ml (n = 95), respectively; the corresponding values for those with the codon 54 mutation were 130 +/- 275 ng/ml (n = 18), 533 +/- 665 ng/ml (n = 35) and 330 +/- 225 ng/ml (n = 28), respectively. Intra-uterine growth retardation in preterm infants does not influence MBP levels. For those without the codon 54 mutation, there is a significant difference in MBP level between the three age groups. For those with the codon 54 mutation, there is a significant difference between preterm and term infants, but not between term infants and adults. We conclude that there is a maturation in MBP levels for preterm infants, and that a moderately low MBP phenotype does not affect survival. We cannot exclude an effect of profoundly reduced MBP levels (characteristic of individuals homozygous for the codon 54 mutation), since no such preterm infant was identified in this study.

Evolution of immunoglobulin and mannose binding protein levels after renal transplantation: association with infectious complications

Hypogammaglobulinemia (hypo-Ig) and low mannose binding protein (MBP) levels might be involved in the infectious risk in renal transplantation. In 152 kidney transplant recipients treated with calcineurin inhibitors (CNI) and mycophenolate mofetil (MMF), during the first year, we prospectively recorded the incidence of hypogammaglobulinemia, and low MBP levels. Their influence on infectious complications was evaluated in 92 patients at 3 and 12 months (T3 and T12). The proportion of deficiency increased significantly: hypo-IgG: 6% (T0), 45% (T3), and 30% (T12) (P < 0.001); hypo-MBP: 5%, 11%, and 12% (P = 0.035). Hypo-IgG at T3 was not associated with an increased incidence of first-year infections. A significantly higher proportion of patients with combined hypogammaglobulinemia [IgG+ (IgA and/or IgM)] at T3 and with isolated hypo-IgG at T0 developed infections until T3 compared with patients free of these deficits (P < 0.05). Low MBP levels at T3 were associated with more sepsis and viral infections. Hypogammaglobulinemia is frequent during the first year after renal transplantation in patients treated with a CNI and MMF. Hypo-IgG at T0 and combined Igs deficts at T3 were associated with more infections. MBP deficiency might emerge as an important determinant of the post-transplant infectious risk.

Plasma levels of cystatin-C and mannose binding protein are not associated with risk of developing systemic atherosclerosis.

Cystatin-C, a cysteine protease inhibitor, and mannose binding lectin, an innate defense protein involved in microbial clearance, have both been hypothesized to mediate atherosclerotic plaque progression. Prospective data evaluating whether levels of these proteins are associated with incident cardiovascular disease are sparse. Employing a prospective, nested, case-control study design, baseline levels of cystatin-C and mannose binding protein were evaluated among 133 apparently healthy men who subsequently developed symptomatic peripheral arterial disease (cases) and among 133 age- and smoking-matched controls who remained free of reported vascular disease during 5 years of follow-up. Overall, median baseline levels of cystatin-C were virtually identical among case and control subjects (0.83 mg/l, p = 0.84), whereas median baseline levels of mannose binding protein among cases and controls were 2.32 mg/l and 2.20 mg/l respectively (p = 0.69). No evidence of association was found between either cystatin-C or mannose binding protein and the development of peripheral arterial disease in analyses evaluating for linear trends or for threshold effects (all p-values > 0.05). In contrast with prior retrospective and cross-sectional studies, no evidence was found that baseline levels of cystatin-C or mannose binding protein are associated with an increased risk of future arterial disease.

Plasma Concentration of Cystatin-C and Mannose Binding Protein and the Risk of Developing Peripheral Vascular Disease

P05 Background- Cystatin-C, a cysteine protease inhibitor, and mannose binding lectin, an innate defense protein involved in microbial clearance, have both been hypothesized to mediate atherosclerotic plaque progression. However, little prospective data are available evaluating whether levels of these proteins in healthy individuals are associated with incident cardiovascular disease. Methods and Results-Employing a prospective, nested, case control study design, baseline levels of cystatin-C and mannose binding protein were evaluated among 133 apparently healthy men who subsequently developed symptomatic peripheral arterial disease (cases) and among 133 age and smoking matched controls who remained free of reported vascular disease during a 5 year follow-up period. Overall, median baseline levels of cystatin-C were virtually identical among case and control subjects (0.83mg/L, p=0.84). Similarly, median baseline levels of mannose binding protein among cases and controls were 2.32mg/L and 2.2mg/L,(p=0.69). We found no evidence of association between either cystatin-C or mannose binding protein and the development of peripheral vascular disease in analyses evaluating for linear trends or for threshold effects (all p values &gt;0.05). Conclusion-In contrast to prior retrospective and cross-sectional studies, we found no evidence in this prospective evaluation that baseline levels of cystatin-C or mannose binding protein are associated with increased risk of future vascular disease.

Assessment of measuring circulating levels of interleukin-6, interleukin-8, C-reactive protein, soluble Fc gamma receptor type III, and mannose-binding protein in febrile children with cancer and neutropenia.

Circulating levels of interleukin (IL)-6, IL-8, soluble Fc gamma receptor type III (sFc gammaRIII), mannose-binding protein (MBP), and C-reactive protein (CrP) were assessed among febrile children with cancer and neutropenia. Levels of IL-6, IL-8, sFc gammaRIII, MBP, and CrP were measured in serum from 56 pediatric cancer patients at the time of admission for 121 episodes of febrile neutropenia (88 febrile episodes without identifiable source, 5 clinically documented infections, 20 episodes of bacteremia due to gram-positive and 5 due to gram-negative organisms, and 3 fungal infections). IL-6 and IL-8 levels were higher in patients with either bacteremia due to gram-negative organisms or fungal infections than in patients with febrile episodes without an identifiable source (P < .00001 for each). IL-6 and IL-8 levels were higher in children with bacteremia due to gram-negative organisms than in those with bacteremia due to gram-positive organisms (P = .0011 and P = .0003, respectively). The measured levels of CrP, MBP, and sFc gammaRIII were not useful for identifying the type of infection. These preliminary results show the potential usefulness of IL-6 and IL-8 as early indicators for life-threatening infections in febrile cancer patients with neutropenia.

Mannose-binding protein B allele confers protection against tuberculous meningitis.

Inhalation is the principal mode of entry for Mycobacterium tuberculosis in humans. Primary infection is usually restricted to the lungs and contiguous lymph nodes. In a subset of infected individuals, predominantly children, the infection is spread hematogenously to the meninges. The host factors that influence the development of tuberculous meningitis have not been well elucidated. The mannose-binding protein (MBP), a serum protein, is considered as an "ante-antibody." MBP has been shown to bind mycobacteria and acts as an opsonin in vitro. Although MBP plays a role in first-line host defense, it may under certain circumstances be deleterious to the host. In tuberculosis (TB), MBP may assist the spread of this intracellular pathogen. Therefore, we hypothesized that MBP genotypes that result in a phenotype of low MBP levels might be protective. We studied a well-defined South African population in which TB has reached epidemic levels. We found that the MBP B allele (G54D), which disrupts the collagen region of the protein and results in low MBP levels, was found in 22 of 79 (28%) of the TB-negative controls from the same community, compared with 12 of 91 (13%) of the patients with pulmonary TB (p < 0.017), and 5 of 64 (8%) of patients with tuberculous meningitis (p < 0.002). In addition, we found significantly lower serum MBP concentrations in TB-negative controls compared with postacute phase, fully recovered TB patients (p < 0.004). These findings suggest that the MBP B allele affords protection against tuberculous meningitis.

Mannose-binding protein in HIV-seropositive patients does not contribute to disease progression or bacterial infections.

This study set out to investigate whether plasma mannose-binding protein (MBP) deficiency caused by mutations in the MBP gene associates with pyogenic or opportunistic infections in HIV-infected patients. Plasma samples were selected randomly from 131 HIV-infected patients followed prospectively for a period not exceeding 12 months or until death. Plasma MBP concentrations were measured by an ELISA and genotyping was determined by amplification of exon 1 of the MBP gene by polymerase chain reaction (PCR) technology, followed by restriction enzyme analysis and Southern blotting using sequence-specific oligonucleotide probes. Neither MBP concentration nor genotype was found to associate with disease progression or opportunistic infection rate. There was an unexpected increased bacterial infection rate in patients with MBP levels greater than 100 ng/ml and wild type genotype. Thus, MBP does not appear to play a role in HIV infection. MBP is an acute phase reactant and this may explain the higher levels in those with more frequent pyogenic infections.

Evaluation of Mannose-binding Protein as a Predictor of Serious Bacterial Illness in Febrile Infants 784

Mannose-binding protein (MBP) is an acute phase reactant important in innate host defence. It recognizes and binds pathogens, promotes their opsonization and phagocytosis and activates complement. Low MBP levels are associated with allelic variants that are unable to activate complement. It is hypothesized that low levels of MBP are associated with serious and/or recurrent infection. To determine whether MBP level is a predictor of serious bacterial illness and if low levels of MBP are associated with increased risk of bacterial infection, we measured MBP in infants <3 years old (n=570) who presented to the Children's Hospital Emergency Department for evaluation of fever. To enhance the number of patients with serious bacterial infection (n= 92), febrile infants with positive cultures were included selectively by using stored discarded blood samples. Temperature, CBC, present diagnosis and history of previous positive culture were recorded for each patient. C-reactive protein (CRP) and interleukin-6 (IL-6) were measured selectively. MBP level was compared in febrile infants and age-matched controls. MBP level was not significantly different between febrile infants and controls or between infants with current or previous serious bacterial illness and those with presumed viral illness with or without otitis media. MBP level was not correlated with IL-6 or CRP. The percent of patients with MBP levels <100, 500, and 1000 ng/ml did not differ between febrile patients with and without serious bacterial illness. We conclude that a single MBP level is not a predictor for bacterial illness and that febrile infants with low MBP levels are not universally at significant risk for serious bacterial illness.Sponsored by Bristol-Myers Squibb.

The role of collectins in host defense.

Mannose-binding protein (MBP) belongs to a group of Ca(2+)-dependent lectins called collectins that play a role in first-line host defense. It recognizes specific carbohydrate residues (mannose and N-acetylglucosamine) on the surface of microorganisms and promotes the killing of microbes either by acting directly as an opsonin or by activating the lectin complement pathway. The collagenlike domain of MBP is important for the binding of MBP to the collectin receptors expressed on different phagocytes, and for activation of complement. The binding of MBP to bacteria, viruses, and parasites has been demonstrated in vitro. Three major mutations have been found in exon 1 of the MBP gene, which encodes the collagenous domain of the protein. These mutations cause low levels of serum MBP and have been linked with lifelong risk of infection. The homozygotes for these mutations are especially susceptible to severe infections.

Mannose-binding protein genetic polymorphisms in black patients with systemic lupus erythematosus.

To determine whether dysfunctional or deficient mannose-binding protein (MBP) variants are found with increased frequency in black patients with systemic lupus erythematosus (SLE) compared with controls. Allele-specific polymerase chain reaction amplification of 4 different polymorphic sites was performed on samples from 92 black SLE patients and 86 geographically matched black controls. Two structural polymorphisms of MBP, associated with low serum levels of MBP, were found with significantly increased frequency in the SLE patient population compared with controls. In contrast, a promoter haplotype associated with particularly high serum levels of MBP was negatively associated with SLE. Deficiencies of MBP predispose individuals to SLE.

IN VIVO ANALYSIS REVEALS A ROLE FOR HUMAN MANNOSE-BINDING PROTEIN IN ACUTE SEPSIS. • 1113

In vitro binding studies indicate that the human mannose-binding protein(MBP) recognizes a broad range of gram-negative and gram-positive bacteria as well as yeast, certain parasites and certain virally infected cells. Crystal structures of MBP have delineated the pattern of recognition. MBP is an acute phase reactant. Our premise is that MBP is an ante-antibody that plays an immediate role in defense against infections. To test this idea, we measured MBP serum levels from 62 children with oncologic disease undergoing chemotherapy, during 84 episodes of fever and neutropenia. Importantly, patients presented within hours of onset of fever. Fifteen patients had documented sepsis; 14 bacteremia (7 gram-negative, 7 gram-positive), 1 varicella-zoster. We found that in 14 of 15 of these patients, there was an initial fall in MBP levels with trough at day 3 to 4, followed by increase in level to 2- to 3-fold baseline by day 8. MBP levels increased in 4 of 6 patients who had unexplained fever. In contrast to MBP, CRP peaked when MBP was at its nadir and then decreased as MBP increased. IL-6 was highest at presentation and rapidly returned to baseline. In vitro findings confirmed that MBP bound to the range of bacteria isolated which includedPseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Streptococcus viridans, Streptococcus pneumoniae, Staphylococcus aureus andStaphylococcus epidermidis. Our results suggest that MBP opsonizes a broad range of pathogens in vivo. The initial reduction in MBP level is consistent with MBP-pathogen interaction and clearance from the circulation. The therapeutic potential for exogenous MBP in acute sepsis may be implied from our results. (Funded by Bristol-Myers Squibb).

Circulating levels of mannose binding protein in human immunodeficiency virus infection

Mannose binding protein (MBP) is a serum lectin which, upon binding to a carbohydrate extremity, acquires the ability to activate the classical complement pathway. MBP binds human immunodeficiency virus (HIV) in vitro via glycans on gp120 and thus, it may play a defensive role in HIV infection and contribute to virus clearance through the activation of complement associated with this condition. We measured serum MBP and activation indices of the classical complement pathway (plasma C4d and C3d) in HIV-seropositive patients at different stages of disease severity, and in normal subjects. MBP was higher in HIV patients as a whole and in each Centers for Disease Control (CDC) group than controls (P<0.01). MBP was not significantly different between CDC groups and and did not significantly correlate either with CD4-positive lymphocytes, neopterin or beta2-microglobulin or with C4d and C3d. The possibility that MBP plays a defensive role in HIV infection cannot be excluded, but, it it is, it does not appear to act by recruiting complement for vital elimination.

Human Serum Mannose Binding Protein (MBP): Development of an Enzyme-Linked Immunosorbent Assay (ELISA) and Determination of Levels in Serum from 1085 Normal Japanese and in Some Body Fluids

We developed an enzyme-linked immunosorbent assay (ELISA) for human serum mannose binding protein (MBP), an animal lectin known to function as opsonin and complement activator. A total of 1085 normal Japanese sera from individuals ranging in age from 3 to 100 years old and additional body fluids were measured for the MBP level. Individual serum MBP levels ranged from 0.07 to 6.40 micrograms/ml with a frequency distribution profile of the log-normal type. Arithmetic mean +/- standard deviation (M +/- SD) of serum MBP as a whole was 1.72 +/- 1.15 micrograms/ml, whereas those of cerebrospinal fluid and urine were 1/100 and 1/1000 of serum levels, respectively. When the M +/- SD of serum MBP was calculated for each age group (10-year intervals) and compared, the value declined from age group of 3-9 years old (2.42 +/- 1.31 micrograms/ml) to that of 20-29 years old (1.72 +/- 1.03 micrograms/ml), and thereafter it remained almost constant. Comparing the frequency distribution profile among each group, that of young group revealed a distinct bimodal pattern, one peak at around 1 micrograms/ml and the other at 3 micrograms/ml. The latter peak was gradually depressed with advance of age and finally a typical log-normal type appeared after the age of 30. There was a high age dependency in serum MBP level as well as in distribution profile. It should be stressed that care should be taken with age in the evaluation of MBP level.

Distinct and overlapping functions of allelic forms of human mannose binding protein.

Human mannose binding protein (MBP) is a C-type serum lectin involved in first-line host defense against a variety of bacterial, fungal and viral pathogens. Recently an association was found between low levels of serum MBP and an increased frequency of recurrent infections in infants. A particular genotype, in which glycine is substituted by aspartic acid at codon 54 of MBP in the fifth collagen repeat, shows apparent concordance with the clinical phenotype. We report, however, that this genotype occurs in 5% of the population and encodes a functional protein. Our results indicate that the Gly54Asp allele does not account for a deficiency state, but instead suggest that MBP may have two predominant allelic forms that have overlapping function and differ only in their ability to activate the classical pathway of complement.