Status of mannose-binding lectin (MBL) and complement system in COVID-19 patients and therapeutic applications of antiviral plant MBLs.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a virus called "Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)." In the majority of patients, infection with COVID-19 may be asymptomatic or may cause only mild symptoms. However, in some patients, there can also be immunological problems, such as macrophage activation syndrome (CSS) that results in cytokine storm syndrome (CSS) and acute respiratory distress syndrome (ARDS). Comprehension of host-microbe communications is the critical aspect in the advancement of new therapeutics against infectious illnesses. Endogenous animal lectins, a class of proteins, may perceive non-self glycans found on microorganisms. Serum mannose-binding lectin (sMBL), as a part of the innate immune framework, recognizes a wide range of microbial microorganisms and activates complement cascade via an antibody-independent pathway. Although the molecular basis for the intensity of SARS-CoV-2 infection is not generally understood, scientific literature indicates that COVID-19 is correlated with unregulated activation of the complement in terms of disease severity. Disseminated intravascular coagulation (DIC), inflammation, and immune paralysis contribute to unregulated complement activation. Pre-existing genetic defects in MBL and their association with complement play a major role in immune response dysregulation caused by SARS-CoV-2. In order to generate anti-complement-based therapies in Covid-19, an understanding of sMBL in immune response to SARS-CoV-2 and complement is therefore essential. This review highlights the role of endogenous sMBL and complement activation during SARS-CoV-2 infection and their therapeutic management by various agents, mainly plant lectins, since antiviral mannose-binding plant lectins (pMBLs) offer potential applications in the prevention and control of viral infections.

Mannan-binding lectin attenuates acetaminophen-induced hepatotoxicity by regulating CYP2E1 expression via ROS-dependent JNK/SP1 pathway.

Mannan-binding lectin (MBL) acts as a soluble pattern recognition molecule in the innate immune system, which is primarily produced by the liver. MBL deficiency occurs with high frequency in the population and is reported to be associated with susceptibility to several liver diseases. In the present study, we investigated the pathophysiological role of MBL in acetaminophen (APAP)-induced hepatotoxicity. After APAP treatment, MBL-deficient (MBL-/- ) mice had significantly higher mortality and aggravated hepatic necrosis as well as elevated serum lactate dehydrogenase and alanine aminotransferase levels compared to control mice. The enhanced hepatotoxicity in MBL-/- mice was associated with increased concentration of APAP toxic metabolisms. Furthermore, we demonstrated here that genetic ablation of MBL resulted in excessive reactive oxygen species (ROS) production and enhanced c-Jun N-terminal kinase (JNK) activation, leading to up-regulated specificity protein 1 (SP1) nuclear expression, thus promoted CYP2E1 hepatic expression and consequently exacerbated APAP-induced liver injury in mice. Importantly, we have validated that MBL protected against APAP toxicity in human HepaRG cells in vitro with the same mechanism. Our study revealed an unexpected function of MBL in drug metabolism, thus providing new insight into the drug-induced liver injury in patients with MBL deficiency.

Clinical and laboratory associations of mannose-binding lectin in 219 adults with IgG subclass deficiency.

BACKGROUND: Mannose-binding lectin (MBL) deficiency may increase risk of respiratory tract infection in adults unselected for IgG or IgG subclass levels. In a retrospective study, we sought to determine associations of serum MBL levels with clinical and laboratory characteristics of unrelated non-Hispanic white adults at diagnosis of IgG subclass deficiency (IgGSD). We computed the correlation of first and second MBL levels expressed as natural logarithms (ln) in a patient subgroup. We compared these characteristics of all adults with and without MBL ≤50 ng/mL: age; sex; body mass index; upper/lower respiratory tract infection; diabetes; autoimmune condition(s); atopy; other allergy; corticosteroid therapy; and subnormal serum IgG subclasses, IgA, and IgM. We performed logistic regression on MBL ≤50 ng/mL (dichotomous) using the three independent variables with the lowest values of p in univariate comparisons. RESULTS: There were 219 patients (mean age 51 ± 13 y; 82.5% women). Thirty-six patients (16.4%) had MBL ≤50 ng/mL. Two MBL measurements were available in 14 patients. The median interval between the first and second measurements was 125 d (range 18-1031). For ln-transformed data, we observed adjusted r2 = 0.9675; Pearson correlation coefficient 0.9849; and p < 0.0001. Characteristics of patients with and without MBL ≤50 ng/mL did not differ significantly in univariate comparisons. We performed a regression on MBL ≤50 ng/mL using: subnormal IgM (p = 0.0565); upper respiratory tract infection (p = 0.1094); and body mass index (p = 0.1865). This regression revealed no significant associations. CONCLUSIONS: We conclude that the proportion of the present IgGSD patients with serum MBL ≤50 ng/mL is similar to that of healthy European adults. MBL ≤50 ng/mL was not significantly associated with independent variables we studied.

Decreased nematode clearance and anti-phosphorylcholine-specific IgM responses in mannose-binding lectin-deficient mice.

Brugia malayi is a nematode that causes human lymphatic filariasis. Previously, we showed that mannose-binding lectin (MBL)-A is necessary for clearance of B. malayi microfilariae in mice and presence of MBL-A is linked with maximal levels of parasite-specific IgM. Common human MBL gene polymorphisms result in low MBL expression and lead to recurring bacterial infections. Furthermore, these low-expressing human MBL polymorphisms result in greatly increased susceptibility to lymphatic filarial infection. Indeed, gain of new filarial infections over a 30-year period are 10-fold higher in people with low, compared to high, MBL-expression phenotypes. Human MBL closely resembles mouse MBL-C, rather than MBL-A; therefore, we examined the role of mouse MBL-C in clearance of microfilariae. Absence of MBL-C alone, or both MBL-A and -C, resulted in delayed clearance of microfilariae and reduced parasite-specific IgM in mice. There were few profound changes in B cell sub-populations or in the ability of MBL-deficient mice to respond to T-dependent or T-independent antigens. However, absence of MBL-A and/or MBL-C resulted in reduced IgM to phosphorylcholine, a constituent of filarial and bacterial antigens, suggesting that inability to form proficient antibody responses to this moiety leads to lack of microfilarial clearance and overall susceptibility to filariasis.

Mannan-binding lectin promotes keratinocyte to produce CXCL1 and enhances neutrophil infiltration at the early stages of psoriasis.

Psoriasis is a chronic, relapsing inflammatory skin disorder. Numerous experimental evidence and therapeutic evidence have shown that the innate immune response is critical for the pathogenesis and development of psoriasis. Mannan-binding lectin (MBL), a prototypic pattern recognition molecule of the innate immune system, plays an essential role in the host defense against certain infections and also appears to be a major regulator of inflammation. In this study, we investigated the function of MBL on the course of experimental murine imiquimod (IMQ)-induced psoriasis. Our data showed that MBL-deficient (MBL-/- ) mice exhibited attenuated skin damage characterized by greatly decreased erythema compared with wild-type control mice during the early stages of IMQ-induced psoriasis-like skin inflammation. The reduced skin inflammation in MBL-/- mice was associated with the decreased infiltration of neutrophils. Furthermore, we have determined that MBL deficiency limited the chemokine CXCL1 production from skin keratinocytes upon IMQ stimulation, which might be responsible for the impaired skin recruitment of neutrophils. Additionally, we have provided the data that MBL protein promotes the IMQ-induced expression of CXCL1 and activation of MAPK/NF-κB signalling pathway in human keratinocyte HaCaT cells in vitro. In summary, our study revealed an unexpected role of MBL on keratinocyte function in skin, thus offering a new insight into the pathogenic mechanisms of psoriasis.

Mannose-Binding Lectin Drives Platelet Inflammatory Phenotype and Vascular Damage After Cerebral Ischemia in Mice via IL (Interleukin)-1α.

Objective- Circulating complement factors are activated by tissue damage and contribute to acute brain injury. The deposition of MBL (mannose-binding lectin), one of the initiators of the lectin complement pathway, on the cerebral endothelium activated by ischemia is a major pathogenic event leading to brain injury. The molecular mechanisms through which MBL influences outcome after ischemia are not understood yet. Approach and Results- Here we show that MBL-deficient (MBL-/-) mice subjected to cerebral ischemia display better flow recovery and less plasma extravasation in the brain than wild-type mice, as assessed by in vivo 2-photon microscopy. This results in reduced vascular dysfunction as shown by the shift from a pro- to an anti-inflammatory vascular phenotype associated with MBL deficiency. We also show that platelets directly bind MBL and that platelets from MBL-/- mice have reduced inflammatory phenotype as indicated by reduced IL-1α (interleukin-1α) content, as early as 6 hours after ischemia. Cultured human brain endothelial cells subjected to oxygen-glucose deprivation and exposed to platelets from MBL-/- mice present less cell death and lower CXCL1 (chemokine [C-X-C motif] ligand 1) release (downstream to IL-1α) than those exposed to wild-type platelets. In turn, MBL deposition on ischemic vessels significantly decreases after ischemia in mice treated with IL-1 receptor antagonist compared with controls, indicating a reciprocal interplay between MBL and IL-1α facilitating endothelial damage. Conclusions- We propose MBL as a hub of pathogenic vascular events. It acts as an early trigger of platelet IL-1α release, which in turn favors MBL deposition on ischemic vessels promoting an endothelial pro-inflammatory phenotype.

Mannose-Binding Lectin-Deficient Donors Increase the Risk of Bacterial Infection and Bacterial Infection-Related Mortality After Liver Transplantation.

Mannose-binding lectin (MBL) is synthesized by the liver and binds to microbes. MBL2 gene polymorphisms produce intermediate/low/null or normal MBL serum levels (MBL-deficient or MBL-sufficient phenotypes, respectively). We aimed to evaluate the incidence and severity of infection, rejection, and survival within 1 year after liver transplantation (LT) according to donor and recipient MBL2 gene polymorphisms. A repeated-event analysis for infection episodes (negative binomial regression, Andersen-Gill model) was performed in 240 LTs. Four hundred twenty-eight infectious episodes (310 bacterial, 15 fungal, 65 cytomegalovirus [CMV]-related, and 38 viral non-CMV-related episodes) and 48 rejection episodes were recorded. The main bacterial infections were urinary (n = 82, 26%) and pneumonia (n = 69, 22%). LT recipients of MBL-deficient livers had a higher risk of bacterial infection (incidence rate ratio [IRR] 1.48 [95% confidence interval 1.04-2.09], p = 0.028), pneumonia (IRR 2.4 [95% confidence interval 1.33-4.33], p = 0.013), and septic shock (IRR 5.62 [95% confidence interval 1.92-16.4], p = 0.002) compared with recipients of MBL-deficient livers. The 1-year bacterial infection-related mortality was higher in recipients of MBL-deficient versus MBL-sufficient livers (65.8% vs. 56.1%, respectively; p = 0.0097). The incidence of rejection, viral, or fungal infection was similar in both groups. Recipient MBL2 genotype did not significantly increase the risk of bacterial infection. LT recipients of MBL-deficient livers have a higher risk of bacterial infection, pneumonia, septic shock, and 1-year bacterial infection-related mortality after LT.

Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD.

BACKGROUND: In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggest MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD. METHODS: Patients with COPD (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested subcohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA PCR and sequencing, or airway inflammation during stable and exacerbated COPD. FINDINGS: Patients with MBL deficiency with COPD were significantly less likely to have severe exacerbations (incidence rate ratio (IRR) 0.66, 95% CI 0.48 to 0.90, p=0.009), or to have moderate or severe exacerbations (IRR 0.77, 95% CI 0.60 to 0.99, p=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the subcohort, patients with MBL deficiency had a more diverse lung microbiota (p=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency. INTERPRETATION: Patients with MBL deficient genotype with COPD have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.

Low maternal serum concentrations of mannose-binding lectin are associated with the risk of shorter duration of pregnancy and lower birthweight.

Chronic inflammation has been implicated as the underlying mechanism responsible for the pathophysiology of preterm labour. Mannose-binding lectin (MBL) plays a central role in the innate immune response and is thus an important component of the first line of defense. The aim of this study was to investigate whether serum concentrations of MBL correlated with the incidence of preterm birth and low birthweight in a cohort of women with signs of threatened preterm birth. A cohort of 60 patients who presented with regular contractions and/or short cervix (group A) between 24 and 32 weeks of gestation and 20 healthy controls (group B) who had no pregnancy complications and delivered at term were recruited into a prospective study. The following outcomes were recorded: presence of preterm labour and birthweight in all patients. MBL and high sensitivity C-reactive protein levels were measured in all serum samples. The serum concentrations of MBL were significantly reduced in patients with threatened preterm labour (Group A), compared to the control Group B. Furthermore, infants born to Group A mothers with MBL deficiency (n = 13, MBL ≤100 ng/mL) had significantly lower birthweights, compared to those born to Group A women with normal MBL serum concentrations (P < .0001). Our small cohort study demonstrated a strong association between MBL deficiency and preterm delivery, and associated low birthweight. MBL deficiency could thus be considered an important risk factor for preterm birth.

Mannose-Binding Lectin Levels Could Predict Prognosis in IgA Nephropathy.

IgA nephropathy (IgAN) is characterized by infections followed by episodic gross hematuria. Deficiency of mannose-binding lectin (MBL) is associated with recurrent infection in many diseases, but controversy exists regarding the role of MBL in IgAN. Here, we measured MBL2 variants and MBL levels in 749 patients with IgAN and 489 healthy controls. Overall, 5.2% (39 of 749) of patients with IgAN had MBL deficiency (MBL levels <100 ng/ml), among whom LYPB/LYPB and LXPA/LYPB were the predominant MBL2 haplotypes (82%; 32 of 39). We found a nonlinear association between MBL levels and renal outcome in IgAN. Patients with IgAN and MBL deficiency had a higher incidence of prodromic infections and gross hematuria than those with sufficient MBL levels (100-3540 ng/ml). Moreover, MBL deficiency independently associated with poor renal outcome in IgAN after multiple adjustments (hazard ratio, 5.18; 95% confidence interval, 2.50 to 10.72; P<0.001). Patients with high MBL levels (>3540 ng/ml) had more severe proteinuria and a higher proportion of crescents, although the association with IgAN progression did not reach statistical significance after adjustments. In conclusion, MBL deficiency and MBL excess may both have deleterious effects on IgAN progression, which suggests that MBL contributes to IgAN pathogenesis through multiple mechanisms.

Recurrent respiratory tract infections (RRTI) in the elderly: A late onset mild immunodeficiency?

Elderly with late-onset recurrent respiratory tract infections (RRTI) often have specific anti-polysaccharide antibody deficiency (SPAD). We hypothesized that late-onset RRTI is caused by mild immunodeficiencies, such as SPAD, that remain hidden through adult life. We analyzed seventeen elderly RRTI patients and matched controls. We determined lymphocyte subsets, expression of BAFF receptors, serum immunoglobulins, complement pathways, Pneumovax-23 vaccination response and genetic variations in BAFFR and MBL2. Twelve patients (71%) and ten controls (59%) had SPAD. IgA was lower in patients than in controls, but other parameters did not differ. However, a high percentage of both patients (53%) and controls (65%) were MBL deficient, much more than in the general population. Often, MBL2 secretor genotypes did not match functional deficiency, suggesting that functional MBL deficiency can be an acquired condition. In conclusion, we found SPAD and MBL deficiency in many elderly, and conjecture that at least the latter arises with age.

Mannose-Binding Lectin Deficiency in Brazilian Patients with Spondyloarthritis.

BACKGROUND: Infections are usually involved in the pathogenesis of spondyloarthritis (SpA). Mannose-binding lectin (MBL) is a component of the innate immune system with an important role in microbial defense. OBJECTIVE: To study the prevalence of MBL deficiency in SpA patients as well as its influence in the clinical profile of these diseases. METHODS: We studied 89 SpA patients and 89 healthy individuals, paired for age and gender. MBL serum levels were measured by ELISA test. Individuals with levels ≤100 ng/mL were considered deficient. SpA patients had determination of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP, Bath Ankylosing Spondylitis Functional Index (BASFI), C reactive protein (CRP), erythrocyte sedimentation rate (ESR), and review of their clinical profile. RESULTS: SpA patients had MBL levels ranging from 100 to 4100 ng/mL (median = 375 ng/mL); controls levels ranged from 100 to 4703 ng/mL (median = 1204 ng/mL; p < 0.0001). The prevalence of MBL deficiency was 27/89 (30.3%) in SpA patients and 12/89 (13.5%) in controls, with p = 0.01; OR = 2.5 (95% IC = 1.2-5.3). No association/correlation was found between MBL levels with BASDAI, BASFI, age at disease onset, ASDAS-CRP, ESR, CRP, presence of uveitis, HLAB27, peripheral arthritis, or SpA subtype (all p = NS). CONCLUSION: MBL levels may be linked with the occurrence of SpA but do not influence its phenotype.

Association between TLR2/TLR4 gene polymorphisms and COPD phenotype in a Greek cohort.

BACKGROUND: Considering that the innate immune system plays a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD), we hypothesized that functional single-nucleotide polymorphisms (SNPs) of innate immune genes affect the disease phenotype and prognosis. AIM: To elucidate the contribution of common functional TLR2 and TLR4 SNPs and genotypic deficiency of the mannose-binding lectin (MBL) protein, both as single parameters and in combination, in Greek COPD patients. RESULTS: In a cohort of 114 Greek COPD patients, we confirmed that the presence of TLR4-D299G or TLR4-T399I SNPs was significantly associated with an earlier COPD stage (p = 0.003 and p = 0.009, respectively). In comparison, the absence of any analyzed polymorphism, including those of TLR2-R753Q and genotypic MBL deficiency, was significantly associated with a more severe disease phenotype, characterized by more frequent exacerbations (p = 0.045). CONCLUSION: Our findings support the notion that the presence of innate immune SNPs, such as functional polymorphisms of TLRs along with MBL deficiency, might exert a protective effect on the COPD phenotype, similar with other immune-mediated disorders.

Phospholipase A2 Receptor-Related Membranous Nephropathy and Mannan-Binding Lectin Deficiency.

Most patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies against phospholipase A2 receptor (PLA2R). C3 and C5b-9 are found in immune deposits of IMN kidney biopsy specimens, but the pathway of complement activation in IMN remains elusive. We report the case of a patient who developed IMN with intense staining for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1. Measurement of mannan binding lectin (MBL) antigenic level and activity revealed MBL deficiency. Genotyping revealed a heterozygous (A/C) polymorphism in codon 57 of MBL2 exon 1 associated with homozygous and heterozygous variations in the promoter region at -550 (L/L) and -221 (X/Y), respectively, suggesting that the patient harbored the LXA/LYC haplotypes linked to MBL deficiency. Genetic sequencing in 77 consecutive patients with IMN identified four patients with MBL2 promoter and coding region variations associated with MBL deficiency and the same complement pattern in immune deposits as the index patient. In contrast, patients with wild-type MBL2 had immune deposits with intense Cd4 staining. Thus, IMN can develop in patients with complete MBL deficiency, with complement activated mainly by the alternative pathway, whereas the lectin pathway is also activated in those with wild-type MBL2.

Scaffold Optimisation of Tetravalent Antagonists of the Mannose Binding Lectin.

Antagonists of mannose binding lectin (MBL) have shown a protective role against brain reperfusion damage after acute ischemic stroke. Here we describe the design and streamlined synthesis of glycomimetic MBL antagonists based on a new tetravalent dendron scaffold. The dendron was developed by optimisation of a known polyester structure previously demonstrated to be very efficient for ligand presentation to MBL. Replacement of a labile succinyl ester bond with a more robust amide functionality, use of a longer and more hydrophilic linker, fast modular synthesis and orthogonal functionalisation at the focal point are the main features of the new scaffold. The glycoconjugate constructs become stable to silica gel chromatography and to water solutions at physiological pH, while preserving water solubility and activity in an SPR assay against the murine MBL-C isoform. Higher-order constructs were easily assembled, as demonstrated by the synthesis of a 16-valent dendrimer, which leads to two orders of magnitude increase in activity over the tetravalent version against MBL-C.

The association of mannose-binding lectin genetic polymorphisms with the risk of rheumatoid arthritis: a meta-analysis.

OBJECTIVE: To better understand the risks of rheumatoid arthritis (RA) and certain subsets conferred by mannose-binding lectin (MBL2) polymorphisms in different races. MATERIALS AND METHODS: Eighteen articles (4810 cases and 4585 controls) were identified from the latest literature search carried out in May 2014 using PubMed, Web of Science, Wanfang Database (Chinese) and Chinese National Knowledge Infrastructure. Three single nucleotide polymorphisms of codon 52, 54 and 57, exonic and extended genotypic variance in MBL2 were synthesized. RESULTS: Codon 54 mutation of MBL2 was unlikely to be a risk factor for RA in overall population, but turned out to be deleterious in East Asian (four studies with 523 cases and 647 controls, pooled OR:1.63, 95% CI: 1.23-2.17). Codon 54 mutation increased the risk of seropositive and erosive RA by 44% and 162%, respectively (three studies with 281 cases and 358 controls, 95% CI: 1.01-2.05; 3 studies with 180 cases and 499 controls, 95% CI: 1.77-3.88). Furthermore, those risks were relatively stronger when restricted in East Asian (two studies with 147 cases and 244 controls, pooled OR: 1.85, 95% CI: 1.19-2.87; 2 studies with 170 cases and 291 controls, pooled OR: 2.78, 95% CI: 1.85-4.20). No remarkable associations were detected regarding codon 52, 57, exon 1 and extended genotype of MBL2. CONCLUSIONS: Polymorphism of codon 54 in MBL2 may predispose to RA, especially seropositive or erosive RA, which East Asian appears to be more vulnerable.

Mannose-binding lectin in chronic hepatitis C in children.

OBJECTIVE: To investigate effect of mannose-binding lectin (MBL) genetic polymorphisms and phenotype in chronic hepatitis C and its impact on response to antiviral therapy in children. METHODS: Fifty four children with chronic hepatitis C, aged 2.5-18 years were enrolled. Forty-five children were treated with interferon-α (IFN-α) alone (n = 2) or IFN-α and ribavirin (n = 43). Twenty-one children who responded to antiviral therapy were defined as sustained responders to therapy (IFN-SR). Before therapy, MBL genotypes and serum MBL levels (by ELISA) were determined. MBL genotype distribution and levels were correlated to disease characteristics and response to therapy. RESULTS: Children with chronic hepatitis C who did not respond to antiviral therapy (IFN-NR) presented more frequently MBL2 polymorphisms, although this did not reach significance (p = 0.08). MBL levels were significantly lower in children classified as IFN-NR when compared to children defined as IFN-SR (1.623 ng/ml vs. 3.699 ng/ml), (p = 0.04). Serum activity levels of ALT and AST were higher in children with A/O MBL genotype when compared to group with A/A genotype (p < 0.05). CONCLUSIONS: Our findings suggest negative effect of MBL deficiency (defined by genotype and phenotype) on progression of chronic hepatitis C in children and response to antiviral therapy.

Post-infectious bronchiolitis obliterans and mannose-binding lectin insufficiency in Argentinean children.

BACKGROUND AND OBJECTIVE: Post-infectious bronchiolitis obliterans (PIBO) is a severe disorder following acute lower pulmonary infection in young children, especially caused by adenovirus. Mannose-binding lectin (MBL) deficiency arising from polymorphisms in the coding and non-coding region on the MBL2 gene has been associated with more frequent and severe respiratory infections. Our aim was to evaluate the influence of MBL variants in the susceptibility and evolution of children with PIBO. METHODS: One hundred eleven children with PIBO diagnosis were studied. The coding A, B, D and X promoter variants of MBL2 gene were assessed by PCR-RFLP. B and D alleles were pooled as O. The combined genotypes A/A and YA/O were grouped as sufficient MBL (sMBL), and O/O and XA/O as insufficient MBL (iMBL) groups. To evaluate the frequency of MBL2 polymorphisms in the general population, we studied DNA samples from 127 healthy donors from the blood bank of the hospital (control group). RESULTS: iMBL variants were significantly more frequent in PIBO children compared with controls (21.6% vs 10.2%, P = 0.01). PIBO patients with iMBL required intensive care unit (P = 0.001) and mechanical assistance at the moment of viral injury (P = 0.001) more frequently than those with sMBL. CONCLUSIONS: Insufficiency of MBL was more common in PIBO children than in healthy controls. This genetic condition was significantly associated with more severe initial disease, illustrating the relevance of innate immune defence factors prior to the maturation of the adaptative immune system.

Recalcitrant rhinosinusitis, innate immunity, and mannose-binding lectin.

BACKGROUND: Mannose-binding lectin (MBL) is a protein produced by the liver that participates in innate immunity by tagging the surface of microbes for opsonization. Mannose-binding lectin deficiency is present in 7% of the population and has been implicated in recurrent respiratory tract infections in children. Mannose-binding lectin deficiency has not been explored in rhinosinusitis but is associated with increased mortality in adult pneumococcal infection. The purpose of this report is to describe a tertiary rhinology patient experience with MBL deficiency and recalcitrant rhinosinusitis. METHODS: This retrospective case series report characterizes predominantly adult patients with low MBL levels from January 2010 to June 2012. Indications for MBL testing, sinus culture data, immunological testing results, and treatments used to control rhinosinusitis are described. RESULTS: Mannose-binding lectin levels were deficient in 12 of 36 patients (33.3%) tested. IgG subclasses were abnormally low in 5 of 12 patients; IgA was normal in 11 of 12 patients; and IgM was normal in 11 of 12 patients. Staphylococcus aureus, coagulase-negative Staphylococcus species, and Pseudomonas aeruginosa, known to be "tagged" by MBL, were the most common organisms grown on culture. Treatments included culture directed systemic antimicrobial therapy and topical steroids/antibiotics. CONCLUSION: Mannose-binding lectin, an important component of the lectin complement pathway and innate immunity, is possibly associated with recalcitrant adult rhinosinusitis. Steroid/antibiotic irrigations appear to benefit patients with recalcitrant rhinosinusitis and possibly those with MBL deficiency. Given that the prevalence of MBL deficiency in this case series is 4 times that seen in the normal population, additional investigations are warranted to further elucidate the role of MBL deficiency in rhinosinusitis.

Mannose-binding lectin promotes local microvascular thrombosis after transient brain ischemia in mice.

BACKGROUND AND PURPOSE: Several lines of evidence support the involvement of mannose-binding lectin (MBL) in stroke brain damage. The lectin pathway of the complement system facilitates thrombin activation and clot formation under certain experimental conditions. In the present study, we examine whether MBL promotes thrombosis after ischemia/reperfusion and influences the course and prognosis of ischemic stroke. METHODS: Middle cerebral artery occlusion/reperfusion was performed in MBL-deficient (n=85) and wild-type (WT; n=83) mice, and the brain lesion was assessed by MRI at days 1 and 7. Relative cerebral blood flow was monitored up to 6 hours after middle cerebral artery occlusion with laser speckle contrast imaging. Fibrin(ogen) was analyzed in the brain vasculature and plasma, and the effects of thrombin inhibitor argatroban were evaluated to assess the role of MBL in thrombin activation. RESULTS: Infarct volumes and neurological deficits were smaller in MBL knockout mice than in WT mice. Relative cerebral blood flow values during middle cerebral artery occlusion and at reperfusion were similar in both groups, but decreased during the next 6 hours in the WT group only. Also, the WT mice showed more fibrin(ogen) in brain vessels and a better outcome after argatroban treatment. In contrast, argatroban did not improve the outcome in MBL knockout mice. CONCLUSIONS: MBL promotes brain damage and functional impairment after brain ischemia/reperfusion in mice. These effects are secondary to intravascular thrombosis and impaired relative cerebral blood flow during reperfusion. Argatroban protects WT mice, but not MBL knockout mice, emphasizing a role of MBL in local thrombus formation in acute ischemia/reperfusion.