Mannose-binding Lectin Genotype Research Articles

Mutations of genes involved in the innate immune system as predictors of sepsis in very low birth weight infants.

Mutations of genes involved in the innate immune system have been reported to be associated with an increased sepsis rate in adults. We determined the -159T mutation of the CD14 gene, the 896G mutation of the toll-like receptor 4 gene, the 3020insC mutation of the NOD2 gene (NOD2-3020insC), the IL-6 174G/C promoter polymorphism (IL6-174G/C), and the mannose-binding lectin genotype and their association to the subsequent development of neonatal sepsis in a large cohort of very low birth weight (VLBW) infants. Fifty (14%) of 356 VLBW infants developed blood culture-proven sepsis during their stay in the hospital. VLBW infants carrying the NOD2-3020insC allele (n =15) and the IL6-174G allele (n =121) had a significantly higher rate of blood culture-proven sepsis (33% and 19.8%, respectively) than VLBW infants without these genotypes (p = 0.046 and 0.035, respectively). In a multivariate logistic regression analysis, gestational age less than 28 wk (odds ratio, 3.2; 95% confidence interval, 1.7-6.0; p < 0.001) and the homozygous IL6-174G allele (odds ratio, 1.9; 95% confidence interval, 1.0-3.9; p = 0.039) were predictive for the development of sepsis, whereas the NOD2-3020insC allele was only of borderline significance (odds ratio, 3.2; 95% confidence interval, 1.0-10.4; p = 0.052). VLBW infants with repeated episodes of sepsis had higher frequencies of the NOD2-3020insC and IL6-174G allele. The increased sepsis rate of homozygous IL6-174G carriers was especially related to an increase in Gram-positive infections, and was not observed in VLBW infants who received prophylaxis with teicoplanin (frequency of Gram-positive sepsis in homozygous IL6-174G carriers without prophylaxis 16.5% versus 2.4% in homozygous IL6-174G carriers with prophylaxis; p = 0.033).

Prospective analysis of mannose-binding lectin genotypes and coronary artery disease in American Indians: the Strong Heart Study.

Mannose-binding lectin (MBL) is a circulating immune factor responsible for opsonization of pathogens and directly activating complement. Common variations in the MBL gene are responsible for an opsonic deficiency that affects 5% to 7% of whites and are associated with increased susceptibility to infections. After a preliminary report associating these variations with coronary artery disease (CAD), we determined MBL genotypes in 3 American Indian communities experiencing an increased mortality and morbidity from CAD. We examined DNA from 434 participants in a population-based cohort, the Strong Heart Study. Genotypes for 3 common MBL coding variations and 1 promoter polymorphism were determined. The frequency of a composite genotype that conferred low MBL levels was 20.7% in 217 cases and 11.1% in matched controls without CAD. A conditional logistic regression model indicated a univariate OR for CAD of 2.3 (95% CI 1.3 to 4.2, P=0.005) for the variant genotypes. After adjustment for demographic and CAD risk factors, including type 2 diabetes mellitus, fibrinogen, triglycerides, and hypertension, the OR was 3.2 (95% CI 1.5 to 7.0, P=0.004). Variant MBL genotypes coding for markedly diminished levels of MBL are predictive of CAD. After adjustment for multiple traditional risk factors for ischemic heart disease, this association remains significant. A high prevalence of variant MBL alleles and CAD in this population suggests that potentially important public health benefits may accrue from future interventions based on these genotypes.

Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome in patients with systemic inflammatory response syndrome

Genetic factors may predispose to increased risk for sepsis in critically ill patients. Mannose-binding lectin (MBL) is an important factor in innate immune defence. Accordingly, we investigated whether MBL gene polymorphisms causing low levels of functional MBL in the the blood are associated with the development and progression of sepsis in adult intensive care patients. In 272 patients with systemic inflammatory response syndrome followed prospectively, different MBL genotypes were compared with respect to microbiology, sepsis development, and survival. The presence of MBL variant alleles was highly significantly associated with development of sepsis, severe sepsis and septic shock in a gene dose-dependent fashion. An increased risk of death was observed in variant allele carriers. These data show that a genetic factor such as MBL insufficiency plays an important role in the susceptibility of critically ill patients for development and progression of sepsis, and confer a substantial risk for fatal outcome.

Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome.

Genetic factors may predispose critically ill patients to increased risk of developing sepsis. Mannose-binding lectin (MBL) is an important factor in innate immune defense. We investigated whether MBL gene polymorphisms causing low levels of MBL are associated with the development and progression of sepsis in adult patients in intensive care units. In 272 prospectively monitored patients with systemic inflammatory response syndrome, different MBL genotypes were compared, with respect to microbiology, sepsis development, and survival. The presence of MBL variant alleles was associated with the development of sepsis, severe sepsis, and septic shock. An increased risk of fatal outcome was observed in patients carrying variant alleles. These data show that MBL insufficiency plays an important role in the susceptibility of critically ill patients to the development and progression of sepsis and confers a substantial risk of fatal outcome.

The development of asthma in children infected with Chlamydia pneumoniae is dependent on the modifying effect of mannose-binding lectin

Background Although several studies found associations between infection with Chlamydia pneumoniae and asthma, these were mainly restricted to the exacerbation of the symptoms in adults with known asthma. Data about the role of C pneumoniae in the initiation and development of asthma in children are controversial. Objective We investigated the role of C pneumoniae infection in 139 children with asthma, comparing them with 174 healthy control subjects. Furthermore, we studied the modifying effect of mannose-binding lectin (MBL) variant alleles on the susceptibility to asthma in children infected with C pneumoniae. Methods C pneumoniae–specific antibodies were measured by means of ELISA, and MBL genotypes were determined by means of PCR-RFLP. Results There were no significant differences in the percentage of children with positive results for C pneumoniae–specific antibodies between patients and control subjects. Among asthmatic children carrying variant MBL alleles, there were significantly more patients with positive results for C pneumoniae–specific IgG than among control children with variant MBL genotypes (63.7% vs 40.7% of asthmatic vs control children, respectively; odds ratio adjusted for age and sex, 2.21; 95% CI, 1.10-4.41; P = .02). Infected children with variant MBL alleles were found to have a higher risk of asthma development than infected children with normal MBL genotype. This risk was especially high in children with chronic or recurrent infection (positive results for both IgA and IgG; adjusted odds ratio, 5.38; 95% CI, 1.75-14.36; P = .01), but no increased risk was seen in children with current C pneumoniae infection (positive results for IgM). Conclusion This study indicates the important role of variant MBL alleles in the susceptibility to asthma in children infected with C pneumoniae. (J Allergy Clin Immunol 2003;112:729-34.)

Inherited mannose-binding lectin deficiency as evidenced by genetic and immunologic analyses: association with severe recurrent infections

Mannose-binding lectin (MBL), an acute-phase serum protein of hepatic origin, plays an essential protective role in host innate immunity in targeting microbial pathogens for destruction via opsonization, enhancement of phagocytosis and complement activation. MBL deficiency, characterized by low serum MBL, has been attributed to genetic mutations in both structural and promoter regions of the gene coding for the protein. Concomitant MBL deficiency in patients with chronic immunologic disease has been associated with increased susceptibility to complicating infections that may hasten disease progression. Few cases of inherited MBL deficiency in adults and possible associations with recurrent infection have been reported. To address this issue, we investigated the MBL profile of four generations within a single adult family whose members have experienced a variety of persistent infections. MBL serum levels and MBL genotypes of each participating family member were ascertained by enzyme-linked immunoadsorbent assay and reverse transcriptase-polymerase chain reaction, respectively. MBL complement activation, as measured by C4b deposition against mannan-coated wells, was assayed using an enzyme-linked immunoadsorbent assay. Routine immunologic and cellular tests were carried out to evaluate the immunologic status of each family member. Six of the 7 family members screened carried one or more of the variant MBL alleles in their genotype and had correspondingly low serum MBL and reduced ability to affect C4b opsonization. Medical histories of the participating family members revealed an array of mild to severe recurrent infections despite no apparent immunodeficiency. Our studies show that MBL deficiency is an inherited characteristic and may be a crucial factor in maintaining immunologic health.

Relationship between gene polymorphisms of mannose‐binding lectin (MBL) and two molecular forms of MBL

Mannose-binding lectin (MBL) activates complement through MBL-associated serine proteases (MASP). A deficiency in MBL due to mutations at exon 1 of the human MBL gene is reported to cause vulnerability to infection. We examined sera of known MBL genotype by gel filtration and assessed their elution patterns using an ELISA for MBL and identified two MBL forms, a high-molecular-mass form and a lower-molecular-mass form. By the identification of either or both forms in individual sera, three types of patterns emerged: type 1 consisted of a high-molecular form; type 2, of a low-molecular form; and type 3, of both forms. Types 1, 2 and 3 corresponded, respectively, to a wild type (A/A), a homozygous mutation at codon 54 (B/B) and their heterozygote (A/B). One exception was a heterozygous LXPA/LYPB phenotype that exhibited the type-2 pattern. Binding to mannan and MASP-1/3 occurred exclusively with the high-molecular form. An apparent MBL deficiency does not in fact representa deficiency in MBL molecules but rather the presence of circulating oligomeric mutant MBL with impaired function.

Mannose Binding Lectin (MBL) gene polymorphism and in vitro fertilization outcome

Objective: MBL is a serum protein and a component of the innate immune system. By binding to carbohydrate residues on microorganisms, MBL activates the complement system and marks microbes for opsonization. MBL binding to Chlamydia has been demonstrated. The gene coding for MBL is polymorphic and the variant alleles result in decreased MBL serum levels. The association between C. pneumoniae and cardiovascular disease was shown to depend on the presence of variant MBL alleles. Given the relationship between Chlamydia and infertility, we examined the relationship between MBL genotype, infertility etiology and IVF outcome.Design: Prospective analysis of the association between MBL genotype, etiology of infertility and IVF outcome.Materials and Methods: MBL genotypes at codon 54 were determined in 185 consecutive IVF patients by polymerase chain reaction, endonuclease digestion and gel electrophoresis, using DNA isolated from cervical swabs. IVF outcome and the etiology of infertility were obtained at the conclusion of MBL genotype testing. Implantation was defined as the presence of a fetal heart beat. Statistics utilized included Categorical Chi-square testing and Student’s t-test where appropriate. P value < 0.05 was considered significant. Data is presented as mean ± standard deviation.Results: The wild type MBL genotype (AA) was present in 138 (74.6%) of the patients; 47 (25.4%) had variant alleles (41 were AB and 6 were BB). There were no differences in the age, oocyte yield, fertilization percentage or number of embryos transferred based on the MBL genotype result. Patients with the variant alleles had a trend towards an increased rate of tubal infertility (25.6% vs. 16.8%, p = 0.2). Among all subjects, the rates of pregnancy, clinical pregnancy and implantation were not related to the MBL genotype. However, among patients carrying the AB genotype, those with tubal infertility were less likely to achieve a clinical pregnancy than patients with non-tubal infertility (20% vs. 57.7%; P < 0.05). Patients with tubal and non-tubal infertility who had the AA genotype did not differ in pregnancy outcome.Conclusion: Possession of the MBL AB genotype is associated with a decreased IVF success rate in women with tubal infertility. Possession of this genotype, which results in reduced serum MBL levels and lowered innate immune defense against infection, may render women less effective in eliminating microorganisms from the upper genital tract. Analysis of tubal infertility patients for MBL genotypes may have predictive value for IVF outcome and for selecting patients that may need antibiotic prophylaxis. Objective: MBL is a serum protein and a component of the innate immune system. By binding to carbohydrate residues on microorganisms, MBL activates the complement system and marks microbes for opsonization. MBL binding to Chlamydia has been demonstrated. The gene coding for MBL is polymorphic and the variant alleles result in decreased MBL serum levels. The association between C. pneumoniae and cardiovascular disease was shown to depend on the presence of variant MBL alleles. Given the relationship between Chlamydia and infertility, we examined the relationship between MBL genotype, infertility etiology and IVF outcome. Design: Prospective analysis of the association between MBL genotype, etiology of infertility and IVF outcome. Materials and Methods: MBL genotypes at codon 54 were determined in 185 consecutive IVF patients by polymerase chain reaction, endonuclease digestion and gel electrophoresis, using DNA isolated from cervical swabs. IVF outcome and the etiology of infertility were obtained at the conclusion of MBL genotype testing. Implantation was defined as the presence of a fetal heart beat. Statistics utilized included Categorical Chi-square testing and Student’s t-test where appropriate. P value < 0.05 was considered significant. Data is presented as mean ± standard deviation. Results: The wild type MBL genotype (AA) was present in 138 (74.6%) of the patients; 47 (25.4%) had variant alleles (41 were AB and 6 were BB). There were no differences in the age, oocyte yield, fertilization percentage or number of embryos transferred based on the MBL genotype result. Patients with the variant alleles had a trend towards an increased rate of tubal infertility (25.6% vs. 16.8%, p = 0.2). Among all subjects, the rates of pregnancy, clinical pregnancy and implantation were not related to the MBL genotype. However, among patients carrying the AB genotype, those with tubal infertility were less likely to achieve a clinical pregnancy than patients with non-tubal infertility (20% vs. 57.7%; P < 0.05). Patients with tubal and non-tubal infertility who had the AA genotype did not differ in pregnancy outcome. Conclusion: Possession of the MBL AB genotype is associated with a decreased IVF success rate in women with tubal infertility. Possession of this genotype, which results in reduced serum MBL levels and lowered innate immune defense against infection, may render women less effective in eliminating microorganisms from the upper genital tract. Analysis of tubal infertility patients for MBL genotypes may have predictive value for IVF outcome and for selecting patients that may need antibiotic prophylaxis.

Mannose-binding lectin is a disease modifier in clinical malaria and may function as opsonin for Plasmodium falciparum-infected erythrocytes.

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.

Mannose-binding lectin polymorphisms in clinical tuberculosis.

Mannose-binding lectin (MBL) mediates protection against infections by using the complement system, but certain microorganisms may increase infectivity by exploiting this host defense system. Thus, it has been speculated whether genetically determined low MBL levels may confer partial protection against certain intracellular microorganisms, such as Mycobacterium tuberculosis. We investigated MBL alleles in 109 culture-positive human immunodeficiency virus-uninfected patients with tuberculosis living in Denmark and 250 white control subjects. Patients and control subjects were divided into 3 different groups defined by undetectable, low, and high serum MBL concentrations, which correlates to deficient, low, and high expressing MBL genotypes. A significantly decreased frequency of patients with the low-expressing MBL genotype was observed in white patients compared to control subjects. The same tendency also was observed in patients of other ethnic origin. It may be hypothesized that heterozygosity for MBL variant alleles, which encodes low serum MBL levels, is associated with protection against clinical tuberculosis.

Mannose-binding lectin deficiency—revisited

There is an emerging interest for mannose-binding lectin (MBL) due to its role in innate immunity. In this survey we present a mixture of old and new data describing the effect MBL polymorphisms may have on the level and function of the molecule. Three single nucleotide substitutions in exon 1 of the mbl2 gene cause a dominant decrease of functional MBL in the circulation. Additionally, promoter variants influence expression of MBL. It has been assumed that the structural variant alleles may disrupt the assembly of MBL trimers or accelerate the degradation of the protein, thereby causing the decrease in MBL serum concentrations. We have analysed 1183 different sera in a double sandwich antibody ELISA using the same antibody to capture and detect MBL and find the same results as have been presented previously showing that different MBL promoter alleles have profound effect of on the MBL serum concentration. The use of a new anti-MBL monoclonal antibody, however, has shown that the amount of MBL in the circulation is less dependent on the presence of structural variant alleles than previously anticipated. Molecular characterisation of MBL revealed that sera from donors homozygous for the normal MBL genotype predominantly contained high molecular weight MBL, while sera from individuals heterozygous for the variant alleles contained both high and low molecular weight MBL. The ratio between high and low molecular weight MBL was dependent on the MBL promoter type on the normal haplotype. Sera deriving from individuals homozygous for MBL variant alleles contained mainly low molecular weight MBL. Of the different oligomers of MBL only the high molecular weight forms bound mannan efficiently and activated complement. In contrast to a previous notion, we demonstrate that variant alleles give rise to relatively high levels of MBL in the circulation. However, the variant MBL has lower molecular weight and is dysfunctional compared to normal MBL. The physiological relevance of variant MBL remains to be established.

Association of mannose-binding lectin genotype with cardiovascular abnormalities in Kawasaki disease

Kawasaki disease is an acute vasculitis of possible infectious cause, which in particular affects the coronary arteries. Young children rely mostly on their innate immune system for protection against invading microorganisms, of which mannose-binding lectin is an important component. We aimed to investigate the possible role of the gene for this molecule (MBL) in white Dutch patients with Kawasaki disease. In 90 patients, frequency of mutations in the MBL gene was higher than in healthy children. In children younger than 1 year, those with mutations were at higher risk of development of coronary artery lesions than were those without (odds ratio 15.7, 95% CI 1.4-176.5, p=0.026). Our findings suggest that the innate immune system contributes differently to pathophysiology of Kawasaki disease at various ages.

Absence of association between mannose-binding lectin gene polymorphisms and HIV-1 infection in a Colombian population.

Mannose-binding lectin (MBL) is a calcium-dependent lectin shown to play an important role in innate immunity to infection by activating the classical complement pathway and phagocytosis. In vitro studies have shown that MBL is able to bind to the gp120 HIV-1 surface antigen, and variants of the gene are associated with increased risk of HIV infection among Scandinavians. We investigated the association of genetic MBL variants and HIV-1 infection in 278 Colombian HIV-infected and control individuals. MBL genotype frequencies were similar for both groups, and no association was detected between MBL alleles B, C, and D and susceptibility to HIV-1 infection ( P=1.0). Since there is a well-documented link between the tested MBL alleles and very low MBL serum concentration, these results do not support the hypothesis that MBL levels are a risk factor for HIV-1 infection in Colombia.

Analysis of the relationship between mannose-binding lectin (MBL) genotype, MBL levels and function in an Australian blood donor population.

The mannose-binding lectin (MBL) pathway of complement activation is an important component of innate host defence. Numerous studies have described associations between the MBL genotype, MBL levels and disease susceptibility. However, genotyping and quantitative assays used in these studies have frequently been limited, and comprehensive data examining the interaction between structural and coding MBL genetic variants, MBL antigenic levels and MBL functional activity are lacking. Such data may be important for accurate planning and interpretation of studies of MBL and disease. This study has examined MBL in a cohort of 236 Australian blood donors. Five MBL promoter and coding single nucleotide polymorphisms were genotyped using polymerase chain reaction-sequence-specific priming (PCR-SSP). Plasma levels of MBL antigen were quantified using a double-antibody enzyme-linked immunosorbent assay (ELISA), and functional MBL levels were quantified using a mannan-binding assay. Activation of the complement pathway by MBL was measured in a C4-deposition assay. Significant associations were found between both coding and promoter polymorphisms and MBL antigenic and functional levels. There was significant correlation between the results of MBL double-antibody, mannan-binding and C4-deposition assays. Comprehensive MBL genotyping and functional MBL quantitation using mannan-binding and C4-deposition assays have the potential to be highly informative in MBL disease association studies.

Increased frequency of mannose-binding lectin insufficiency among children with acute lymphoblastic leukemia

Epidemiological data indicate that acute lymphoblastic leukemia (ALL) could be induced by interactions between the immune system and early childhood infections. Mannose-binding lectin (MBL) plays a critical role in the immune response in early childhood before specific immune protection develops. We investigated whether there may be an association between childhood ALL and low-producing MBL genotypes. Serum MBL levels depend on normal (A) or defective (O) alleles, and on normal (Y) or reduced (X) promoter activities. For this study, 137 noninfants with ALL and 250 controls were classified into 3 MBL genotype groups according to their influence on the serum level of functional MBL: group I, YA/YA and YA/XA (higher levels); group II, XA/XA and YA/O (intermediate levels); and group III, MBL insufficiency with XA/O or O/O (MBL-deficient) genotypes. Compared with controls, cases more often had low-level genotypes (I/II/III: 63 [46%]/44 [32%]/30 [22%] vs 145 [58%]/65 [26%]/40 [16%]; P =.02) and MBL deficiency (8.8% vs 2.8%; P =.009). Thus, the ALL odds ratio for MBL-deficient versus nondeficient individuals was 3.3 (95% CI, 1.3-8.7), whereas the ALL odds ratio for group I versus group II/III genotypes was 0.62 (95% CI, 0.41-0.94). MBL group III patients were significantly younger at diagnosis than patients in group I/II (median, 3.9 vs 5.2 years; P =.04). The study shows that the presence of low-level MBL genotypes is associated with an increased risk of childhood ALL, particularly with early age at onset.

MBL genotype and risk of invasive pneumococcal disease: a case-control study

Streptococcus pneumoniae is a major cause of morbidity and mortality in developed and developing countries. No common genetic determinants of susceptibility have been defined. Mannose-binding lectin (MBL) is a key mediator of innate host immunity that activates the complement pathway and directly opsonises some infectious pathogens. Mutations in three codons in the MBL gene have been identified, and individuals homozygous for a mutant genotype have very little or no serum MBL. We did a case-control study in the UK to assess whether these mutant genotypes were associated with invasive pneumococcal disease. The frequencies of genotypes defined by the three mutations in codons 52, 54, and 57, and a functional promoter polymorphism at -221, were compared in a two-stage study of 337 patients with invasive pneumococcal disease and 1032 controls. All individuals were recruited from an ethnically homogeneous white population in Oxfordshire, UK. Patients had S pneumoniae isolated from a normally sterile site. In our initial set of participants, 28 (12%) of 229 patients and 18 (5%) of 353 controls were homozygotes for MBL codon variants (odds ratio 2.59 [95% CI 1.39-4.83], p=0.002). Neither heterozygosity for these codon variants nor the promoter polymorphism was associated with susceptibility. In a confirmatory study, 11 (10%) of 108 patients were MBL homozygotes compared with 36 (5%) of 679 controls (p=0.046). Homozygotes for MBL codon variants, who represent about 5% of north Europeans and north Americans and larger proportions of populations in many developing countries, could be at substantially increased risk of invasive pneumococcal disease.

Variant mannose-binding lectin alleles are not associated with susceptibility to or outcome of invasive pneumococcal infection in randomly included patients.

Invasive pneumococcal disease is a serious infection that primarily affects very young children and elderly or immunocompromised individuals but also affects previously healthy people. Variant mannose-binding lectin (MBL) alleles are associated with recurrent infections and may be a risk factor for pneumococcal infections. To assess the influence of MBL genotypes on the course and outcome of invasive pneumococcal disease, clinical data for 141 adult patients were collected prospectively and their genotypes were determined. All patients included had positive blood cultures for Streptococcus pneumoniae. The distribution of variant MBL alleles related to low MBL serum concentrations was similar among the patients and healthy individuals, and MBL genotype was not associated with infection outcome. Thus, in a random adult population with invasive pneumococcal infection, MBL does not seem to play a role in the pathophysiology, in contrast to earlier observations in patients with other concomitant immune abnormalities.

Single Nucleotide Polymorphisms of the Mannose-binding Lectin are Associated with Susceptibility to Primary Biliary Cirrhosis

Although the immunopathogenesis of primary biliary cirrhosis (PBC) remains unknown, familial clustering of patients with PBC suggests an important role for genetic factors. In addition, recent data support the thesis that the mucosal immune response against intraluminal pathogens may be involved with the onset of PBC. Mannose-binding lectin (MBL) is a key factor in innate mucosal defenses and has several key single nucleotide polymorphisms (SNPs). To study whether MBL gene SNPs are associated with susceptibility to PBC, we studied 65 patients with PBC and 218 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequence specific priming-polymerase chain reaction (SSP-PCR) to examine four polymorphic loci: two (H/L and X/Y) within the promoter region and the other two (P/Q and A/B) within exon-1. We also analyzed serum MBL concentrations. Interestingly, the prevalence of haplotype HYPA, leading to hyper-production of MBL, as well as HYPA/HYPA genotype were significantly increased in PBC compared to controls (0.53 vs. 0.44, P=0.031; 33.9%vs. 17.0%, P=0.003, respectively). Furthermore, individuals homozygous for HYPA had a significantly increased risk for PBC (odds ratio (OR)=2.51, 95% confidence interval (CI)=1.34–4.66). Our results demonstrate that the MBL genotype can be significantly associated with increased risk for PBC, and further, that increased production of MBL plays a critical role in immunopathogenesis.

Deficiency of mannose-binding lectin and burden of infection in children with malignancy: a prospective study

Infection is a major cause of morbidity and mortality in children with malignancy. Individuals with serum deficient in mannose-binding lectin (MBL)-an important component of the innate immune system-are more susceptible to infection than those with adequate concentrations. In this study, we investigated the capacity of this protein to influence infectious complications in children undergoing treatment for malignancy. We enrolled 100 children receiving chemotherapy for malignancy at a children's hospital in London, UK. The frequency, duration, and causes of febrile neutropenic episodes were recorded, and MBL genotype and phenotype were determined by heteroduplex analysis and ELISAs, respectively. Serial MBL concentrations were also measured in patients during febrile episodes, and the results correlated with the MBL genotype (A/A indicating wild type, O/O indicating homozygous for MBL structural-gene mutations, and A/O indicating heterozygous for such mutations). In the A/A patients, MBL concentrations almost doubled by day 7 of the febrile neutropenic episode before declining by day 14 (p=0.004). By contrast, in patients with MBL mutations, concentrations did not alter significantly during the neutropenic episode. In the 6 months after initial diagnosis, most patients had at least one febrile neutropenic episode, but the median duration in patients with MBL mutations was twice as long as that in children with the wildtype genotype (20.5 days vs 10.0 days; p=0.014). Individuals with the lowest serum MBL concentrations at the time of diagnosis (<1000 microg/L) had a higher median number of days of febrile neutropenia than did individuals with higher concentrations of MBL (p=0.012). MBL deficiency seems to have an important influence on the duration of febrile neutropenic episodes in children with malignancy. This finding suggests that MBL infusions could represent a new therapeutic approach which would aid the management of chemotherapy-induced complications in this population of children.

Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood.

Hospital-based studies have found that increased susceptibility to certain infections is associated with low serum levels of mannose-binding lectin (MBL) due to MBL variant alleles. However, the contribution of MBL insufficiency to incidence of common childhood infections at a population level is unknown. To investigate the effect of MBL insufficiency on risk for acute respiratory tract infection (ARI) in unselected children younger than 2 years. Population-based, prospective, cohort study conducted in Sisimiut, Greenland. Two hundred fifty-two children younger than 2 years who were followed up weekly between August 1996 and August 1998 for morbidity surveillance. Risk of ARI, based on medical history and clinical examination, compared by MBL genotype, determined from blood samples based on presence of structural and promoter alleles. A 2.08-fold (95% confidence interval [CI], 1.41-3.06) increased relative risk (RR) of ARI was found in MBL-insufficient children (n = 13) compared with MBL-sufficient children (n = 239; P<.001). The risk association was largely restricted to children aged 6 to 17 months (RR, 2.92; 95% CI, 1.78-4.79) while less effect (RR, 1.47; 95% CI, 0.45-4.82) and no effect (RR, 1.00; 95% CI, 0.42-2.37) was shown among children aged 0 to 5 months and 18 to 23 months, respectively. These data suggest that genetic factors such as MBL insufficiency play an important role in host defense, particularly during the vulnerable period of childhood from age 6 through 17 months, when the adaptive immune system is immature.