Mannan-binding Lectin Levels Research Articles

Association of MBL2 polymorphism with Leg Ulcers Development in Sickle Cell Anemia Patients

Leg ulcers are the most common clinical manifestations of sickle cell anemia (SCA), a monogenic disease with huge clinical diversity among patients. They affect 8% to 10% of SCA patients, reaching a percentage greater than 50% in patients residing in tropical areas. These ulcers occur due to vascular occlusion, tissue hypoxia, hemolysis and genetic factors, presenting a slow healing, high recurrence rate and huge susceptibility to infection. Recently, some studies have shown a positive relationship between the complement system and the development of some vascular diseases and injuries such as leg ulcers in non-SCA patients. Mannan-binding lectin (MBL) is an important component of the humoral innate immune system, and MBL possesses several characteristics indicating that it may play an essential role in wound healing; modulating inflammation and contributing to the clearance of microorganisms and apoptotic cells. In a recent study of chronic leg and foot ulcer patients, serum MBL levels were significantly different between wounds of different etiologies, with chronic venous leg ulcers patients having a higher frequency of MBL deficiency. Polymorphisms in the MBL2 are associated with a reduction in the MBL protein serum levels, increasing risk of developing leg ulcers and also the maintenance of these wounds, compromising the integrity of the immune defence and its response to potential invading pathogens. Here, we aimed to determine the frequency of polymorphisms in the promoter region -221 (Y / X) and -550 (H / L) and exon 1 of the MBL2 and assess the clinical impact of these variants in a northeastern Brazilian SCA population who presented leg ulcers. Two-hundred seventy-five unrelated SCA patients were included. According the leg ulcers presence, the total cohort was classified in patients presenting current or prior history of leg ulcers (n=100) and SCA patients above 18 years with no history of leg ulcers (n=175). Molecular analysis was performed by qPCR. Our population was in Hardy-Weinberg equilibrium. The allelic frequency of haplotypes associated with high MBL production (HYA, LYA) was 54.5% for cases and 62.9% in controls. The genotypes related to low MBL production (HYO, LYO) in cases and controls was 27.5% and 18.6%, respectively. The frequency of genotype related to intermediate MBL production (LXA) was 18% in cases and 18.5% in controls. We had no statistically significant results when we analyzed only the polymorphisms (P>0.05). However, the phenotypic analysis between high and low MBL production revealed that patients with leg ulcers have lower MBL protein levels (P=0.019). We focused specifically on a possible role of MBL deficiency on healing complications, based on the facts that MBL deficiency is the most common immune disorder, and that a common causality for prolonged healing of these ulcers is infection or colonization by bacteria. In our study, MBL deficiency appears to increase the risk of developing leg ulcers in SCA patients. DisclosuresNo relevant conflicts of interest to declare.

Circulating mannan-binding lectin, M-, L-, H-ficolin and collectin-liver-1 levels in patients with acute liver failure.

The complement system is activated in liver diseases including acute liver failure (ALF); however, the role of the lectin pathway of complement has scarcely been investigated in ALF. The pathway is initiated by soluble pattern recognition molecules: mannan-binding lectin (MBL), M-, L-, and H-ficolin and collectin-liver-1 (CL-L1), which are predominantly synthesized in the liver. We aimed to study lectin levels in ALF patients and associations with clinical outcome. Serum samples from 75 patients enrolled by the US ALF Study Group were collected on days 1 and 3. We included 75 healthy blood donors and 20 cirrhosis patients as controls. Analyses were performed using sandwich-type immunoassays (ELISA, TRIFMA). At day 1, the MBL level in ALF patients was 40% lower compared with healthy controls {[median (interquartile range) 0.72 μg/ml(0.91) vs. 1.15 (1.92)(P = 0.02]}, and increased significantly by day 3 [0.83 μg/ml(0.94)(P = 0.01)]. The M-ficolin level was 60% lower [0.54 μg/ml(0.50) vs. 1.48(1.01)(P < 0.0001)]. The CL-L1 level at day 1 was slightly higher compared with healthy controls [3.20 μg/ml(2.37) vs. 2.64(0.72)(P = 0.11)]; this was significant at day 3 [3.35(1.84)(P = 0.006)]. H- and L-ficolin levels were similar to healthy controls. Spontaneous ALF survivors had higher levels of MBL at day 1 [0.96 μg/ml(1.15) vs. 0.60(0.60)(P = 0.02)] and lower levels of L-ficolin by day 3 compared with patients who died or were transplanted [1.61 μg/ml(1.19) vs. 2.17(2.19)(P = 0.02)]. We observed significant dynamics in lectin levels in ALF patients, which may suggest they play a role in ALF pathogenesis. High MBL and low L-ficolin levels are associated with survival.

Mannan-binding lectin polymorphisms and serum levels in patients with endometriosis

ObjectiveTo investigate a possible association between endometriosis and low levels of mannan-binding lectin (MBL). Study designCase-control study of blood samples from 100 patients with endometriosis compared with results from a group of 350 blood donors. ResultThe frequency of MBL levels <100ng/ml was 14.0% in patients and 14.9% in controls. Correspondingly, the frequencies of low producing MBL genotypes were 15.0% and 16.0%, respectively. ConclusionNo association was found between endometriosis and low levels of MBL.

Changes in the levels of mannan-binding lectin and ficolins during head-down tilted bed rest.

Spaceflight studies and ground-based analogues of microgravity indicate a weakening of human immunity. Mannan-binding lectin (MBL) and H-, L-, and M-ficolin together constitute the lectin pathway and mediate the clearance of pathogens through complement activation. We hypothesized that simulated microgravity may weaken human innate immune functions and studied the impact of 6° head-down tilted bed rest (HDT) for 21 d on MBL and ficolin levels. Within a 6-mo period, seven men underwent two periods of HDT. Blood samples were analyzed for MBL, H-, L-, and M-ficolin, mannose-binding lectin-associated protein of 44 kDa (MAp44), and collectin liver 1 (CL-L1) by time-resolved immunofluorometric assays (TRIFMA). We observed well-defined individual preintervention levels of MBL and ficolins. Remarkably similar intraindividual changes occurred for MBL and MBL levels decreased (mean 282 ng · ml⁻¹) in the recovery phase. Conversely, CL-L1, a protein with MBL-like properties, increased (mean 102 ng · ml⁻¹) during the recovery phase. M-ficolin increased (mean 79 ng · ml⁻¹) within the first 2 d of HDT, followed by a decrease (mean 112 ng · ml⁻¹) during the recovery phase. L-ficolin increased (mean 304 ng · ml⁻¹) during HDT, while H-ficolin was essentially unaffected. MAp44, a down-regulator of the lectin pathway, decreased initially (mean 78 ng · ml⁻¹) in the recovery phase followed by an increase (mean 131 ng · ml⁻¹). Alterations in MBL and ficolin levels were modest and with our current knowledge do not lead to overt immunodeficiency. Pronounced changes occurred when the subjects resumed the upright position. In selected individuals, these changes appear to be a conserved response to HDT.

Elevated MBL Levels in Type 1 Diabetic Patients Are Reversed After Simultaneous Pancreas-Kidney Transplantation.

Aim: High levels of circulating Mannan-binding lectin (MBL) are associated with the development of diabetic nephropathy (DN). MBL is an essential component of the acute-phase immune response and initiates the lectin pathway of complement upon binding sugar moieties. In animals, an injurious effect of MBL on diabetic kidney changes has been observed and vasculopathy resulting from hyperglycemia has been shown to be dependent on MBL and lectin complement pathway activation. In humans, the effect of diabetic control on circulating levels of MBL has not been studied so far. Simultaneous pancreas-kidney transplantation (SPK) is an advanced treatment option for type I diabetes (T1D) patients with diabetic nephropathy. By assessing MBL in healthy control subjects and T1D patients before and following SPK, we studied the effect of T1D and SPK on the circulating levels of MBL. Methods: Circulating MBL levels were assessed using sandwich ELISA in plasma of DN (n=21) and SPK patients (n=37), healthy controls (n=19) and DM1 patients (n=15, DM ≥ 40 mL/min). To differentiate between diabetic control and renal failure as possible causes for change in the MBL levels, a subgroup of DN patients receiving a kidney but no pancreas transplant (n=15) were included. In addition, MBL levels were correlated with Hba1c and glucose levels. Results: We found significant elevated levels of MBL in plasma of DN patients compared to healthy controls. MBL levels in DN patients with a normal kidney function were also elevated, although not significant. MBL levels in patients receiving a SPK completely normalized compared to healthy controls. In contrast, MBL levels in DN patient receiving only a kidney transplant remained elevated, suggesting that diabetic control but not reversal of renal failure is associated with a decrease in circulating MBL. In line, glucose levels and Hba1C, but not creatinine levels in DN patients were significantly correlated with levels of MBL. Of interest, we also found a significant correlation between the plasma level of MBL and the duration of T1D before a SPK was needed, suggesting that elevated levels of MBL accelerate the disease progress. Conclusion: In short, we demonstrated that circulating levels of MBL are elevated in DN patients and normalized after SPK. The normalization of MBL levels was independent of renal function, but dependent on diabetic control.

Complement Profile in Neonates of Different Gestational Ages

Blood levels of regulators of the complement system in preterm babies were reported in few studies only. The aim of this study was to set up a complement profile in premature and term babies focusing on the development of blood levels of MBL, key regulatory proteins and on classical pathway activity, which may allow an estimation of potential susceptibility to infection. Complement activity (CH50), levels of mannan-binding lectin (MBL), complement regulators (factors H and I, C1 inhibitor, properdin) and C3a as marker of complement activation were assessed in three groups of healthy newborns: (1) prematures (≤34 weeks); (2) late prematures (>34-<37 weeks) and (3) term neonates (≥37 weeks). CH50 increased with gestational age with lower titres in cord blood than in day 5 post-delivery venous blood. MBL concentrations were not significantly different among groups. Quantitative and functional C1 inhibitor were below adult normal range in prematures <34 weeks and lower in cord blood as compared to day 5. Factor I, factor H and properdin remained below adult values in all groups. Low C3a levels excluded that low complement titres were due to activation-induced consumption. These results demonstrate the relative immaturity of the complement system and its regulation, especially in premature infants.

Collectins, C3 complement protein, annexin V and C-reactive protein in acute ischemic stroke: interrelation and implication to upregulated apoptosis and inflammation

Upregulated inflammatory response and apoptosis, both triggered by ischemia, are the most destructive pathologic processes developed after acute ischemic stroke (IS) at both central and peripheral levels. Identification of molecular mediators of these processes and understanding of their pathomechanisms will support the development of therapies, which can significantly improve outcomes of IS-affected subjects. Mannan-binding lectin (MBL), ficolin L (FL), ficolin H (FH) and C3 complement proteins participate in apoptotic cells recognition and clearance through various mechanisms. In the present study we performed comparative determination of the blood levels of MBL, FL and FH, and hemolytic activity of C3 protein (C3H50) as well as apoptosis marker protein, circulating annexin V (cANXV), and inflammatory marker C-reactive protein (CRP) in 99 patients with acute IS on the first day of stroke onset and 110 healthy subjects. Potential circulating correlation between all measured parameters was analyzed. Methods included enzyme-linked immunosorbent, hemolytic, and immunonephelometric assays; statistics were performed by Student's t-test and Pearson's correlation analysis. The obtained data demonstrated significantly increased and correlated with each other blood levels of MBL and C3H50, cANXV and CRP in patients compared to controls. Slight, while significant, changes in the blood levels of FL and FH were also observed. We concluded that post-ischemic response at the first day of IS onset is characterized by sufficiently elevated and positively correlated with each other blood levels of MBL, C3H50, cANXV and CRP as well as by slightly increased blood levels of FH and FL. The obtained results suggest that MBL and C3 are implicated in upregulated inflammatory response and apoptosis developed after IS onset at a peripheral level, and that these pathological processes are interrelated and interdependent.

Association between Low Levels of Mannan-Binding Lectin and Markers of Autoimmune Thyroid Disease in Pregnancy

Functional deficiency of mannan-binding lectin (MBL) has been associated with adverse pregnancy outcome. Adverse events during pregnancy have also been described in women with autoimmune thyroid diseases (AITD), and thyroid hormones have been shown to influence serum levels of MBL. Therefore, the aim of this study was to analyse the impact of MBL-deficiency on the outcome of pregnancy in relation to the presence of AITD. Almost one year after delivery, we assessed serum MBL levels and MBL2-genotypes in 212 women positively screened for AITD in pregnancy. In 103 of these women, we could also measure MBL levels in frozen serum samples from the 9-12th gestational week, obtaining 96 pairs of MBL values (pregnancy vs. follow-up). As controls, 80 sera of pregnant women screened negatively for AITD were used. MBL2-genotyping was performed using multiplex PCR. Women with thyroid dysfunction and/or thyroid peroxidase antibodies (TPOAb) had lower MBL levels during pregnancy than controls, (3275 vs. 5000 ng/ml, p<0.05). The lowest levels were found in women with elevated thyroid-stimulating hormone (TSH) levels in the absence of TPOAb (2207 ng/ml; p<0.01 as compared to controls). MBL2 genotype distribution did not differ between subgroups. At a median follow-up period of 17 months (range: 3–78 months) after delivery, median MBL level had decreased further to 1923 ng/ml (p<0.0001) without significant changes in TSH. In an explorative survey, functional MBL-deficiency was neither linked to a history of spontaneous abortion, nor other obstetric complications, severe infections throughout life/pregnancy or antibiotics use in pregnancy. In conclusion, hypothyroidism during pregnancy is associated with decreased MBL levels, and the levels decreased further after delivery.

The lectin pathway of the complement system is downregulated in Crohn's disease patients who respond to anti-TNF-α therapy

Background and aimsThe lectin pathway of the complement system is initiated through the recognition of pathogens or altered self-structures by mannan-binding lectin (MBL) or ficolins and subsequent activation of MBL-associated serine proteases (MASPs). Altered ficolin levels may contribute to a dysregulated immune response in Crohn's disease (CD). A complete analysis of the lectin pathway has not been performed in patients with CD. We hypothesised that the lectin pathway proteins exacerbate inflammation in CD. MethodsWe assessed the lectin pathway proteins in 43 patients with active CD & 350 blood donors by measuring the serum levels of MBL; M-, H-, and L-ficolin; MASP-2; MASP-3; and MAp44. In patients with CD, the blood samples were obtained during induction treatment with infliximab or adalimumab. ResultsOf 43 patients with CD, 32 (74%) were classified as responders. We observed a nearly 50% decrease in median M-ficolin levels between day 0 and weeks 1/7 in the responders (p<0.001), whereas there was no decrease in the non-responders. MASP-2 levels decreased from baseline to week 1 in both the responders (37%, p<0.0001) and the non-responders (29%, p=0.02). In the responders only, the level of the inhibitory serine protease MASP-3 increased by 26% from baseline to week 1 (p<0.001) and remained high at week 7. ConclusionsOur findings indicated that M-ficolin, MASP-2, and MASP-3 may act in concert to reduce the activity of the lectin pathway, in patients with CD who respond to biological therapy.

Plasma levels of mannan-binding lectin (MBL)-associated serine proteases (MASPs) and MBL-associated protein in cardio- and cerebrovascular diseases

Growing evidence suggests a prominent role of the complement system in the pathogenesis of cardio- and cerebrovascular diseases (CVD). Mannan-binding lectin-associated serine proteases (MASPs) MASP-1 and MASP-2 of the complement lectin pathway contribute to clot formation and may represent an important link between inflammation and thrombosis. MBL-associated protein MAp44 has shown cardioprotective effects in murine models. However, MAp44 has never been measured in patients with CVD and data on MASP levels in CVD are scarce. Our aim was to investigate for the first time plasma levels of MAp44 and MASP-1, -2, -3 concomitantly in patients with CVD. We performed a pilot study in 50 healthy volunteers, in stable coronary artery disease (CAD) patients with one-vessel (n = 51) or three-vessel disease (n = 53) and age-matched controls with normal coronary arteries (n = 53), 49 patients after myocardial infarction (MI) and 66 patients with acute ischaemic stroke. We measured MAp44 and MASP-1 levels by in-house time-resolved immunofluorometric assays. MASP-2 and MASP-3 levels were measured using commercial enzyme-linked immunosorbent assay kits. MASP-1 levels were highest in subacute MI patients and lowest in acute stroke patients. MASP-2 levels were lower in MI and stroke patients compared with controls and CAD patients. MASP-3 and MAp44 levels did not differ between groups. MASP or MAp44 levels were not associated with severity of disease. MASP and MAp44 levels were associated with cardiovascular risk factors including dyslipidaemia, obesity and hypertension. Our results suggest that MASP levels may be altered in vascular diseases. Larger studies are needed to confirm our results and elucidate the underlying mechanisms.

Diabetes‐induced Changes in Mannan‐binding Lectin Levels and Complement Activation in a Mouse Model of Type 1 Diabetes

Circulating mannan-binding lectin (MBL) levels are elevated in type 1 diabetes. Further, high MBL levels are associated with the development of diabetic nephropathy. In animals, a direct effect of MBL on diabetic kidney changes is observed. We hypothesized that MBL levels and detrimental complement activation increase as a consequence of diabetes. We measured plasma MBL before and 7 weeks after inducing diabetes by streptozotocin. Mice have two MBLs, MBL-A and MBL-C. Diabetes induction led to an increase in MBL-C concentration, whereas no change during the study was found in the control group. The increase in MBL-C was associated with the increasing plasma glucose levels. In accordance with the observed changes in circulating MBL levels, liver expression of Mbl2mRNA (encoding MBL-C) was increased in diabetes. Mbl1expression (encoding MBL-A) did not differ between diabetic and control animals. The estimated half-life of recombinant human MBL was significantly prolonged in mice with diabetes compared with control mice. Complement activation in plasma and glomeruli did not differ between groups. We demonstrate for the first time that MBL levels increase after induction of diabetes and in parallel with increasing plasma glucose. Our findings support the previous clinical observations of increased MBL in type 1 diabetes. This change may be explained by alternations in both MBL production and turnover.

Low Levels of Mannan-Binding Lectin or Ficolins Are Not Associated with an Increased Risk of Cytomegalovirus Disease in HIV-Infected Patients

BackgroundIn HIV-infected patients, prediction of Cytomegalovirus (CMV) disease remains difficult. A protective role of mannan-binding lectin (MBL) and ficolins against CMV disease has been reported after transplantation, but the impact in HIV-infected patients is unclear.MethodsIn a case-control study nested within the Swiss HIV Cohort Study, we investigated associations between plasma levels of MBL/ficolins and CMV disease. We compared HIV-infected patients with CMV disease (cases) to CMV-seropositive patients without CMV disease (controls) matched for CD4 T-cells, sampling time, and use of combination antiretroviral therapy. MBL and M-ficolin, L-ficolin, and H-ficolin were quantified using ELISA.ResultsWe analysed 105 cases and 105 matched controls. CMV disease was neither associated with MBL (odds ratio [OR] 1.03 per log10 ng/mL increase (95% CI 0.73–1.45)) nor with ficolins (OR per log10 ng/mL increase 0.66 (95% CI 0.28–1.52), 2.34 (95% CI 0.44–12.36), and 0.89 (95% CI 0.26–3.03) for M-ficolin, L-ficolin, and H-ficolin, respectively). We found no evidence of a greater association between MBL and CMV disease in patients with low CD4 counts; however in the multivariable analysis, CMV disease was more likely in patients with an increased HIV RNA (OR 1.53 per log10 copies/mL; 95% CI 1.08–2.16), or a shorter duration of HIV-infection (OR 0.91 per year; 95% CI 0.84–0.98).ConclusionsCMV disease is not associated with low levels of MBL/ficolins, suggesting a lack of a protective role in HIV-infected patients.

Low levels of mannan-binding lectin or ficolins are not associated with an increased risk of cytomegalovirus disease in HIV-infected patients – A case–control study nested within the Swiss HIV Cohort Study

Low levels of mannan-binding lectin or ficolins are not associated with an increased risk of cytomegalovirus disease in HIV-infected patients – A case–control study nested within the Swiss HIV Cohort Study

MBL and MASP-2 concentrations in serum and MBL2 promoter polymorphisms are associated to schizophrenia.

Objective:Causative relations between infections and psychosis, especially schizophrenia, have been speculated for more than a century, suggesting a hypothesis of association between schizophrenia and hereditary immune defects. Mannan-binding lectin (MBL) is a pattern-recognition molecule of the innate immune defence. MBL deficiency is the most common hereditary defect in the immune system and may predispose to infection and autoimmunity. Mannan-binding lectin serine protease-2 (MASP-2) is an MBL-associated serine protease mediating complement activation upon binding of MBL/MASP to microorganisms. The objective was to investigate if schizophrenia is associated with serum concentrations of MBL and MASP-2 or with genetic variants of the genesMBL2andMASP2encoding these proteins.Methods:The sample consisted of 100 patients with schizophrenia and 350 controls. Concentrations of MBL and MASP-2 in serum were measured and seven single nucleotide polymorphisms known to influence these concentrations were genotyped.Results:Significant association of disease with genetic markers was found inMBL2but not inMASP2. Significant difference in MBL serum concentration was found between patients and controls when adjusting forMBL2haplotypes. For concentrations of MASP-2, a significant interaction effect between aMASP2variant and disease was found. Interestingly, MASP-2 levels also depended significantly on variants inMBL2exon 1.Conclusion:This study supports previous studies showing increased complement activity in patients with schizophrenia, indicates aetiological heterogeneity among patients and underlines that multilocus genotypes have to be considered when investigating effects on MBL level. It appears that inclusion of additional components from the system of complement activation is warranted.

Effects of interferon-beta therapy on elements in the antiviral immune response towards the human herpesviruses EBV, HSV, and VZV, and to the human endogenous retroviruses HERV-H and HERV-W in multiple sclerosis

Effects of treatment of multiple sclerosis patients with IFN-β on elements of the antiviral immune response to herpesviruses were analysed in a longitudinal study. We found significantly increased seroreactivity to EBV EBNA-1, and to VZV, in patients who did not respond to IFN-β therapy. We found no significant changes in seroreactivity to EBV EA, or to HSV. For the same patient cohort, we have previously demonstrated significant decreases in seroreactivities to envelope antigens for the two human endogenous retroviruses HERV-H and HERV-W, closely linked to efficacy of therapy.We further searched for correlations between seroreactivities to EBV, HSV, and VZV, and levels of mannan-binding lectin (MBL), and MBL-associated serine protease 3. We found no such correlations.Our results are in accord with recent reports of increased seroreactivity to EBV EBNA-1, and to VZV in active MS, and they support that the herpesviruses EBV and VZV together with HERV-H/HERV-W and the antiviral immune response may play a role in MS development.

Mannan-Binding Lectin Mediates Renal Ischemia/Reperfusion Injury Independent of Complement Activation

Ischemia/reperfusion injury (IRI) remains a major problem in renal transplantation. Clinical studies have identified that high serum levels of Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, are associated with inferior renal allograft survival. Using a rat model, we identified an entirely novel role for MBL in mediating renal IRI. Therapeutic inhibition of MBL was protective against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. Following reperfusion, exposure of tubular epithelial cells to circulation-derived MBL resulted in internalization of MBL followed by the rapid induction of tubular epithelial cell death. Interestingly, this MBL-mediated tubular injury was completely independent of complement activation since attenuation of complement activation was not protective against renal IRI. Our identification that MBL-mediated cell death precedes complement activation strongly suggests that exposure of epithelial cells to MBL immediately following reperfusion is the primary culprit of tubular injury. In addition, also human tubular epithelial cells in vitro were shown to be susceptible to the cytotoxic effect of human MBL. Taken together, these data reveal a crucial role for MBL in the early pathophysiology of renal IRI and identify MBL as a novel therapeutic target in kidney transplantation.

Defective activities, but not secretions, resulting from gene point mutations of human mannan-binding lectin

Human mannan-binding lectin (MBL) plays a pivotal role in innate immunity. Substantial literature supports the belief that three point mutations, CGT52TGT, GGC54GAC and GGA57GAA, in the collagen-like region (CLR) of the human MBL gene, are associated with increased susceptibility to infection, autoimmunity and carcinogenesis. To investigate the mechanisms of MBL deficiency, human wild-type and three variant MBL genes were expressed in COS-7 and Chinese hamster ovary (CHO) cells. Results showed that no apparent differences were found among the levels of gene transcription and protein secretion of four forms of MBL. However, the degree of oligomerization of variant forms of MBL was found to be much lower than that of recombinant human wild-type MBL. The ability of variant MBL proteins to bind mannan was much weaker than that of the wild-type MBL protein, and the MBL variants failed to effectively activate the complement lectin pathway. These data suggested that a lower order oligomer, but not decreased plasma levels of MBL, may be the main result of MBL gene mutations and may be associated with immunodeficiency.

M-ficolin levels are associated with the occurrence of severe infections in patients with haematological cancer undergoing chemotherapy

The pattern recognition molecules H-ficolin, L-ficolin and M-ficolin bind to micro-organisms. They activate the lectin pathway of complement through mannan-binding lectin (MBL)-associated serine proteases (MASPs). Association between low MBL levels and infections in patients undergoing chemotherapy for haematological diseases has been observed previously. We now examine for MASP-2, MASP-3 and ficolin levels. We assessed the concentration of lectin pathway molecules as risk factors for infection in patients with haematological malignancy undergoing chemotherapy. Samples taken before the initiation of chemotherapy covering 117 chemotherapy cycles in 105 patients were available. MASPs and ficolins were measured by time-resolved immunoflourometric assays and the levels related to parameters of infections. End-points included febrile neutropenia, documented infections, bacteraemia or severe infections. Lower M-ficolin concentrations were found in patients who developed a severe infection: median 0·27 µg/ml compared to 0·47 µg/ml in patients who did not develop a severe infection (P = 0·01). Conversely, MASP-2 was higher in these patients: median 0·53 µg/ml compared to 0·37 µg/ml, respectively (P = 0·008). When considering M-ficolin levels below 0·36 µg/ml as deficient, the time to development of severe infection was shorter in the M-ficolin deficient group: the hazard ratio was 2·60 (95% confidence interval: 1·23-5·49). No associations were revealed between infections and H-ficolin, L-ficolin or MASP-3. Patients with low M-ficolin are more likely to develop severe infections, whereas MASP-2 showed the opposite.

Mannan-Binding Lectin in Diabetic Kidney Disease: The Impact of Mouse Genetics in a Type 1 Diabetes Model

Background. Mannan-binding lectin (MBL) is involved in the development of diabetic nephropathy. MBL is a part of the innate immune system where it can activate the complement system. Serum MBL level predicts later renal impairment in diabetes patients. Direct involvement of MBL in the development of diabetic kidney disease is observed in one animal strain. However, this involvement may differ among the animal strains. We thus examined the impact of the genetic background on the role of MBL in diabetic nephropathy. Materials/Methods. C57BL/6JBomTac and 129S6/SvEvTac mice were compared. In both strains, experimental type 1 diabetes was induced in wild-type (WT) and MBL-knockout (MBL-KO) mice by streptozotocin. Nondiabetic WT and MBL-KO mice were used as controls. We tested if MBL modified the diabetes-induced kidney changes by two-way ANOVA allowing for interaction. Results. MBL aggravated diabetes-induced kidney growth and glomerulus enlargement in C57BL/6JBomTac mice. MBL did not modify diabetes effects on glomerular basement membrane thickness or mesangial volume in any strain. Diabetes-induced changes in renal gene transcription of growth factors and matrix components were unaffected by MBL. Conclusions. Strain-specific MBL effects were found on downstream diabetic kidney changes. This emphasizes the importance of genetic background in this model of diabetic complications.

Mannan-Binding Lectin and Mannan-Binding Lectin-Associated Serine Protease 2 in Acute Pancreatitis

Complement activation may play a prominent role in acute pancreatitis (AP). Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) participate in complement activation. The objective of the present study was to evaluate the role of MBL and MASP-2 as markers in AP with regard to etiology, inflammatory activity, severity, and development of multiorgan failure. Sixty patients with AP were included. All patients were diagnosed and treated according to a standardized regimen. Blood samples were obtained immediately on admission and again on days 1, 2, and 14. Both MBL (P < 0.001) and MASP-2 (P = 0.002) levels changed significantly over time, but without any significant relation to severity, multiorgan failure, or mortality. We found significantly higher levels of MBL (P = 0.04) in alcohol- than in gallstone-induced AP, but no significant difference in MASP-2 levels. The MBL and MASP-2 acted as acute-phase reactants, but overall, they were not markers for severity, multiorgan failure, nor for mortality in AP. Our results suggest that MBL and MASP-2 play only a minor role in the inflammatory response in AP.