Mannose-binding lectin in pre-menopausal women with recurrent urinary tract infections

Mannose-binding lectin (MBL) comprises an oligomeric serum protein that is a member of the collectin class of the C-type lectin super-family. Its deficiency is genetically determined and confers predisposition to recurrent infections as well as increased infection severity. This correlation has been demonstrated in recurrent furunculosis caused by Staphylococcus aureus, and in pneumococcal and Candida infections. The present study aimed to determine whether there is a correlation between MBL serum levels and recurrent urinary tact infections (UTI) in pre-menopausal women. The present aged-matched double-blind controlled study was conducted in 100 pre-menopausal adult women: 50 who suffered from recurrent UTI and 50 without UTI. The MBL concentration was measured in a single serum sample from each patient using an enzyme-linked immunosorbent assay. MBL serum levels [median (range)] were 2500 (4–12 000) ng/mL and 2105 (4–22 800) ng/mL for the research and control groups, respectively. The results from the two groups were compared and were not statistically different (p 0.4). According to these results, MBL serum levels are not associated with an increased risk for recurrent UTI in pre-menopausal women.     

Mannose-binding lectin deficiency and miscarriages in rheumatoid arthritis

Objective: To investigate the association between mannose-binding lectin (MBL) serum level and MBL2 polymorphisms, and the frequency of spontaneous miscarriages in rheumatoid arthritis (RA) patients.

Methods: One hundred seventy seven women (mean age 50?years) with RA from Southern Brazil were studied and 4.5% had a history of abortion (8/177). The MBL levels were determined by ELISA. MBL2 polymorphisms in the promoter (?550H/L, ?221X/Y), 5′ untranslated region (4?P/Q) and exon 1 (p.Gly54Asp: B allele, p.Arg52Cys: D allele and p.Gly57Glu: C allele; collectively labelled O) were genotyped by sequencing.

Results: Mannose-binding lectin levels of RA patients ranged from ≤100?ng/mL to 6640?ng/mL (median 541.5?ng/mL). There was a significant difference in MBL median levels (100?ng/mL vs. 625?ng/mL, respectively, p?=?.001) and frequency of MBL deficiency (75.0% vs. 24.1%, p?=?.007, OR?=?10.3, 95%CI?=?1.9–55.4), in patients with a history of miscarriage vs those without it. Patients with RA and miscarriage had more frequently haplotypes related with low MBL levels (p?=?.007, OR?=?10.5, 95%CI?=?1.3–84) than high producers. Moreover, LYPB haplotype and O allele were significantly associated with the occurrence of miscarriage (p?=?.001, OR?=?9.7, 95%CI?=?2.4–39.1 and p?=?.009, OR?=?5.9, 95%CI?=?1.4–23.4, respectively).

Conclusions: The results suggest that MBL deficiency and the presence of MBL2 gene polymorphisms that lead to MBL deficiency are risk factors for the occurrence of miscarriage in patients with RA.     

Mannose-binding lectin alleles in sub-Saharan Africans and relation with susceptibility to infections

Mannose-binding lectin (MBL) plays an important role in the early stages of primary infections and during the decay of maternal antibodies in infants. Various studies have looked at the relation between serum MBL concentrations, MBL gene alterations and susceptibility to infections. We investigated the distribution of variant MBL alleles in 626 unrelated adults from sub-Saharan African countries and looked for a potential relation between these alleles and the incidence, prevalence and death rate of tuberculosis for sub-Saharan Africa. We also evaluated the relation between MBL genotypes and susceptibility to HIV-1 infection in 188 Gabonese adults. We found that (i) the prevalence of the common variant MBL alleles is correlated with the incidence of tuberculosis in sub-Saharan Africa (r=0.565), (ii) the mutant MBL G57E allele, in either the homozygous or compound heterozygous state, is associated with susceptibility to HIV-1 infection in the Gabonese population (P=0.019).Our data plus those in the literature suggest that individuals who are homozygous for the mutant MBL alleles display increased susceptibility to infections. Interestingly, we found that individuals who are heterozygous for MBL mutations are much less susceptible to infections than those who are homozygous for the wild-type MBL allele.     

Mannose-binding lectin deficiency does not appear to predispose to cryptococcosis in non-immunocompromised patients.

While most patients with cryptococcosis have obvious cellular immune deficiency, a minority have no apparent predisposing factors. However, in the latter there may be subtle innate immune system deficiencies which go unrecognized. Mannose-binding lectin (MBL) deficiency is associated with increased susceptibility to infectious diseases and may predispose to cryptococcosis, particularly when it disseminates to the central nervous system (CNS) in apparently immunocompetent patients. MBL function and levels, as well as MBL2 genotype were determined in 36 HIV-negative cryptococcosis patients (25 with CNS involvement) using C4 deposition and mannan-binding ELISA. MBL deficiency was defined using C4 deposition level < 0.2 U/microl or mannan-binding level < 0.5 microg/ml. MBL results were compared between patients with cryptococcosis and healthy controls and among the cryptococcosis patients according to the site of their disease. There was no difference in MBL function, mannan-binding level or increase in the frequency of MBL deficiency or low producing MBL2 genotypes in any of these comparisons. Patients with CNS cryptococcosis were no more likely to be MBL deficient than those with non-CNS disease. It appears that MBL deficiency is not associated with cryptococcosis in non-immunocompromised hosts. Beta errors consequent on the small number of patients studied may account for the lack of association.     

Mannose-binding lectin gene polymorphism predicts hospital admissions for COPD infections

Infection frequently causes exacerbations of chronic obstructive pulmonary disease (COPD). Mannose-binding lectin (MBL) is a pattern-recognition receptor that assists in clearing microorganisms. Polymorphisms in the MBL2 gene reduce serum MBL levels and are associated with risk of infection. We studied whether the MBL2 codon 54 B allele affected serum MBL levels, admissions for infective exacerbation in COPD and disease susceptibility. Polymorphism frequency was determined by PCR-RFLP in 200 COPD patients and 104 smokers with normal lung function. Serum MBL was measured as mannan-binding activity in a subgroup of 82 stable COPD patients. Frequency of COPD admissions for infective exacerbation was ascertained for a 2-year period. The MBL2 codon 54 B allele reduced serum MBL in COPD patients. In keeping, patients carrying the low MBL-producing B allele had increased risk of admission for infective exacerbation (OR 4.9, P(corrected)=0.011). No association of MBL2 genotype with susceptibility to COPD was detected. In COPD, serum MBL is regulated by polymorphism at codon 54 in its encoding gene. Low MBL-producing genotypes were associated with more frequent admissions to hospital with respiratory infection, suggesting that the MBL2 gene is disease-modifying in COPD. MBL2 genotype should be explored prospectively as a prognostic marker for infection risk in COPD.     

Mannose-binding lectin (MBL) in adult patients with inflammatory bowel disease

Inflammatory bowel disease (IBD) refers to disorders associated with progressive inflammatory processes in the gastrointestinal system. IBD consists of two major forms, Crohn’s disease (CD), and ulcerative colitis (UC). IBD became a global disease in the 21^st century. Its pathogenesis is still not fully understood. Mannose-binding lectin (MBL) is a pattern-recognising molecule, involved in anti-microbial and anti-cancer immunity. It is able to opsonize microorganisms and abnormal host cells, and to initiate complement activation. The aim of this study was to investigate possible involvement of MBL in inflammatory bowel disease in adults. Forty persons diagnosed with CD and 28 with ulcerative colitis were recruited. The control group consisted of 136 healthy persons. Single nucleotide polymorphisms of the MBL2 gene (localised to both promoter and exon 1) were determined as were serum MBL concentrations. The exon 1 variant alleles and MBL deficiency-associated genotypes were more frequent among patients compared with controls, although this difference was not statistically significant. No differences of MBL levels were found between the major groups. However in MBL2 A/A homozygous IBD patients, the median was significantly higher than in corresponding healthy subjects. That was particularly evident in the case of active Crohn’s disease (1493 ng/ml vs. 800 ng/ml, p = 0.021). It may suggest that MBL and MBL-dependent complement activation contributes to excessive inflammation and its adverse effects in the course of CD. It cannot also be excluded that high MBL activity constitutes in some cases part of a multifactorial network conducing to development of CD.     

Mannose-binding lectin deficiency influences innate and antigen-presenting functions of blood myeloid dendritic cells

Mannose-binding lectin (MBL) is a serum lectin that plays a significant role in innate host defence. Individuals with mutations in exon 1 of the MBL2 gene have reduced MBL ligand binding and complement activation function and increased incidence of infection. We proposed that, during infection, MBL deficiency may impact on dendritic cell (DC) function. We analysed the blood myeloid DC (MDC) surface phenotype, inflammatory cytokine production and antigen-presenting capacity in MBL-deficient (MBL-D) individuals and MBL-sufficient (MBL-S) individuals using whole blood culture supplemented with zymosan (Zy) or MBL-opsonized zymosan (MBL-Zy) as a model of infection. Zy-stimulated MDCs from MBL-D individuals had significantly increased production of interleukin (IL)-6 and tumour necrosis factor (TNF)-α. Stimulation with MBL-Zy significantly decreased IL-6 production by MDCs from MBL-D, but had no effect on TNF-α production. MDCs from both MBL-S and MBL-D individuals up-regulated expression of the activation molecule CD83, and down-regulated expression of homing (CXCR4), adhesion (CD62L, CD49d) and costimulatory (CD40, CD86) molecules in response to Zy and MBL-Zy. MDC from both MBL-D and MBL-S individuals induced proliferation of allogeneic (allo) T cells following Zy or MBL-Zy stimulation; however, MBL-D individuals demonstrated a reduced capacity to induce effector allo-T cells. These data indicate that MBL deficiency is associated with unique functional characteristics of pathogen-stimulated blood MDCs manifested by increased production of IL-6, combined with a poor capacity to induce effector allo-T-cell responses. In MBL-D individuals, these functional features of blood MDCs may influence their ability to mount an immune response.     

Mannose-binding lectin exon 1 polymorphisms in Egyptian patients with chronic hepatitis C virus infection

Persistent infection with hepatitis C virus (HCV) is a major cause of liver cirrhosis and subsequently liver cancer. Mannose-binding lectin 2 (MBL2) plays an important role in innate immunity, and its genetic polymorphisms are associated with deficient serum level of MBL2 and with frequent and prolonged infections. This study was undertaken to investigate the association between polymorphisms of MBL2 gene and hepatitis C virus infection and its association with response to treatment. We determined MBL2 gene polymorphism within exon 1 in 51 Egyptian patients with chronic hepatitis C virus infection and 49 healthy blood donors. MBL2 gene mutations were determined by means of polymerase chain reaction and restriction fragment length polymorphism analysis. Codons 52 and 54 mutant genotypes were significantly lower in HCV cases: odds ratio (OR) 0.28, 95 % confidence interval (CI) 0.10 to 0.76, p?=?0.012; and OR 0.15, 95 % CI 0.04 to 0.55, p?=?0.004, respectively. While codon 57 mutant genotypes were significantly higher in HCV cases: OR 4.54, 95 % CI 1.56 to 13.23, and p?=?0.006. MBL2 mutant genotypes at codons 52 and 54 are a protective factor for HCV infection, while MBL2 mutant genotypes at codon 57 are a risk factor for HCV infection. MBL2 D allele at codon 52 and B allele at codon 54 are a protective factor for HCV infection, while C allele at codon 57 is a risk factor for HCV infection.     

Mannose-binding lectin polymorphisms in common variable immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by hypogammaglobulinemia and increased susceptibility to infections, autoimmunity and malignancies. This study was performed to analyze the Mannose-binding lectin (MBL) polymorphisms in Iranian patients with CVID. Thirty-five CVID patients who were treated at Children’s Medical Center and 100 matched controls were enrolled in this study. Sixth single-nucleotide polymorphisms of the MBL gene were analyzed using PCR–SSP method. Comparison of MBL exon 1 coding alleles between patients and controls revealed that A allele (wild-type) was significantly decreased in CVID group, whereas B allele was overrepresented in the patient group. High frequency of heterozygous (A/O) in the patient group and high frequency of homozygous for wild-type coding regions in the control group were detected. Comparison of MBL haplotype promoters between CVID patients and controls showed that LYPB haplotype was significantly overrepresented in the CVID group. Mutant and low-producing MBL alleles and haplotypes might reflect as an associated genetic factor in CVID patients, which could play as a susceptibility factor in CVID.     

Mannose-binding lectin genotype and serum levels in patients with chronic and allergic pulmonary aspergillosis

Several studies suggest mannose-binding lectin (MBL) deficiency is associated with various manifestations of aspergillosis. MBL serum levels and function are genetically determined, but levels rise during inflammation. We address the relative frequency of deficient genotypes, the relationship between serum level and genotype and both age and disease manifestations in patients with chronic pulmonary (CPA) and allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS). DNA was extracted from blood samples, and MBL2 genotyping was performed using the INNO-LiPA MBL2 kit. Serum MBL concentrations were determined using ELISA. One hundred and eight patients were evaluated, 70 (65%) with CPA, 38 (35%) with allergic disease (ABPA, SAFS or undefined) and 13 (12%) had both CPA and ABPA. The mean MBL serum level was 1849 μg L(-1) and did not differ between groups. Forty subjects (37%) had exon 1 genotypes producing nonfunctional MBL (A/B, A/C, A/D and O/O), a frequency not different from published normal controls. A/A subjects with CPA had higher levels (2981 μg L(-1)) compared with allergic A/A subjects (2202 μg L(-1)) (pc0.012). No single haplotype, genotype or allele was significantly related to any aspergillosis phenotype. Worse breathlessness was associated with higher MBL levels among A/A subjects (P = 0.009) and conversely nonfunctional genotypes. Mean MBL values were higher in those with an Medical Research Council (MRC) breathlessness score of 5 compared with those with and MRC score of 1 (P = 0.023). A/A allergic subjects (n = 27) in this study were ≈ 11 years younger than allergic A/O subjects (n = 11, P = 0.02). Subjects with worse respiratory status or more severe CPA had higher MBL serum levels (P = 0.023; P = 0.034). Bronchiectasis was not associated with MBL levels in CPA or allergic aspergillosis. MBL genotype and serum level modulate progression of aspergillosis.     

Mannose-binding lectin deficiency linked to cytomegalovirus (CMV) reactivation and survival in lung transplantation

Despite the use of immunosuppressives mainly influencing T and B cell responses, the prevalence of the bronchiolitis obliterans syndrome (BOS) after lung transplantation is high. Mannose-binding lectin (MBL) is a pattern recognition molecule of complement and an important component of the innate immunity. MBL is associated with rejection, infection and survival in other solid organ transplantations. In this study the relation between functional MBL levels and cytomegalovirus (CMV) reactivations and the development of BOS and survival after lung transplantation was investigated. MBL levels were measured in 85 patients before and in 57 of these patients after lung transplantation. The relation of MBL on survival, CMV reactivation and the development of BOS were investigated with Kaplan-Meier (log-rank) survival analysis. MBL levels decreased on average by 20% (P < 0·001) after transplantation and eventually returned to pretransplant levels. Fourteen of the 85 patients had deficient pretransplant MBL levels and these patients had a tendency towards a better survival compared to those with normal MBL levels (P = 0·08). Although no correlation was found between MBL deficiency and the development of BOS, more CMV reactivations occurred in recipients with deficient versus normal levels of MBL (P = 0·03). Our results suggest that MBL deficiency is associated with CMV reactivations and a longer overall survival, but not with the development of BOS.     

Mannose-binding lectin (MBL) as prognostic factor in paediatric oncology patients

Deficiency of mannose-binding lectin (MBL) has been suggested to influence duration of febrile neutropenia and prognosis in paediatric oncology patients. However, there is no consensus on the definition of MBL deficiency. In a cohort of children with cancer, we investigated (i) how to determine MBL deficiency and (ii) whether MBL is a prognostic factor for disease severity. In 222 paediatric oncology patients, 92 healthy children and 194 healthy adults, MBL plasma levels and MBL2 genotype (wild-type: A, variant: O) were determined. Event-free survival (EFS), overall survival (OS) and paediatric intensive care unit (PICU) admissions were recorded prospectively. In febrile neutropenic patients admitted to the PICU, disease severity was assessed by clinical, microbiological and laboratory parameters. An optimal cut-off value for MBL deficiency was determined to be < 0·20 μg/ml. Wild-type MBL2 genotype patients, including the XA/XA haplotype, had increased MBL levels compared to healthy individuals. MBL deficiency was associated with decreased EFS (P = 0·03), but not with need for PICU admission. A trend for a twice increased frequency of septic shock (80% versus 38%, P = 0·14), multiple organ failure (40% versus 17%, P = 0·27) and death (40% versus 21%, P = 0·27) was observed in the absence of microbiological findings. MBL deficiency was associated with decreased EFS and possibly with an increased severity of disease during PICU admission after febrile neutropenia in the absence of any association with microbiological findings. These findings suggest prognosis to be worse in MBL-deficient compared to MBL-sufficient paediatric oncology patients.     

Mannose-binding lectin (MBL2) polymorphisms and inflammation in hypertensive patients

We investigated the possible role of Mannose binding lectin 2 (MBL2) functional polymorphisms in the prevalence of hypertension and hypertensive end-organ damage in 300 hypertensive patients and 313 normotensive individuals from Southern Brazil. Hypertensive subjects with MBL2 AO/OO genotypes presented lower C-reactive protein levels than AA individuals and consequently lower inflammatory status.     

Mannose-binding lectin engagement with late apoptotic and necrotic cells

The serum opsonin mannose-binding lectin (MBL) has been shown to be involved in the handling of apoptotic cells. However, at what stage in the process this happens and whether this mediates activation of complement is unknown. Cells rendered apoptotic or necrotic were incubated with purified MBL/MBL-associated serine protease (MASP) complexes and assessed by flow cytometry and fluorescence microscopy. MBL bound specifically to late apoptotic cells, as well as to apoptotic blebs and to necrotic cells, but not to early apoptotic cells. Binding of MBL could be inhibited by EDTA as well as with an antibody against the CRD region. Addition of C1q, another serum opsonin involved in the handling of apoptotic cells, prior to MBL partly inhibited MBL binding to apoptotic cells and vice versa. MBL/MASP could initiate deposition of purified complement C4 on the target cells. However, addition of MBL/MASP to whole serum deficient for both C1q and MBL did not enhance deposition of C4, but MBL enhanced phagocytosis of apoptotic cells by macrophages. These results demonstrate that MBL interacts with structures exposed on cells rendered late apoptotic or necrotic and facilitates uptake by macrophages. Thus, MBL may promote non-inflammatory sequestration of dying host cells.     

单纯性热性惊厥患儿血浆甘露糖结合凝集素水平分析

了解单纯性热性惊厥患儿血浆甘露糖结合凝集素(MBL)水平。对2010年8月至2011年7月住院的61例单纯性热性惊厥患儿,采集急性期与恢复期全血标本各一份,同时收集来院参加入托体检的健康儿全血标本90份,应用ELISA法检测血浆MBL浓度。统计分析采用SPSS软件11.0版。结果显示,疾病组急性期和恢复期血浆MBL浓度分别为(610.4±549.6)ng/ml和(591.5±442.1)ng/ml,二者无显著性差异(Z=0.16,P=0.87),但疾病组急性期(Z=2.23,P=0.03)和恢复期(Z=2.03,P=0.04)血浆MBL浓度均显著低于对照组(765.9±559.9)ng/ml,疾病组血浆MBL浓度低于200ng/ml的个体显著多于对照组(χ2=10.84,P<0.01)。CRP与MBL值间无明显相关性。提示,血浆MBL水平低下导致机体易患呼吸道感染可能是本组大部分患儿发生热性惊厥的潜在诱因。     

Circulating immune complexes in patients with Candida albicans infections

The existence of circulating immune complexes in patients with candidiasis has been suggested but not confirmed. In this study we have used four immune complex screening techniques (direct nephelometry, Clq binding assay, PEG-IgG assay and PEG-C4 assay) and an immune complex score compiled from results of the individual tests to establish that elevated levels of immune complexes do exist in a series of 11 patients with systemic candidiasis as compared with a group of 18 normal controls. Isolation and characterization of high molecular weight fractions from the sera of five patients with candidiasis and further purification by affinity chromatography on Sepharose 4B-protein A substantiated the presence of anti-Candida antibody and/or Candida antigen in at least three of them. The presence of complement components and IgG in these fractions further supported the existence of immune complexes containing microbial antigen and antibody.