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2.
BMC Immunol ; 20(1): 15, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31117958

RESUMO

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 , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Risco , Estados Unidos/epidemiologia
3.
Clin Microbiol Infect ; 25(3): 384.e1-384.e3, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30832899

RESUMO

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 Jovem
4.
Immunol Cell Biol ; 97(3): 305-316, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30457677

RESUMO

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/metabolismo
5.
J Leukoc Biol ; 105(1): 177-186, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30351498

RESUMO

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 C57BL
6.
Arterioscler Thromb Vasc Biol ; 38(11): 2678-2690, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354247

RESUMO

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 Sinais
7.
Thromb Res ; 169: 50-56, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30015228

RESUMO

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 (n = 24) and age- and sex-matched healthy controls (n = 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 (≤100 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€¯0.6 min vs. 5.8 ±â€¯2.1 min, p < 0.001) and a higher endogenous thrombin potential (ETP) (1383 ±â€¯267 nM∗h vs. 1265 ±â€¯247 nM∗h, p = 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/imunologia
8.
Scand J Immunol ; 88(1): e12675, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29758096

RESUMO

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.


Assuntos
Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/complicações , Trabalho de Parto Prematuro/sangue , Nascimento Prematuro/sangue , Adulto , Biomarcadores/sangue , Peso ao Nascer , Estudos de Coortes , Feminino , Humanos , Erros Inatos do Metabolismo/epidemiologia , Gravidez , Estudos Prospectivos , Fatores de Risco
9.
J Thorac Cardiovasc Surg ; 155(3): 1139-1147.e2, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29452463

RESUMO

OBJECTIVES: The MBL2 gene is the major genetic determinant of mannose-binding lectin (MBL)-an acute phase reactant. Low MBL levels have been associated with adverse outcomes in preterm infants. The MBL2Gly54Asp missense variant causes autosomal dominant MBL deficiency. We tested the hypothesis that MBL2Gly54Asp is associated with worse neurodevelopmental outcomes after cardiac surgery in neonates. METHODS: This is an analysis of a previously described cohort of patients with nonsyndromic congenital heart disease who underwent cardiac surgery with cardiopulmonary bypass before age 6 months (n = 295). Four-year neurodevelopment was assessed in 3 domains: Full-Scale Intellectual Quotient, the Visual Motor Integration development test, and the Child Behavior Checklist to assess behavior problems. The Child Behavior Checklist measured total behavior problems, pervasive developmental problems, and internalizing/externalizing problems. A multivariable linear regression model, adjusting for confounders, was fit. RESULTS: MBL2Gly54Asp was associated with a significantly increased covariate-adjusted pervasive developmental problem score (ß = 3.98; P = .0025). Sensitivity analyses of the interaction between age at first surgery and MBL genotype suggested effect modification for the patients with MBL2Gly54Asp (Pinteraction = .039), with the poorest neurodevelopment outcomes occurring in children who had surgery earlier in life. CONCLUSIONS: We report the novel finding that carriers of MBL2Gly54Asp causing autosomal dominant MBL deficiency have increased childhood pervasive developmental problems after cardiac surgery, independent of other covariates. Sensitivity analyses suggest that this effect may be larger in children who underwent surgery at earlier ages. These data support the role of nonsyndromic genetic variation in determining postsurgical neurodevelopment-related outcomes in children with congenital heart disease.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Transtornos Globais do Desenvolvimento Infantil/etiologia , Desenvolvimento Infantil , Cardiopatias Congênitas/cirurgia , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/genética , Mutação de Sentido Incorreto , Sistema Nervoso/crescimento & desenvolvimento , Fatores Etários , Lista de Checagem , Comportamento Infantil , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Transtornos Globais do Desenvolvimento Infantil/psicologia , Pré-Escolar , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Masculino , Lectina de Ligação a Manose/genética , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/fisiopatologia , Destreza Motora , Exame Neurológico , Fenótipo , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
11.
Thorax ; 73(6): 510-518, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29101284

RESUMO

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.


Assuntos
Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/genética , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/microbiologia , Adulto , Idoso , Progressão da Doença , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Lectina de Ligação a Manose/genética , Microbiota , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Escarro/microbiologia
13.
Am J Transplant ; 18(1): 197-206, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28649744

RESUMO

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.


Assuntos
Infecções Bacterianas/mortalidade , Rejeição de Enxerto/mortalidade , Transplante de Fígado/mortalidade , Lectina de Ligação a Manose/genética , Polimorfismo Genético , Complicações Pós-Operatórias , Doadores de Tecidos , Adulto , Idoso , Infecções Bacterianas/etiologia , Infecções Bacterianas/patologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Lectina de Ligação a Manose/deficiência , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida
14.
Clin Rheumatol ; 37(2): 555-558, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28879439

RESUMO

Ankylosing spondylitis (AS) patients may have higher prevalence of mannose-binding lectin (MBL) deficiency than normal individuals. MBL deficiency may influence susceptibility to infections. The aim of the study was to verify if MBL deficiency in patients with AS predisposes to infections. We studied 60 patients with AS diagnosed according to the Assessment of SpondyloArthritis international Society (ASAS) criteria. These patients had their MBL serum levels determinated. Twenty-five individuals were identified as MBL deficient (serum values 100 ng/mL). These patients were paired with 35 "sufficient" MBL producers (median serum level = 700 ng/mL; range 150-4100 ng/mL) for gender, age, use of medications, and tobacco exposure. Medical records of all patients were retrospectively investigated for the period of 5 years and the rate of infection occurrence was compared in the two groups. AS patients with MBL deficiency had higher number of urinary tract infections (p = 0.03; IRR = 2.33; 95% CI = 0.95-6.04) and tuberculosis (p = 0.008; IRR = 9.8; 95% CI = 1.2-441.6) than controls. Regarding tuberculosis infection, one patient (2.8%) in the MBL-sufficient group and six (24.0%) from the deficient group had this infection. The MBL-sufficient patient and five from the deficient group have had latent infections, detected in the screening tests done previous to anti-TNF drug use. The other, in the deficient group, had lung infection while not on anti-TNF treatment. Another patient, from the deficient group, has had tuberculosis skeletal infection in the past. We found a significant association between MBL deficiency and higher risk of tuberculosis and urinary tract infection in patients with AS. More studies with higher number of patients are needed to confirm this finding.


Assuntos
Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/complicações , Espondilite Anquilosante/complicações , Tuberculose/complicações , Adulto , Idoso , Antirreumáticos/uso terapêutico , Feminino , Humanos , Masculino , Lectina de Ligação a Manose/sangue , Erros Inatos do Metabolismo/sangue , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Espondilite Anquilosante/sangue , Espondilite Anquilosante/tratamento farmacológico , Tuberculose/sangue , Adulto Jovem
16.
Autoimmunity ; 50(7): 409-413, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28898115

RESUMO

OBJECTIVE: To investigate the association between mannose-binding lectin (MBL) serum level and MBL2 polymorphisms, and the frequency of spontaneous miscarriages in rheumatoid arthritis (RA) patients. METHODS: One hundred seventy seven women (mean age 50 years) with RA from Southern Brazil were studied and 4.5% had a history of abortion (8/177). The MBL levels were determined by ELISA. MBL2 polymorphisms in the promoter (-550H/L, -221X/Y), 5' untranslated region (4 P/Q) and exon 1 (p.Gly54Asp: B allele, p.Arg52Cys: D allele and p.Gly57Glu: C allele; collectively labelled O) were genotyped by sequencing. RESULTS: Mannose-binding lectin levels of RA patients ranged from ≤100 ng/mL to 6640 ng/mL (median 541.5 ng/mL). There was a significant difference in MBL median levels (100 ng/mL vs. 625 ng/mL, respectively, p = .001) and frequency of MBL deficiency (75.0% vs. 24.1%, p = .007, OR = 10.3, 95%CI = 1.9-55.4), in patients with a history of miscarriage vs those without it. Patients with RA and miscarriage had more frequently haplotypes related with low MBL levels (p = .007, OR = 10.5, 95%CI = 1.3-84) than high producers. Moreover, LYPB haplotype and O allele were significantly associated with the occurrence of miscarriage (p = .001, OR = 9.7, 95%CI = 2.4-39.1 and p = .009, OR = 5.9, 95%CI = 1.4-23.4, respectively). CONCLUSIONS: The results suggest that MBL deficiency and the presence of MBL2 gene polymorphisms that lead to MBL deficiency are risk factors for the occurrence of miscarriage in patients with RA.


Assuntos
Aborto Espontâneo/sangue , Aborto Espontâneo/etiologia , Artrite Reumatoide/complicações , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/complicações , Adulto , Alelos , Substituição de Aminoácidos , Biomarcadores , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Lectina de Ligação a Manose/genética , Erros Inatos do Metabolismo/genética , Pessoa de Meia-Idade , Razão de Chances
17.
Stem Cell Rev Rep ; 13(6): 793-800, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28918528

RESUMO

Several mechanisms have been postulated for orchestrating the mobilization of hematopoietic stem/progenitor cells (HSPCs), and we previously proposed that activation of the complement cascade plays a crucial role in the initiation and execution of the egress of HSPCs from bone marrow (BM) into peripheral blood (PB). In support of this notion, we demonstrated that mice deficient in the mannan-binding lectin (MBL) pathway, which activates the proximal part of the complement cascade, as well as mice deficient in the fifth component of the complement cascade (C5), which is part of the distal part of the complement cascade, are poor mobilizers. To further narrow down on the exact mechanisms and the molecules involved, we performed studies in mice that do not express the receptor C5aR, which binds the C5 cleavage fragments, C5a and C5adesArg. We also employed the plasma stable nucleic acid aptamer AON-D21 that binds and neutralizes C5a and C5adesArg. We present evidence that mice deficient in C5aR or treated with AON-D21 are poor HSPC mobilizers, thereby establishing a critical role for the C5a/C5adesArg-C5aR axis in the mobilization process. While enhancing mobilization is of clinical importance for poor mobilizers, inhibition of the complement cascade could be of therapeutic importance in patients suffering from paroxysmal nocturnal hemoglobinuria (PNH) or acquired hemolytic syndrome (aHUS).


Assuntos
Complemento C5a/genética , Células-Tronco Hematopoéticas/citologia , Lectina de Ligação a Manose/genética , Receptor da Anafilatoxina C5a/genética , Anafilatoxinas/genética , Animais , Ativação do Complemento/genética , Complemento C5a des-Arginina/genética , Lectina de Ligação a Manose da Via do Complemento/genética , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Hemoglobinúria Paroxística , Humanos , Lectina de Ligação a Manose/deficiência , Camundongos
18.
J Am Soc Nephrol ; 28(11): 3175-3181, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28698271

RESUMO

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.


Assuntos
Glomerulonefrite por IGA/sangue , Lectina de Ligação a Manose/sangue , Adulto , Feminino , Glomerulonefrite por IGA/complicações , Humanos , Masculino , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/etiologia , Prognóstico , Estudos Retrospectivos
19.
J Allergy Clin Immunol Pract ; 5(6): 1609-1616, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28634103

RESUMO

BACKGROUND: Infection is the leading cause of death in rheumatoid arthritis (RA). Corticosteroid (CS) use is a known and important risk factor for serious infections (SIs). Mannose binding lectin (MBL) is a genetically determined component of the innate immune system implicated in neonatal infections. OBJECTIVE: Our aim was to determine whether MBL deficiency is a risk factor for SIs in RA and to compare it with CS use and also synthetic and biologic disease-modifying antirheumatic drug (DMARD) therapy. METHODS: Data on 228 patients with RA were collected for up to 7 years (median = 5.9 years). Serum MBL concentrations were determined in all patients receiving synthetic (n = 96) or biologic (n = 132) DMARD therapy. RESULTS: High rates of SIs were observed in RA irrespective of treatment (17%). Similar rates of SIs were observed in synthetic and biologic DMARD users. The rates of single and multiple SIs were similar, irrespective of the use of a biologic agent. Undetectable MBL (<56 ng/mL) concentrations and maintenance prednisolone at 10 mg per day or higher were associated with an increased risk for an SI, with incident risk ratio of 4.67 (P = .001) and 4.70 (P < .001), respectively. CONCLUSIONS: Undetectable MBL and prednisolone confer a high risk for an SI. The use of biologic DMARDs did not confer substantial SI risk in this observational study. MBL deficiency is hitherto an unrecognized risk factor for an SI in RA.


Assuntos
Artrite Reumatoide/epidemiologia , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/epidemiologia , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Austrália , Feminino , Humanos , Imunidade Inata , Masculino , Lectina de Ligação a Manose/sangue , Erros Inatos do Metabolismo/tratamento farmacológico , Pessoa de Meia-Idade , Risco , Adulto Jovem
20.
PLoS One ; 12(5): e0178032, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28558032

RESUMO

OBJECTIVES: Studies on the influence of mannose-binding lectin (MBL) deficiency on infection susceptibility in preterm infants have yielded controversial results. We investigated the association of genotype-based MBL levels with outcome in very-low-birth weight infants (VLBWI). METHODS: We genotyped 3 genetic variants of MBL2 (rs1800450, rs1800451, rs5030737) in 6878 VLBWI. MBL plasma levels were categorized as normal (wild type, A/A), low (heterozygotes, A/O) or undetectable (homozygotes, O/O). Primary outcome was the effect of genotype-based MBL2 levels on blood-culture proven and clinical sepsis during primary stay in hospital. We also evaluated burden of infection within 24 months after discharge. RESULTS: We found no association between MBL levels and sepsis risk in the whole cohort. Infants without measurable MBL levels born between 32 0/7 to 36 6/7 weeks of gestation, however, had a higher rate of Gram-negative sepsis than infants with normal or reduced MBL levels. In a follow-up investigation at 24 months (n = 1070 infants), infants without measurable MBL levels suffered more frequently from stomatitis and urinary tract infection. CONCLUSIONS: In a large cohort of VLBWI MBL2 deficiency had no major impact on infection risk unless children were born between 32 0/7 and 36 6/7 weeks of gestation.


Assuntos
Recém-Nascido de muito Baixo Peso , Lectinas de Ligação a Manose/genética , Polimorfismo Genético , Estudos de Coortes , Humanos , Recém-Nascido , Lectina de Ligação a Manose/deficiência , Lectina de Ligação a Manose/genética , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/genética
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