Studies evaluating associations between polymorphisms of innate immunity genes and prognosis of infectious diseases have yielded conflicting results. Our aim was to assess the impact on mortality of different genotypic variants of the innate immunity in patients with pneumococcal sepsis. All adults admitted to the hospital with diagnosis of sepsis caused by Streptococcus pneumoniae were enrolled and single-nucleotide polymorphisms (SNP) in mannose-binding lectin 2 (MBL2), toll-like receptor (TLR) 2, TLR4, and Fcγ receptor IIa genes were genotyped. Underlying diseases, severity of illness, and antibiotic management were also recorded. We included 117 patients: 98 pneumonias (83.6%), 17 meningitis (14.5%), and 2 patients (1.9%) with primary pneumococcal bacteremia. Allelic variants of the MBL2 gene (individuals heterozygous or homozygous for one of the 3 allelic variants B, C, and D: AO/OO) were present in 37 patients (32%), T399I polymorphism in TLR4 in 19 (16.2%), TLR4 D299G/T399I in 11 (9.4%), TLR2 R753Q in 3 (2.5%), and FcγRIIa-R/R131 in 26 patients (23%). Factors associated independently with in-hospital mortality were SNP MBL2 AO/OO (adjusted hazard ratios [aHR] 3.2, 95% confidence interval [CI] 1.01-9.8) and septic shock (aHR 15.3, 95% CI 3.5-36.5), whereas first adequate antibiotic dose ≤ 4 h was a protective factor (aHR 0.2, 95% CI 0.06-0.8). SNP MBL2 AO/OO (aHR 2.2, 95% CI 1.1-8.1) remained as a variable independently associated with 90-day mortality. In conclusion, variant alleles in the MBL2 gene are independently associated with in-hospital and medium-term mortalities in patients admitted to the hospital with pneumococcal sepsis.

BACKGROUND: Chorioamnionitis is a common underlying cause of preterm birth (PTB). It is hypothesised that polymorphisms in immunoregulatory genes influence the host response to infection and subsequent preterm birth. The relationship between histologic chorioamnionitis and 22 single nucleotide polymorphisms in 11 immunoregulatory genes was examined in a case-control study. METHODS: Placentas of 181 Caucasoid women with spontaneous PTB prior to 35 weeks were examined for histologic chorioamnionitis. Polymorphisms in genes IL1A, IL1B, IL1RN, IL1R1, tumour necrosis factor (TNF), IL4, IL6, IL10, transforming growth factor beta-1 (TGFB1), Fas (TNFRSF6), and mannose-binding lectin (MBL2) were genotyped by polymerase chain reaction and sequence specific primers. Multivariable logistic regression including demographic and genetic variables and Kaplan-Meier survival analyses of genotype frequencies and pregnancy outcome were performed. RESULTS: Sixty-nine (34%) women had histologic evidence of acute chorioamnionitis. Carriage of the IL10-1082A/-819T/592A (ATA) haplotype [Multivariable Odds ratio (MOR) 1.9, P = 0.05] and MBL2 codon 54Asp allele (MOR 2.0, P = 0.04), were positively associated with chorioamnionitis, while the TNFRSF6-1377A/-670G (AG) haplotype (MOR 0.4, P = 0.03) and homozygosity for TGFB1-800G/509T (GT) haplotype (MOR 0.2, P = 0.04) were negatively associated. CONCLUSION: These findings demonstrate that polymorphisms in immunoregulatory genes IL10, MBL2, TNFRSF6 and TGFB1 may influence susceptibility to chorioamnionitis.

The peroxisome proliferator activated receptor-α (PPARα) is a major transcriptional regulator of lipid metabolism in liver and represents the molecular target for hypolipidemic fibrate drugs. Effects of PPARα on lipid metabolism are partially mediated by circulating proteins such as FGF21 and ANGPTL4. The present study was undertaken to screen for and identify circulating proteins produced by human liver that are under the control of PPARα. Toward that aim, primary human hepatocytes were treated with the synthetic PPARα agonist Wy-14643 and whole genome expression data selected for secreted proteins. Expression of FGF21, ANGPTL4, and mannose-binding lectin (MBL), a soluble mediator of innate immunity and primary component of the lectin branch of the complement system, was markedly upregulated by Wy-14643 in primary human hepatocytes. Mice express two MBL isomers, Mbl1 and Mbl2. Mbl1 mRNA was weakly induced by Wy-14643 in primary mouse hepatocytes and remained unaltered by Wy-14643 in mouse liver. Mbl2 mRNA was unchanged by Wy-14643 in primary mouse hepatocytes and was strongly reduced by Wy-14643 in mouse liver. Remarkably, plasma Mbl1 levels were increased by chronic PPARα activation in lean and obese mice. Importantly, in two independent clinical trials, treatment with the PPARα agonist fenofibrate at 200 mg/day for 6 wk and 3 mo increased plasma MBL levels by 73 (P = 0.0016) and 86% (P = 0.017), respectively. It is concluded that hepatocyte gene expression and plasma levels of MBL are stimulated by PPARα and fenofibrate in humans, linking PPARα to regulation of innate immunity and complement activation in humans and suggesting a possible role of MBL in lipid metabolism.

Structural and promoter MBL2 gene polymorphisms responsible for low MBL levels are associated with increased risk of infection. The objective of this study was to assess the possible association between polymorphisms of the MBL2 gene and the incidence of septic shock and bacteremia in patients with acute pyelonephritis due to Escherichia coli. The study included 62 female patients with acute pyelonephritis due to E. coli who required hospital admission, as well as 133 healthy control subjects. Six single-nucleotide polymorphisms (-550 G/C, -221 C/G, +4 C/T, codon 52 CGT/TGT, codon 54 GGC/GAC, and codon 57 GGA/GAA) in the MBL2 gene were genotyped by using a sequence-based typing technique. No significant differences were observed in the frequencies for low-expression MBL2 genotypes (O/O and LXA/O) between patients with acute pyelonephritis and healthy controls. Patients with acute pyelonephritis and septic shock had a higher incidence of low-expression MBL2 genotypes than patients with acute pyelonephritis without septic shock (odds ratio = 9.019, 95% confidence interval = 1.23 to 65.93; P = 0.03). No association was found between bacteremic acute pyelonephritis and low-expression MBL2 genotypes. We found that low-expression MBL2 genotypes predispose to septic shock but not to bacteremia in patients with E. coli-induced acute pyelonephritis. Determination of MBL2 polymorphisms could be useful for assessing the risk of septic shock in women undergoing acute pyelonephritis.

Dengue viruses (DENV) cause a spectrum of disease in humans, ranging from dengue fever (DF) to a severe, life-threatening syndrome called dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Despite the global morbidity and mortality associated with DENV infection, mechanisms of immune control and viral pathogenesis are poorly understood. In a recent article, Avirutnan et al. [mBio 2(6):e00276-11, 2011] demonstrated that DENV can be directly neutralized via the mannose binding lectin (MBL) pathway of the complement system and that deficiency in MBL level or activity due to host polymorphisms in the MBL2 gene correlates with reduced levels of DENV neutralization. These findings implicate a role for the MBL pathway in controlling DENV infections and modulating DHF/DSS manifestations.

We hypothesize that variations in the frequency of genetic polymorphisms, reflecting ancestral differences in living conditions and exposure to microorganisms, increase susceptibility to adverse pregnancy outcome among present day Black North American women. Striking differences were observed in the frequency of genetic variants between Black and White or Hispanic women in 5 genes (IL1RN, MBL2, PPARA, ATG16L1, CIAS1) associated with inflammation and anti-microbial immunity. The CIAS1 and IL1RN polymorphisms were associated with altered interleukin-1β serum levels; the MBL2 polymorphism resulted in a decreased serum mannose-binding lectin concentration. Gene polymorphisms associated with an alteration in innate immunity were most frequent in Black women. This may reflect an evolutionary selection in response to an ancient environment containing a high multitude of microorganisms, and may increase susceptibility of Black women to infection-associated preterm birth in the current North American environment.

Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) are key factors of the lectin pathway of complement activation. Polymorphisms of the MBL2 and MASP-2 genes affect serum levels of MBL and MASP-2. In patients with colorectal cancer (CRC), the MBL and MASP-2 serum levels are increased and high MASP-2 levels are associated with recurrence and poor survival, whereas low MBL levels predict post-operative pneumonia. It is not known whether these associations are genetically based. In this study, the MBL and MASP-2 genotypes are investigated in 593 patients with CRC and 348 healthy controls. The potential association between genetic profile and infections, recurrence and survival is evaluated. Four single-nucleotide polymorphisms (SNPs) of MBL2 were analysed using TaqMan assays, with characterization of MBL2 wildtype A, variants B, C and D and alleles H/L, Y/X and P/Q. The SNP D120G for MASP-2 was determined. Serum levels of MBL and MASP-2 were measured. The MBL2 and MASP-2 genotype distribution was similar among patients with CRC and healthy controls and MBL2 genotype significantly associated with MBL concentration in serum (P<0.0001). No significant association between MBL2/MASP-2 genotype and post-operative infectious complications (P=0.33 and 0.22), recurrent cancer or survival (P=0.74 and P=0.61 respectively) was found. Thus, the increased serum levels of MBL and MASP-2 found in patients with CRC are not explained for by genetic profiles. In contrast to what has been demonstrated for serum levels of MBL and MASP-2, the genotypes do not predict disease course of the CRC patients.

Mannose-Binding Lectin (MBL) is a serum pattern recognition molecule, able to activate complement in association with MASP proteases. Serum levels of MBL and MASP-2, activities of MBL-MASP complexes, single nucleotide polymorphisms of the MBL2 and MASP2 genes and/or their specific mRNA expression in ovarian sections were investigated in 128 patients suffering from primary ovarian cancer (OC) and compared with 197 controls (C), encompassing both patients with benign ovarian tumours (n = 123) and others with no ovarian pathology (n = 74). MBL deficiency-associated genotypes were more common among OC patients than among controls. The O/O group of genotypes was associated with ovarian cancer (OR 3.5, p = 0.02). In A/A homozygotes, MBL concentrations and activities were elevated in the OC group and correlated with C-reactive protein. Moreover, high MBL serum levels were associated with more advanced disease stage. No differences in distribution of the MASP2 +359 A>G (D120G) SNP or MASP-2 serum levels were found between cancer patients and their controls. However, the highest frequency of the A/G (MASP2) and LXA/O or O/O (MBL2) genotypes was found among OC patients with tumours of G1-2 grade (well/moderately differentiated). Furthermore, MBL deficiency-associated genotypes predicted prolonged survival. None of the parameters investigated correlated with CA125 antigen or patients' age. The local expression of MBL2 and MASP2 genes was higher in women with ovarian cancer compared with controls. It is concluded that the expression of MBL and MASP-2 is altered in ovarian cancer, possibly indicating involvement of the lectin pathway of complement activation in the disease.

The pathogenesis of hepatocellular carcinoma (HCC) is not fully understood, but the majority of patients with HCC are associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Mannan-binding lectin (MBL) is a collectin that can act directly as opsonine or activate MBL-associated serine proteases (MASPs) thus initiating the antibody-independent pathway of the complement system. In our study, we analysed two MBL2 and MASP2 functional polymorphisms (MBL2 allele A/0 and MASP2 D120G) as well as MASP2 polymorphism (Y371D) responsible for an amino acidic change in the protein in 215 HCC patients (HBV-infected, HCV-infected, HBV/HCV co-infected and patients with HCC with no viral infection) and 164 healthy controls to give new insights regarding the role of these two molecules in HCC and viral infection pathogenesis. No significant association was found between MBL2 or MASP2 alleles or genotypes, neither comparing the total patients with HCC and healthy controls nor between the different groups of HCC subjects divided for type of viral infection. Also, dividing the total HCC patients group into low MBL producer (A0 and 00 genotypes) and normal producer (AA genotype) and comparing MASP2 polymorphisms in these two groups, no significant differences were found. Our data do not seem to suggest a role for MBL2 and MASP2 polymorphisms in HCC susceptibility either for HBV-HCV infection-dependent HCC or for HCC raised as a consequence of exposure to different risk factors.

The mannose-binding lectin (MBL) pathway of complement system is activated when carbohydrate-bound MBL forms complexes with different serine proteases (MASP-1, MASP-2 and MASP-3), among which MASP-2 has a predominant functional role. Polymorphisms impairing the quantity and/or the functional activity of proteins encoded by the MBL2 and MASP2 genes have been reported in all human populations showing different allelic frequency and distribution. This likely reflects the existence of environmental influences on MBL2 and MASP2 genetic evolution. Herewith, we conducted a study in a children population from Mozambique to analyse the genetic diversity of sequences corresponding to the promoter and collagen-like region (exon 1) of MBL2 and to the CUB-1 and epidermal growth factor domain (exon 3) of MASP2, which are critical regions for the formation of functional MBL/MASP-2 complexes. Our results show a high prevalence of MBL-intermediate/low genotypes (43.5%); the description of new alleles and a high level of sequence polymorphism at both MBL2 and MASP2, with no statistical evidence for positive or balancing selection. Furthermore, Biacore analyses performed to explore the functional relevance of the MASP2 variants found [T73M (2.9%), R84Q (12.7%) and P111L (25.4%)] were compared with those of two previously reported variants (R103C and D105G). None of the analysed MASP2 variants, with the exception of D105G, interfered with interactions with either MBL or ficolins (H and L).

Mannose-binding lectin (MBL), a calcium-dependent collagenous lectin, plays an important role in the host immune defence against a wide range of pathogens. There are MBL1 and MBL2 genes which encode the MBL-A and MBL-C proteins, respectively. This study was carried out to investigate the relationship between the variants of the bovine MBL2 gene and milk production traits, mastitis, serum MBL-C levels and hemolytic complement activity in both classical pathway (CH50) and alternative pathway (ACH50) in Chinese Holstein cattle. Four single-nucleotide polymorphisms (SNPs) in the exon 1 of the MBL2 gene in Chinese Holstein cattle and Luxi yellow cattle were identified by the direct sequencing method. The SNP g.201 G>A was identified as a non-synonymous mutation (codon 31, Arg>Gln) at the N-terminus cysteine-rich domain and the SNPs g.234 C>A and g.235 G>A (codon 42) made Pro to Gln at the 1st Gly-X-Y repeat of the collagen-like domain, while the SNP g.244 T>C (codon 45) was identified as a synonymous mutation (Asn>Asn) at the 2 th Gly-X-Y repeat of the collagen-like domain. The SNP markers (g.201 G>A, and g.234 C>A) were significantly correlated with somatic cell score (SCS) (P<0.05). The concentration of MBL-C protein in serum ranges from 0.8 to 7.4 μg/mL by enzyme-linked immunosorbent assay. Six combinations of different haplotypes from the four SNPs were identified in Chinese Holstein cattle. Statistical analysis revealed that cows with the haplotype combination H4H5 exhibited the lowest SCS. The CH50 value of H4H5 and H5H5 cow are significantly higher than H2H5 haplotype combination (P<0.05). The association analysis results showed that the haplotype combination H4H5 may be used as a tolerance haplotype combination for the bovine mastitis.

BACKGROUND

Mannose-binding lectin (MBL) activates the complement system promoting opsonophagocytosis, which could represent an advantage for Mycobacterium leprae, an intracellular pathogen. Therefore, a single nucleotide polymorphism (SNP) in the MBL2 gene associated with low levels of MBL could confer protection against the development of leprosy disease.

METHODS

In this study, we investigated SNPs of the MBL2 gene and MBL levels in 228 Brazilian leprosy patients and 232 controls.

RESULTS

There were no differences in the frequencies of variant genotypes and haplotypes of MBL2 between patients and controls, or between the different clinical forms of leprosy. In the group of patients with a genotype for high expression of MBL2, those aged>40 years had decreased MBL levels compared to patients aged ≤ 40 years (p = 0.037).

CONCLUSIONS

Our results demonstrate that age could influence the phenotype of MBL2, but no evidence was found for an association of MBL2 polymorphism with susceptibility to leprosy or its clinical forms.

Mannose-binding lectin (MBL) deficiency is associated with reduced intestinal ischemia-reperfusion (IR) damage in rodents. We set out to investigate an association between frequently observed MBL deficiency and IR associated intestinal cell damage in man. Using a newly developed IR model of the human small intestine 29 patients were consecutively included. Part of the jejunum was subjected to 30 min of ischemia and reperfusion. The MBL genotype was assessed by means of quantitative-PCR analysis. Enterocyte loss was explored by measuring plasma intestinal-fatty acid binding protein (I-FABP) levels. Arterial and venous MBL plasma levels were measured to assess MBL consumption, MBL deposition was analyzed by immunofluorescence. Ethical approval and informed consent were obtained. The amount of epithelial cell damage varied significantly between the carriers of different mbl2 genotypes (ANOVA, p=0.02). I-FABP release, representing disintegration of differentiated enterocytes, observed in homozygous wildtype individuals was twice (p=0.03) that measured in heterozygous and ten times (p=0.04) that observed in homozygous variant individuals. No MBL deposition was observed over the course of reperfusion. The data indicate that MBL influences intestinal epithelial cell integrity in an immediate and non-complement dependent manner during ischemia and reperfusion.

Mannose-binding lectin (MBL) binds to pathogens and induces complement-mediated opsonophagocytosis. Although the association between MBL2 polymorphisms and tuberculosis (TB) has been studied in various populations, the results are controversial. We explored the stages of TB associated with MBL2 polymorphisms. X/Y (rs7096206) and A/B (rs1800450) were genotyped in 765 new patients with active pulmonary TB without HIV infection and 556 controls in Hanoi, Viet Nam. The MBL2 nucleotide sequences were further analyzed, and plasma MBL levels were measured in 109 apparently healthy healthcare workers and 65 patients with TB. Latent TB infection (LTBI) was detected by interferon-gamma release assay (IGRA). The YA/YA diplotype, which exhibited high plasma MBL levels, was associated with protection against active TB in younger patients (mean age = 32)≦ 45 years old (odds ratio, 0.61; 95% confidence interval, 0.46-0.80). The resistant diplotype was less frequently found in the younger patients at diagnosis (P = 0.0021). MBL2 diplotype frequencies and plasma MBL levels were not significantly different between the IGRA-positive and -negative groups. MBL2 YA/YA exhibited a protective role against the development of TB in younger patients, whereas the MBL2 genotype and MBL levels were not associated with LTBI. High MBL levels may protect against the early development of pulmonary TB after infection.

BACKGROUND

Mannose-binding lectin (MBL) forms an integral part of the innate immune system. Persistent, subclinical infections and chronic inflammatory states are hypothesized to contribute to the pathogenesis of atherosclerosis. MBL gene (MBL2) variants with between 12 to 25% allele frequency in Caucasian and other populations, result in markedly reduced expression of functional protein. Prospective epidemiologic studies, including a nested, case-control study from the present population, have demonstrated the ability of MBL2 genotypes to predict complications of atherosclerosis,. The genetic control of MBL2 expression is complex and genetic background effects in specific populations are largely unknown.

METHODS

The Strong Heart Study is a longitudinal, cohort study of cardiovascular disease among American Indians. A subset of individuals genotyped for the above mentioned case-control study were selected for analysis of circulating MBL levels by double sandwich ELISA method. Mean MBL levels were compared between genotypic groups and multivariate regression was used to determine other independent factors influencing MBL2 expression.

RESULTS

Our results confirm the effects of variant structural (B, C, and D) and promoter (H and Y) alleles that have been seen in other populations. In addition, MBL levels were found to be positively associated with male gender and hemoglobin A1c levels, but inversely related to triglyceride levels. Correlation was not found between MBL and other markers of inflammation.

CONCLUSIONS

New data is presented concerning the effects of known genetic variants on MBL levels in an American Indian population, as well as the relationship of MBL2 expression to clinical and environmental factors, including inflammatory markers.

A protein, with a novel N-terminal amino acid sequence and a molecular mass of 30 kDa, was purified from fresh Smilax glabra rhizomes by adsorption on DEAE-cellulose, CM-cellulose, Con A-Sepharose, and Mono S, and by fast protein liquid chromatography-gel filtration on Superdex 75. The protein, designated as smilaxin, stimulated uptake of [methyl-3H]thymidine by murine splenocytes, peritoneal macrophages, and bone marrow cells, and production of nitric oxide by peritoneal macrophages. It inhibited uptake of [methyl-3H]thymidine by MBL2 and PU5 tumor cells but not uptake by S180 and L1210 cells. Smilaxin augmented glucose uptake into rat adipose tissue. It attenuated the activity of HIV-1-reverse transcriptase with an IC50 of 5.6 microM. However, it did not display hemagglutinating, antifungal or translation-inhibitory activities, indicating that it is not a lectin, an antifungal protein, or a ribosome-inactivating protein.

OBJECTIVE

Mannan-binding lectin (MBL) is a complement-activating carbohydrate-recognizing molecule associated with diabetic nephropathy. MBL is associated with all-cause mortality in type 2 diabetes, but whether MBL is associated with mortality in type 1 diabetes remains unknown. We therefore aimed to investigate this.

METHODS

We studied an existing 12-year prospective cohort with type 1 diabetes with 198 patients with diabetic nephropathy (121 men, age 41 years [95% CI 40-42], estimated glomerular filtration rate [eGFR] 67 mL/min/1.73 m(2) [95% CI 63-70]) and 174 normoalbuminuric patients (103 men, age 43 years [95% CI 41-44], eGFR 93 mL/min/1.73 m(2) [95% CI 91-95]). Mortality rates were compared according to the concentration-determining MBL2 genotype or the MBL concentration. Patients were classified as having high or low MBL expression genotypes. The effect of MBL concentration was estimated by comparing patients with MBL concentrations above or below the median.

RESULTS

Ninety-eight patients died during follow-up. The unadjusted hazard ratio (HR) for all-cause mortality was 1.61 (95% CI 1.07-2.43) for patients with high MBL expression genotypes versus patients with low MBL expression genotypes (P = 0.023). All-cause mortality was higher in patients with MBL concentrations above the median than in patients with MBL concentrations below the median (unadjusted HR 1.90 [95% CI 1.26-2.87], P = 0.002).

CONCLUSIONS

High MBL expression genotypes and high MBL concentrations are both associated with increased mortality rates in type 1 diabetes compared with low MBL expression genotypes and low MBL concentrations.

Infectious complications, sepsis, and multiple organ dysfunction syndrome (MODS) remain important causes for morbidity and mortality in patients who survive the initial trauma. Increasing evidence suggests that genetic variants, particularly single nucleotide polymorphisms (SNPs), are critical determinants for interindividual differences in both inflammatory responses and clinical outcome in sepsis patients. Although the effect of SNPs on sepsis and MODS has been studied in many populations and diseases, this review aimed to summarize the current knowledge on the effect of SNPs on infectious complication specifically in trauma patients. A review of available literature was performed in PubMed database. The following genes have been studied in populations of trauma patients: CD14, HMGB1, IFNG, IL1A, IL1B, IL1RN, IL4, IL6, IL8, IL10, IL17F, IL18, MBL2, MASP2, FCN2, TLR1, TLR2, TLR4, TLR9, TNF, LTA, GR, MYLK, NLRP3, PRDX6, RAGE, HSPA1B, HSPA1L, HSP90, SERPINE1, IRAK1, IRAK3, VEGFA, LY96, ANGPT2, LBP, MicroRNA, and mtDNA. In this review, we discuss the genes of the Pattern Recognition Receptors, Signal Transducing Adaptor Proteins, and Inflammatory Cytokines of the innate immune system. A number of genetic variations have so far been studied in cohorts of trauma patients. Studies are often unique and numbers sometimes small. No definitive conclusions can be reached at this time about the influence of specific sequence variations on outcome in trauma patients.

HCV infection transmission rate in infants born to HCV-positive mothers is about 5%. HIV co-infection and high maternal RNA viral load are associated with increased transmission. The only genetic factor previously evaluated is HLA. We investigated the role of genetic factors already associated in adults with HCV infection evolution (HLA-DRB1, MBL2, TNF-alpha, IFN-gamma and IL-10), or liver disease progression (HFE and TGF-beta1). 384 Italian subjects were recruited, including 38 HCV-positive mother/child pairs; 104 infected, non-transmitting mothers with their 114 children; 21 vertically infected children and 69 HCV-exposed, uninfected children. Samples were analysed for previously described gene polymorphisms. Maternal HLA-DRB104 correlated with protection from vertical transmission (p=0.023), while HLA-DRB110 in children was a risk factor (p=0.036). Investigation of concordance degree in HLA-DRB1 locus revealed that a HLA mismatch between mother and child was a protective factor (p=0.017) indicating that alloreactive immune responses are involved in preventing HCV vertical transmission.

Activation of the complement system is initiated by the alternative, the classical, or the lectin pathway. As the complement system is involved in the pathophysiology of graft rejection after kidney transplantation, we investigated the possible role of mannose-binding lectin in kidney transplantation and the influence of human leukocyte antigen (HLA) immunization on this process. In a prospective study of 544 kidney transplant patients over a follow-up period of 5 years, low serum levels of this lectin at the time of transplantation were found to be significantly associated with decreased 5-year death-censored graft survival (hazard ratio 1.68). Subanalysis showed that this association was confined to non-HLA-immunized patients (hazard ratio 1.93). The strongest association was seen in non-HLA-immunized patients receiving a kidney from a deceased donor (hazard ratio 2.93). No significant association with mannose-binding lectin levels and graft survival were found in HLA-immunized patients. Variant MBL2 genotypes causing low mannose-binding lectin serum concentrations showed the same association pattern. Our findings demonstrate a clear protective role of mannose-binding lectin and thus innate immunity in maintaining kidney graft survival, but these are probably overruled by HLA immunization.

In a cohort study of children < 4 years of age in Greenland, mannose-binding lectin (MBL2) genotypes and Epstein-Barr virus (EBV) antibody levels were determined. EBV seropositivity was significantly lower and time to seroconversion increased in MBL-insufficient compared with MBL-sufficient children, indicating that MBL may be involved in primary EBV infection in infancy.

OBJECTIVE

This study investigates the role of mannose-binding lectin (MBL) in susceptibility and clinical expression of systemic lupus erythematosus (SLE), through the analysis of promoter region and exon 1 polymorphisms of the MBL2 gene.

METHODS

We analysed 325 SLE patients from the Hospital de Clínicas de Porto Alegre and 344 controls. All individuals were grouped according to ethnic origin. Genotyping of the promoter and exon 1 variants were performed by PCR-SSP and PCR-RFLP, respectively. Polymorphisms frequencies between patients and controls were compared by Chi-square or Fisher's exact tests.

RESULTS

A statistically significant difference was observed among the frequencies of both promoter haplotypes (p=0.005) and haplotypic combinations (p=0.004) in African-derived patients, with a higher incidence of HY haplotype and LY/HY combination in SLE patients when compared to controls. These results showed a tendency to higher frequencies of genotypes related to high MBL levels in African-derived patients. A joint analysis of data from the promoter and exon 1 polymorphisms showed an increased frequency of genotypes conferring a deficient of MBL levels in European-derived patients (p<0.001).

CONCLUSIONS

Our data suggest a possible influence of MBL deficiency in SLE European-derived although we did not observe any involvement of MBL2 variants in SLE clinical progression. The conflicting results shown by the analysis of patients grouped by ethnicity emphasise the need for studies considering this variable.

BACKGROUND

Cystic fibrosis is the most common lethal recessive disorder among Caucasians. Over 1500 mutations have been identified in cystic fibrosis transmembrane conductance regulator disease-gene so far. A large variability of the clinical phenotype has been observed both in cystic fibrosis patients bearing the same genotype, and in affected sibpairs. Thus, genes inherited independently from cystic fibrosis transmembrane conductance regulator could modulate the clinical expression of cystic fibrosis.

METHODS

We analysed some putative modifier genes of liver cystic fibrosis phenotype (serpin 1, hemochromatosis, transferrin receptor 2, ferroportin 1, mannose binding lectin and adenosine triphospate-binding cassette subfamily B member 4) in 108 unrelated cystic fibrosis patients with and without liver involvement.

RESULTS

HYPD mannose binding lectin haplotype was significantly (p<0.05) more frequent in cystic fibrosis patients with liver disease versus those without liver disease. This haplotype already related to a more severe pulmonary cystic fibrosis phenotype, is associated to a reduced MBL immunological activity. The c.834-66G>T variant of adenosine triphospate-binding cassette subfamily B member 4 gene was significantly (p<0.05) less frequent in cystic fibrosis patients with liver disease as compared to those with no liver disease.

CONCLUSIONS

The HYPD mannose binding lectin haplotype may predispose a subgroup of cystic fibrosis patients to a more severe liver involvement impairing the local defence mechanisms whereas the c.834-66G>T adenosine triphospate-binding cassette subfamily B member 4 variant may enhance the activity of the protein and thus exert a protective effect toward liver disease.

BACKGROUND

Mannose-binding lectin (MBL) and ficolin-2 (FCN) are activators of the lectin pathway of complement and act as primary defences against infection. Single-nucleotide polymorphisms (SNPs) in the MBL2 and FCN2 genes influence the functionality of the proteins. Both proteins are capable of binding staphylococci, which are pathogens that frequently cause peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD). We studied the role of polymorphisms in the MBL2 and FCN2 genes as a risk factor for developing CAPD peritonitis caused by staphylococci.

METHODS

We analysed SNPs in the MBL2 and FCN2 genes in 40 CAPD patients with staphylococcal peritonitis and in 65 CAPD patients without any history of peritonitis. Additionally, we analysed the prevalence of exit site infections and nasal Staphylococcus aureus carriage in both groups.

RESULTS

The + 6359C>> T SNP leading to the Thr236Met amino acid alteration in the FCN2 gene, associated with decreased substrate binding, was significantly more prevalent in CAPD patients with a history of staphylococcal peritonitis compared with patients on CAPD without a history of peritonitis (P = 0.037). No difference was found in MBL2 genotypes between the two groups. In CAPD patients with a history of staphylococcal peritonitis, exit site infection with S. aureus was also more prevalent (P < 0.01), while S. aureus carriage was not (P = 0.073).

CONCLUSIONS

In addition to known risk factors such as exit site infection, the + 6359C>> T SNP in the FCN2 gene might be a risk factor for staphylococcal peritonitis in CAPD patients due to decreased binding of FCN to staphylococci.