RESUMO
BACKGROUND: Mannose-binding lectin (MBL) is an important component of the innate immune system. Polymorphisms in the MBL2 gene and promoter region are directly associated with MBL-deficiency. We sought to determine the association between MBL genotype on the frequency of common childhood respiratory infections, respiratory symptoms, and atopic outcomes in early childhood. METHODS: MBL2 gene variants were analyzed in newborns recruited to the GO-CHILD multicenter prospective cohort study. Follow-up for respiratory infection and atopy diagnoses and symptoms, healthcare utilization, and medication prescription were conducted by postal questionnaires at 12 and 24 months. RESULTS: Genotyping and follow-up were completed in 1004 children. Genotypes associated with MBL-deficiency were associated with an increased risk of bronchiolitis (relative risk [RR] 1.95, 95% confidence interval [CI] 1.33-2.85) and pneumonia (RR 2.46, 95% CI 1.16-5.22). MBL-deficient genotypes were associated with an increased risk of wheeze with shortness of breath episodes (RR 1.22, 95% CI 1.04-1.43), emergency department attendance (RR 1.90 95% CI 1.13-3.19), and hospital admission (RR 2.01, 95% CI 1.04-3.89) for wheeze. MBL-deficient genotypes were associated with a reduced risk of developing atopic dermatitis (RR 0.72, 95% CI 0.53-0.98). CONCLUSION: The positive association between MBL-deficient genotypes and bronchiolitis and pneumonia, as well as a severe wheeze phenotype in some young children, supports the hypothesis that MBL is an important component of innate immunity in the vulnerable period before the maturation of the adaptive immune system. Identification of disease-modifying genotypes may help target preventative strategies in high-risk infants.
Assuntos
Bronquiolite , Lectina de Ligação a Manose , Transtornos Respiratórios , Infecções Respiratórias , Bronquiolite/genética , Pré-Escolar , Estudos de Coortes , Predisposição Genética para Doença , Genótipo , Humanos , Lectina de Ligação a Manose/deficiência , Lectina de Ligação a Manose/genética , Erros Inatos do Metabolismo , Estudos Prospectivos , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/genéticaRESUMO
Objectives: Dysregulation of the immune response appears to play a significant role in recurrent aphthous stomatitis (RAS) development. The main objective of this case-control study is to investigate the blood levels of mannose-binding lectin (MBL) and the frequency of the MBL2 gene (gly54asp) polymorphism in RAS patients, including 40 RAS patients and 40 healthy controls. Methods: Serum MBL levels were determined by ELISA, while the PCR-restriction fragment length polymorphism was used in MBL2 genotyping. Results: The median serum MBL level was significantly lower in the RAS group than in the control group (975 ng/mL (545-1320) vs. 1760 ng/mL (1254-2134); p≤ 0.001). The MBL levels were significantly lower in the BB genotype, whereas they were significantly higher in the wild type AA with a median of 525 and 1340 ng/mL, respectively (p =0.005). The B allele was expressed in significantly higher percentages of RAS patients than in controls. There was no significant association between MBL serum levels (p=0.685) or MBL2 codon 54 genotypes (p=0.382) with the type of ulcers. Conclusion: There was an association between low MBL serum levels and the variant allele B of the MBL2 (gly54asp) gene, and the susceptibility to RAS. As a result, potential novel therapeutic options for RAS patients with MBL deficiency should be investigated.
Assuntos
Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo , Estomatite Aftosa , Adulto , Estudos de Casos e Controles , Egito/epidemiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Técnicas de Genotipagem/métodos , Técnicas de Genotipagem/estatística & dados numéricos , Humanos , Masculino , Lectina de Ligação a Manose/genética , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/fisiopatologia , Polimorfismo de Nucleotídeo Único , Estomatite Aftosa/sangue , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/genética , Estomatite Aftosa/terapiaRESUMO
Leukocyte infiltration and blood-brain barrier breakdown contribute to secondary brain damage after traumatic brain injury (TBI). TBI induces neuroimmune responses triggering pathogenic complement activation through different pathways, including the lectin pathway. We investigated mechanisms underlying mannose-binding lectin (MBL)-mediated brain damage focusing on neutrophil infiltration and blood-brain barrier breakdown in a TBI mouse model. Wild type mice and MBL-/- null mice were subjected to controlled cortical impact. We studied neutrophil infiltration and regional localization by confocal microscopy 1, 4 and 15 days post-trauma, and investigated neutrophil extracellular trap (NET) formation. By immunofluorescence and/or Western blotting in various brain regions we studied the presence of fibrin(ogen), pentraxin-3, albumin and immunoglobulin G. Finally, we studied neurofilament proteins, synaptophysin, and αII-spectrin, and assessed white matter content in the injured tissue. TBI triggered an acute wave of neutrophil infiltration at day 1 followed by a more discrete persistence of neutrophils in the injured tissue at least until day 15. We detected the presence of NETs and pentraxin-3 in the injured tissue, as well as accumulation of fibrin(ogen), increased blood-brain barrier permeability, and neurofilament, synaptophysin and white matter loss, and calpain-mediated αII spectrin breakdown. MBL-/- mice showed reduced number of Ly6G+ neutrophils 4 days after TBI, lower accumulation of pentraxin-3 and fibrin(ogen) in the injured tissue, reduced global plasma protein extravasation, and better preservation of axonal and white matter integrity. These results show that MBL participates in secondary neutrophil accumulation and blood-brain barrier breakdown, and promotes axonal and white matter damage after TBI in mice.
Assuntos
Axônios/metabolismo , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Encéfalo/metabolismo , Lectina de Ligação a Manose/deficiência , Animais , Axônios/imunologia , Axônios/patologia , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/patologia , Encéfalo/imunologia , Encéfalo/patologia , Lesões Encefálicas Traumáticas/imunologia , Lesões Encefálicas Traumáticas/patologia , Masculino , Lectina de Ligação a Manose/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
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.
Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , COVID-19/metabolismo , Proteínas do Sistema Complemento/metabolismo , Lectina de Ligação a Manose/metabolismo , Antivirais/farmacologia , COVID-19/sangue , COVID-19/imunologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/química , Lectina de Ligação a Manose/deficiência , SARS-CoV-2/efeitos dos fármacosRESUMO
BACKGROUND: Mannose-binding lectin (MBL) plays a pivotal role in innate immunity; however, its impact on susceptibility to opportunistic infections (OIs) has not yet been examined in a natural history cohort of people living with HIV/AIDS. METHODS: We used archived samples to analyze the association between MBL expression types and risk of major OIs including Pneumocystis jirovecii pneumonia (PCP), cryptococcosis, talaromycosis, toxoplasmosis, and tuberculosis in a prospective cohort in Northern Thailand conducted from 1 July 2000 to 15 October 2002 before the national antiretroviral treatment programme was launched. RESULTS: Of 632 patients, PCP was diagnosed in 96 (15.2%) patients, including 45 patients with new episodes during the follow-up period (1006.5 person-years). The total history of PCP was significantly associated with low MBL expression type: high/intermediate (81/587, 13.8%), low (10/33, 30.3%) and deficient (5/12, 41.7%) (p = 0.001), whereas the history of other OIs showed no relation with any MBL expression type. Kaplan-Meier analysis (n = 569; log-rank p = 0.011) and Cox's proportional hazards model revealed that deficient genotype dramatically increased the risk of PCP, which is independent upon sex, age, CD4 count, HIV-1 viral load and hepatitis B and C status (adjusted hazard ratio 7.93, 95% confidence interval 2.19-28.67, p = 0.002). CONCLUSIONS: Deficiency of MBL expression is a strong risk factor determining the incidence of PCP but not other major OIs.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Lectina de Ligação a Manose/deficiência , Pneumocystis carinii/isolamento & purificação , Pneumonia por Pneumocystis/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/genética , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Adolescente , Adulto , Feminino , Seguimentos , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Imunidade Inata/genética , Incidência , Masculino , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Pneumocystis carinii/imunologia , Pneumonia por Pneumocystis/diagnóstico , Pneumonia por Pneumocystis/genética , Pneumonia por Pneumocystis/microbiologia , Estudos Prospectivos , Fatores de Risco , Tailândia/epidemiologia , Adulto JovemRESUMO
Cardiovascular (CV) morbidity is the major cause of death in patients with Systemic Lupus Erythematosus (SLE). Previous studies on mannose-binding lectin (MBL) gene polymorphisms in SLE patients suggest that low levels of complement MBL are associated with cardiovascular disease (CVD). However, as large studies on MBL deficiency based on resulting MBL plasma concentrations are lacking, the aim of our study was to analyze the association of MBL concentrations with CVD in SLE patients. Plasma MBL levels SLE patients included in the Swiss SLE Cohort Study were quantified by ELISA. Five different CV organ manifestations were documented. Of 373 included patients (85.5% female) 62 patients had at least one CV manifestation. Patients with MBL deficiency (levels below 500 ng/ml or 1000 ng/ml) had no significantly increased frequency of CVD (19.4% vs. 15.2%, P = 0.3 or 17.7% vs. 15.7%, P = 0.7). After adjustment for traditional CV risk factors, MBL levels and positive antiphospholipid serology (APL+) a significant association of CVD with age, hypertension, disease duration and APL+ was demonstrated. In our study of a large cohort of patients with SLE, we could not confirm previous studies suggesting MBL deficiency to be associated with an increased risk for CVD.
Assuntos
Hipertensão , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo , Adulto , Fatores Etários , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Hipertensão/genética , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Masculino , Lectina de Ligação a Manose/genética , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/genética , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Mannose-binding lectin (MBL) is a complement protein involved in the innate immune system, and is associated with some chronic respiratory diseases including noncystic fibrosis (non-CF) bronchiectasis in adults. The aim of this study was to investigate the frequency of MBL2 gene polymorphisms in children with non-CF bronchiectasis, and the effect of MBL deficiency on disease severity. METHODS: Fifty children with non-CF bronchiectasis (bronchiectasis group) and 50 healthy controls (control group) were included. The demographic findings, number of acute pulmonary exacerbations in the previous year, airway cultures, pulmonary function tests, and radiologic scores of the bronchiectasis group were recorded. DNA extraction was performed in both groups and MBL2 gene polymorphisms in codons 52, 54, 57 in exon 1 and H/L, Y/X in the promoter region were studied using real-time polymerase chain reaction. Haplotypes were made by genotypes, and MBL serum expression was classified according to the genotypes in the literature. RESULTS: The bronchiectasis group consisted of 23 (46%) patients with primary ciliary dyskinesia, 5 (10%) with primary immunodeficiency diseases, and 22 (44%) with idiopathic bronchiectasis. There were no statistically significant differences between the bronchiectasis and control groups in terms of allele and genotype frequencies of polymorphisms in codons 52, 54, 57 in exon 1 and promoter H/L. However, the YX heterozygote genotype was more frequent in the control group (82%) compared with the bronchiectasis group (50%) (P = .002). The frequency of patients with intermediate serum MBL expression genotype was higher in the bronchiectasis group (20%) than in the control group (0%) (P = .001). In the bronchiectasis group, there were no significant differences in growth, annual pulmonary exacerbation rates in the last year, pulmonary function tests, radiologic scores, and microbiologic findings between low, intermediate, and high-expressing genotypes. CONCLUSIONS: In children with non-CF bronchiectasis, MBL genotype was different from healthy controls. MBL deficiency associated only with MBL genotype was not related to disease severity in this group of patients.
Assuntos
Bronquiectasia/genética , Lectina de Ligação a Manose/genética , Adolescente , Bronquiectasia/fisiopatologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Pulmão/fisiopatologia , Masculino , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/fisiopatologia , Polimorfismo Genético , Testes de Função Respiratória , Índice de Gravidade de DoençaRESUMO
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.
Assuntos
Quimiocina CXCL1/biossíntese , Quimiotaxia de Leucócito , Queratinócitos/metabolismo , Lectina de Ligação a Manose/fisiologia , Neutrófilos/fisiologia , Psoríase/imunologia , Animais , Linhagem Celular Transformada , Quimiocina CXCL1/genética , Derme/imunologia , Derme/patologia , Feminino , Humanos , Imiquimode/toxicidade , Inflamação , Queratinócitos/efeitos dos fármacos , Lectina de Ligação a Manose/deficiência , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Lectina de Ligação a Manose/farmacologia , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/imunologia , Camundongos , Camundongos Knockout , Psoríase/induzido quimicamente , Psoríase/metabolismo , Organismos Livres de Patógenos Específicos , Regulação para CimaRESUMO
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.
Assuntos
Doenças Autoimunes/epidemiologia , Deficiência de IgG/epidemiologia , Imunoglobulina G/genética , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/epidemiologia , Infecções Respiratórias/epidemiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Risco , Estados Unidos/epidemiologia , População BrancaRESUMO
OBJECTIVE: Primary ciliary dyskinesia (PCD) is a congenital lung disease that leads to recurrent and chronic lung infection. The resulting inflammation causes lung damage and declines in lung function. Mannose-binding lectin (MBL) is a first line host defense protein of importance for the innate immunity. Polymorphisms in the MBL gene named MBL2 result in unstable and low functional levels MBL proteins. MBL insufficiency is linked to an increased risk of lung infection and to declines in lung function in patients with cystic fibrosis. We investigated whether there is a similar link in patients with PCD. METHODS: This retrospective longitudinal study included 85 patients with PCD. Diagnostics and age at diagnosis were recorded, complete spirometry data starting at diagnosis, and Pseudomonas aeruginosa infection status over the last 2 years were collected, and the patients were grouped according to MBL2 genotype status (MBL2-sufficient or MBL2-deficient). RESULTS: MBL-deficient patients were diagnosed almost 3 years earlier than MBL-sufficient patients (median 6.1 vs 8.9 years, P < 0.05). There were no differences in the first measured spirometry values, but MBL-deficient patients showed greater declines in forced expiratory volume in one sec (FEV1 ) than patients with MBL sufficiency (z-score: -0.049 per year [95% CI, -0.075; -0.021] vs -0.009 per year [95% CI, -0.033; 0.015]; P = 0.023). No differences were found in forced vital capacity (FVC), FEV1 /FVC, or infection status. CONCLUSION: MBL-deficiency, which is associated with MBL2 mutations, was associated with a lower age at diagnosis and with steeper declines in FEV1 in patients with PCD. This suggests that the MBL genotype might be a disease modifier in PCD.
Assuntos
Transtornos da Motilidade Ciliar/genética , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/genética , Infecções por Pseudomonas/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Transtornos da Motilidade Ciliar/fisiopatologia , Feminino , Volume Expiratório Forçado , Genótipo , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Pulmão/fisiopatologia , Masculino , Lectina de Ligação a Manose/genética , Erros Inatos do Metabolismo/fisiopatologia , Pessoa de Meia-Idade , Polimorfismo Genético , Infecções por Pseudomonas/fisiopatologia , Estudos Retrospectivos , Espirometria , Adulto JovemRESUMO
OBJECTIVES: To evaluate the association of mannose-binding lectin (MBL) deficiency with susceptibility and clinical features of group B Streptococcus (GBS) causing meningitis in Chinese infants. METHODS: During 2014-2017, 33 infants with laboratory-confirmed GBS meningitis were included. Six polymorphisms (H/L, Y/X, P/Q, A/D, A/B and A/C) of MBL were sought for in these patients and in 330 healthy controls by PCR-based sequencing. Serum MBL concentration was determined. RESULTS: Significantly higher frequency of MBL variant genotype A/B was found in patients than controls (15/33, 45%, vs. 79/330, 24%, p=0.011). Patients with variant genotype A/B had significantly lower serum MBL than those with wild-type genotype A/A (median, 482.87 vs. 1455.13 ng/mL, p=0.002). Moreover, patients with genotype A/B had significantly higher level of C-reactive protein (median, 146 vs. 41 mg/L, p=0.007), neutrophil (median, 58.1% vs. 45.7%, p=0.033) and neutrophil-to-lymphocyte ratio in blood (median, 2.32 vs. 1.03, p=0.018) compared to those with genotype A/A. No significant differences were observed in clinical features of patients with different genotypes. CONCLUSIONS: Our result suggested that infants with MBL deficiency are at higher risk of meningitis caused by GBS. Further studies in different populations with larger number of subjects are needed.
Assuntos
Estudos de Associação Genética , Lectina de Ligação a Manose/deficiência , Meningites Bacterianas/complicações , Erros Inatos do Metabolismo/complicações , Infecções Estreptocócicas/complicações , Adulto , Alelos , Estudos de Casos e Controles , China , Suscetibilidade a Doenças , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Lectina de Ligação a Manose/genética , Meningites Bacterianas/microbiologia , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Streptococcus agalactiae/genética , Streptococcus agalactiae/patogenicidade , Adulto JovemRESUMO
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.
Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Citocromo P-450 CYP2E1/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lectina de Ligação a Manose/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Fator de Transcrição Sp1/metabolismo , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Expressão Gênica , Lectina de Ligação a Manose/deficiência , Camundongos , Camundongos KnockoutRESUMO
Noninfectious liver injury, including the effects of drugs and diet, is a major cause of liver diseases worldwide. The innate inflammatory response to hepatocyte death plays a crucial role in the outcome of liver injury. Mannan-binding lectin (MBL) is a pattern recognition molecule of the innate immune system, which is primarily produced by liver. MBL deficiency occurs with high frequency in the population and is reported associated with predisposition to infectious diseases. We here observed that genetic MBL ablation strongly sensitizes mice to sterile liver injury induced by carbon tetrachloride (CCl4 ). Aggravated liver damage was shown in CCl4 -administrated MBL-/- mice, as evidenced by severe hepatocyte death, elevated serum alanine aminotransferase and lactate dehydrogenase activity, and enhanced production of inflammatory cytokines. Mechanistic studies established that MBL deficiency caused increased chemokine CXCL2 production from liver macrophages upon CCl4 stimulation, thereby promoting the hepatic recruitment of neutrophils and subsequent liver damage. Furthermore, MBL-mediated protection from CCl4 -induced liver injury was validated by administration of an MBL-expressing liver-specific adeno-associated virus, which effectively ameliorated the hepatic damage in CCl4-treated MBL-/- mice. We propose that MBL may be exploited as a new therapeutic approach in the treatment of chemical-induced sterile liver injury in patients with MBL deficiency.
Assuntos
Fígado/lesões , Fígado/metabolismo , Lectina de Ligação a Manose/deficiência , Infiltração de Neutrófilos , Animais , Tetracloreto de Carbono , Quimiocina CXCL2/metabolismo , Dependovirus/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Lectina de Ligação a Manose/metabolismo , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Anticorpos Antiprotozoários/imunologia , Especificidade de Anticorpos/imunologia , Imunoglobulina M/imunologia , Lectina de Ligação a Manose/deficiência , Nematoides/parasitologia , Infecções por Nematoides/genética , Infecções por Nematoides/imunologia , Fosforilcolina/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Vacinas Bacterianas/imunologia , Ativação do Complemento/imunologia , Complemento C3/imunologia , Complemento C3/metabolismo , Modelos Animais de Doenças , Imunização , Masculino , Camundongos , Camundongos Knockout , Microfilárias/genética , Microfilárias/imunologia , Infecções por Nematoides/parasitologia , Carga Parasitária , Ligação Proteica , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
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.
Assuntos
Plaquetas/metabolismo , Células Endoteliais/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/metabolismo , Interleucina-1alfa/metabolismo , Lectina de Ligação a Manose/metabolismo , Artéria Cerebral Média/metabolismo , Ativação Plaquetária , Animais , Morte Celular , Hipóxia Celular , Células Cultivadas , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Células Endoteliais/patologia , Hemodinâmica , Humanos , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Interleucina-1alfa/deficiência , Interleucina-1alfa/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Lectina de Ligação a Manose/deficiência , Lectina de Ligação a Manose/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Artéria Cerebral Média/patologia , Artéria Cerebral Média/fisiopatologia , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Transdução de SinaisRESUMO
INTRODUCTION: Deep vein thrombosis (DVT) originates in the valvular sinuses of large veins in a local milieu characterized by stasis and severe hypoxia. This may induce complement- and coagulation activation, which potentially increases the risk of venous thromboembolism (VTE). The aim of the present study was to investigate whether the activity of the complement pathways, the level of mannose-binding lectin (MBL) and tissue-factor (TF) induced thrombin generation were associated with risk of unprovoked VTE. METHODS: A case-control study was performed in patients with unprovoked VTE (nâ¯=â¯24) and age- and sex-matched healthy controls (nâ¯=â¯24). Serum complement pathway activity was measured by the total complement screen assay (Wieslab®). MBL was quantified by ELISA. Plasma TF-induced thrombin generation was measured using the CAT-assay. RESULTS: Activity in the highest quintile of the classical pathway was associated with increased odds of unprovoked VTE (OR 4.5, 95% CI; 0.8-24.7). Moreover, MBL deficiency (≤100â¯ng/ml) was associated with unprovoked VTE (OR 3.5, 95% Cl; 0.8-15.3). VTE patients had shortened TF-induced lag-time (4.8⯱â¯0.6â¯min vs. 5.8⯱â¯2.1â¯min, pâ¯<â¯0.001) and a higher endogenous thrombin potential (ETP) (1383⯱â¯267â¯nM∗h vs. 1265⯱â¯247â¯nM∗h, pâ¯=â¯0.07) than controls. No association between the classical complement pathway activity or MBL deficiency, and parameters of TF-induced thrombin generation was observed. CONCLUSION: Our findings suggest that high activity of the classical complement pathway, and MBL deficiency, might be associated with an increased odds of unprovoked VTE, independent of activation of TF-induced coagulation.
Assuntos
Ativação do Complemento , Lectina de Ligação a Manose/deficiência , Lectina de Ligação a Manose/imunologia , Erros Inatos do Metabolismo/complicações , Tromboembolia Venosa/etiologia , Adulto , Idoso , Coagulação Sanguínea , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Lectina de Ligação a Manose/sangue , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/imunologia , Pessoa de Meia-Idade , Trombina/imunologia , Tromboplastina/imunologia , Tromboembolia Venosa/sangue , Tromboembolia Venosa/imunologiaRESUMO
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.