RESUMO
The poor remodeling of placental spiral arteries seen in preeclampsia is also discussed to contribute to recurrent pregnancy loss (RPL) preceded by abnormal angiogenesis and excessive complement activation. Low levels of Mannose-binding-lectin (MBL), a pattern recognition molecule (PRM) of the lectin pathway, have been found in women with RPL. We propose that pregnancy loss is connected to defective angiogenesis with reperfusion damage in the placenta and decreased levels of PRM in the lectin pathway in women with RPL. In this cohort study, we investigate the angiogenic factors and the lectin complement pathway in early pregnancy and their time-dependent relationship with pregnancy outcomes in 76 women with secondary RPL (sRPL) who have at least four prior pregnancy losses and a live birth. We evaluated levels of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Vascular Endothelial Growth Factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PRMs, MBL, ficolin-1, -2, -3 and an additional soluble PRM, Pentraxin-3, during the 5th, 6th, and 7th gestational weeks. Our results showed that, compared to live births, pregnancies that ended in loss were associated with elevated VEGF levels and decreased levels of the Ang-2/Ang-1 ratio. Also, increasing levels of ficolin-2 were significantly associated with pregnancy loss, with MBL showing no association. Our research suggests that women with sRPL may have inadequate placentation with impaired angiogenesis in pregnancies ending in a loss.
Assuntos
Aborto Habitual , Lectina de Ligação a Manose da Via do Complemento , Lectinas , Lectina de Ligação a Manose , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Humanos , Feminino , Gravidez , Adulto , Aborto Habitual/imunologia , Aborto Habitual/sangue , Lectina de Ligação a Manose da Via do Complemento/imunologia , Lectinas/metabolismo , Lectinas/sangue , Lectinas/imunologia , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue , Angiopoietina-2/metabolismo , Angiopoietina-2/imunologia , Angiopoietina-2/sangue , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Angiopoietina-1/sangue , Angiopoietina-1/metabolismo , Componente Amiloide P Sérico/metabolismo , Ficolinas , Estudos de Coortes , Placenta/imunologia , Placenta/metabolismo , Placenta/patologia , Resultado da Gravidez , Indutores da Angiogênese/metabolismo , Ativação do Complemento/imunologiaRESUMO
Preoperative glucocorticoid administration reduces the systemic inflammatory response. Pentraxin 3 (PTX3) is a novel inflammatory marker belonging to the humoral arm of innate immunity exerting a potentially protective host response. This study evaluated PTX3 and other complement marker changes after preoperative methylprednisolone (MP) early after total knee arthroplasty (TKA). Seventy patients were randomized (1 : 1) to preoperative intravenous (i.v.) MP 125 mg (group MP) or isotonic saline i.v. (group C). The outcomes included change in plasma PTX3, mannose-binding lectin (MBL), ficolins (ficolin-1, -2 and -3), complement components (C4 and C3), terminal complement complex (TCC) and C-reactive protein (CRP) concentrations. Blood samples were analysed at baseline and 2, 6, 24 and 48 h after surgery with complete sampling from 63 patients for analyses. MP resulted in an increase in circulating PTX3 compared to saline from baseline to 24 h postoperatively (P < 0·001), while MP reduced the systemic inflammatory response (CRP) 24 and 48 h postoperatively (P < 0·001). However, the small postoperative changes in MBL, ficolin-1, -2 and -3, C4, C3 and TCC concentrations did not differ between groups (P > 0·05). In conclusion, preoperative MP 125 mg increased circulating PTX3 and reduced the general inflammatory response (CRP) early after TKA, but did not affect other complement markers.
Assuntos
Anti-Inflamatórios/uso terapêutico , Artroplastia do Joelho , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Inflamação/imunologia , Metilprednisolona/uso terapêutico , Componente Amiloide P Sérico/metabolismo , Idoso , Proteínas do Sistema Complemento/metabolismo , Método Duplo-Cego , Feminino , Humanos , Imunidade Inata , Lectinas/metabolismo , Masculino , Lectina de Ligação a Manose/sangue , Pessoa de Meia-Idade , Efeito Placebo , Cuidados Pré-Operatórios , FicolinasRESUMO
AIM: To compare HbA1c and fasting plasma glucose assessment, with the 2-h oral glucose tolerance test as reference, in screening for diabetes in people with turberculosis. METHODS: Individuals (N=268) with newly diagnosed smear-positive tuberculosis were screened for diabetes at a tertiary hospital in Lahore, Pakistan. Diabetes diagnosis was based on WHO criteria: thresholds were ≥48 mmol/mol (≥6.5%) for HbA1c and ≥7.0mmol/l for fasting plasma glucose. RESULTS: The proportion of participants diagnosed with diabetes was 4.9% (n =13) by oral glucose tolerance test, while 11.9% (n =32) and 14.6% (n =39) were diagnosed with diabetes using HbA1c and fasting plasma glucose criteria, respectively. The area under the receiver-operating characteristic curve was 0.79 (95% CI 0.64 to 0.94) for HbA1c and 0.61 (95% CI 0.50 to 0.73) for fasting plasma glucose, with a borderline significant difference between the two tests (P=0.07). CONCLUSIONS: HbA1c and fasting plasma glucose performed equally in terms of diagnosing new diabetes cases in individuals with tuberculosis, but the proportion of participants falsely classified as positive was higher for fasting plasma glucose. This may be explained by acute blood glucose fluctuations when using fasting plasma glucose. HbA1c may be a more reliable test in individuals with transient hyperglycaemia.
Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Jejum/sangue , Hemoglobinas Glicadas/análise , Programas de Rastreamento/métodos , Tuberculose/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/complicações , Reações Falso-Positivas , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Programas de Rastreamento/normas , Pessoa de Meia-Idade , Paquistão , Tuberculose/complicaçõesRESUMO
Essentials Abdominal aortic aneurysm (AAA) is asymptomatic and its evolution unpredictable. To find novel potential biomarkers of AAA, microvesicles are an excellent source of biomarkers. Ficolin-3 is increased in microvesicles obtained from activated platelets and AAA tissue. Increased ficolin-3 plasma levels are associated with AAA presence and progression. SUMMARY: Background Abdominal aortic aneurysm (AAA) patients are usually asymptomatic and AAA evolution is unpredictable. Ficolin-3, mainly synthesized by the liver, is a molecule of the lectin complement-activation pathway involved in AAA pathophysiology. Objectives To define extra-hepatic sources of ficolin-3 in AAA and investigate the role of ficolin-3 as a biomarker of the presence and progression of AAA. Methods Microvesicles (exosomes and microparticles) were isolated from culture-conditioned medium of ADP-activated platelets, as well as from AAA tissue-conditioned medium (thrombus and wall). Ficolin-3 levels were analyzed by western-blot, real-time PCR, immunohistochemistry and ELISA. Results Increased ficolin-3 levels were observed in microvesicles isolated from activated platelets. Similarly, microvesicles released from AAA tissue display increased ficolin-3 levels as compared with those from healthy tissue. Moreover, ficolin-3 mRNA levels in the AAA wall were greatly increased compared with healthy aortic walls. Immunohistochemistry of AAA tissue demonstrated increased ficolin-3, whereas little staining was present in healthy walls. Finally, increased ficolin-3 levels were observed in AAA patients' plasma (n = 478) compared with control plasma (n = 176), which persisted after adjustment for risk factors (adjusted odds ratio [OR], 5.29; 95% confidence interval [CI], 3.27, 8.57)]. Moreover, a positive association of ficolin-3 with aortic diameter (Rho, 0.25) and need for surgical repair was observed, also after adjustment for potential confounding factors (adjusted hazard ratio, 1.55; 95% CI, 1.11, 2.15). Conclusions In addition to its hepatic expression, ficolin-3 may be released into the extracellular medium via microvesicles, by both activated cells and pathological AAA tissue. Ficolin-3 plasma levels are associated with the presence and progression of AAA, suggesting its potential role as a biomarker of AAA.
Assuntos
Aneurisma da Aorta Abdominal/sangue , Glicoproteínas/sangue , Lectinas/sangue , Idoso , Biomarcadores/sangue , Plaquetas/metabolismo , Meios de Cultivo Condicionados/química , Dinamarca , Progressão da Doença , Humanos , Hipertensão/diagnóstico , Masculino , Programas de Rastreamento , Microcirculação , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnósticoRESUMO
YKL-40, also called chitinase-3-like-1 protein, is an inflammatory biomarker that has been associated with disease severity in inflammatory and malignant diseases, including AML, multiple myeloma and lymphomas. The objective of the current study was to assess the prognostic value of pretransplant recipient and donor plasma YKL-40 concentrations in patients with AML (n=624) or myelodysplastic syndrome (n=157) treated with allogeneic hematopoietic cell transplantation (HCT). In recipients, the plasma YKL-40 concentrations were increased when the HCT-comorbidity index was ⩾5 (P=0.028). There were no significant associations between plasma YKL-40 concentrations in recipients and any outcome measures. In donors with YKL-40 plasma concentrations above the age-adjusted 95th percentile, a trend toward increased grade II-IV acute GvHD in recipients was observed (adjusted hazard ratio 1.39 (95% confidence interval 1.00-1.94), P=0.050), with no significant associations with overall survival, treatment-related mortality or relapse. In conclusion, our study shows that YKL-40 does not aid risk stratification of patients undergoing allogeneic HCT, but suggests that YKL-40 may aid donor selection when multiple, otherwise equal, donors are available.
Assuntos
Proteína 1 Semelhante à Quitinase-3/sangue , Seleção do Doador/métodos , Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Adolescente , Adulto , Idoso , Aloenxertos , Doadores de Sangue , Estudos de Coortes , Feminino , Substâncias de Crescimento/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
In patients with typical angina pectoris, inducible myocardial ischaemia and macroscopically normal coronaries (cardiac syndrome X (CSX)), a significantly elevated plasma level of terminal complement complex (TCC), the common end product of complement activation, has been observed without accompanying activation of the classical or the alternative pathways. Therefore, our aim was to clarify the role of the ficolin-lectin pathway in CSX. Eighteen patients with CSX, 37 stable angina patients with significant coronary stenosis (CHD) and 54 healthy volunteers (HC) were enrolled. Serum levels of ficolin-2 and ficolin-3, ficolin-3/MASP-2 complex and ficolin-3-mediated TCC deposition (FCN3-TCC) were determined. Plasma level of TCC was significantly higher in the CSX than in the HC or CHD group (5.45 versus 1.30 versus 2.04 AU/ml, P < 0.001). Serum levels of ficolin-2 and ficolin-3 were significantly lower in the CSX compared to the HC or CHD group (3.60 versus 5.80 or 5.20 µg/ml, P < 0.05; 17.80 versus 24.10 or 26.80 µg/ml, P < 0.05). The ficolin-3/MASP-2 complex was significantly lower in the CSX group compared to the HC group (92.90 versus 144.90 AU/ml, P = 0.006). FCN3-TCC deposition was significantly lower in the CSX group compared to the HC and CHD groups (67.8% versus 143.3% or 159.7%, P < 0.05). In the CSX group, a significant correlation was found between TCC and FCN3-TCC level (r = 0.507, P = 0.032) and between ficolin-3/MASP-2 complex level and FCN3-TCC deposition (r = 0.651, P = 0.003). In conclusion, in patients with typical angina and myocardial ischaemia despite macroscopically normal coronary arteries, low levels of several lectin pathway parameters were observed, indicating complement activation and consumption. Complement activation through the ficolin-lectin pathway might play a role in the complex pathomechanism of CSX.
Assuntos
Complexo de Ataque à Membrana do Sistema Complemento/genética , Lectina de Ligação a Manose da Via do Complemento/genética , Glicoproteínas/imunologia , Lectinas/imunologia , Serina Proteases Associadas a Proteína de Ligação a Manose/imunologia , Angina Microvascular/imunologia , Adulto , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação da Expressão Gênica , Glicoproteínas/sangue , Glicoproteínas/genética , Humanos , Lectinas/sangue , Lectinas/genética , Masculino , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Angina Microvascular/sangue , Angina Microvascular/genética , Angina Microvascular/patologia , Pessoa de Meia-Idade , Transdução de Sinais , FicolinasRESUMO
BACKGROUND: Several lines of evidence support the involvement of the lectin pathway of complement (LP) in the pathogenesis of acute ischemic stroke. The aim of this multicenter observational study was to assess the prognostic value of different circulating LP initiators in acute stroke. METHODS: Plasma levels of the LP initiators ficolin-1, -2, and -3 and mannose-binding lectin (MBL) were measured in 80 stroke patients at 6 h only and in 85 patients at 48 h and later. Sixty-one age- and sex-matched healthy individuals served as controls. Stroke severity was measured on admission using the National Institutes of Health Stroke Scale (NIHSS). The outcome was measured at 90 days by the modified Rankin Scale (mRS). RESULTS: Ficolin-1 was decreased in patients compared with controls measured at 6 h (median 0.13 vs 0.33 µg/ml, respectively, p < 0.0001). At 48 h, ficolin-1 was significantly higher (0.45 µg/ml, p < 0.0001) compared to the 6 h samples and to controls. Likewise, ficolin-2 was decreased at 6 h (2.70 vs 4.40 µg/ml, p < 0.0001) but not at 48 h. Ficolin-3 was decreased both at 6 and 48 h (17.3 and 18.23 vs 21.5 µg/ml, p < 0.001 and <0.05, respectively). For MBL no difference was detected between patients and controls or within patients at the different time points. In multivariate analysis, early ficolin-1 was independently associated with unfavorable mRS outcome (adjusted odds ratio (OR): 2.21, confidence interval (CI) 95 % 1.11-4.39, p = 0.023). Early ficolin-1 improved the discriminating ability of an outcome model including NIHSS and age (area under the curve (AUC) 0.95, CI 95 % 0.90-0.99, p = 0.0001). CONCLUSIONS: The ficolins are consumed within 6 h after stroke implicating activation of the LP. Early ficolin-1 is selectively related to 3-month unfavorable outcome.
Assuntos
Isquemia Encefálica/complicações , Lectinas/sangue , Acidente Vascular Cerebral/sangue , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Regressão , Fatores de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Fatores de Tempo , FicolinasRESUMO
UNLABELLED: ESSENTIALS: The lectin pathway's MASP-1/2 activates coagulation factors but the trigger of the activation is unknown. MASP-1/2 activation was assessed by quantifying complexes between MASPs and antithrombin/C1-inhibitor. Activated platelets and fibrin were demonstrated to activate MASP-1 and MASP-2 both in vitro and in vivo. These findings may represent a crossroad between the complement and the coagulation systems. BACKGROUND: The activated forms of the complement lectin pathway (LP) proteases MASP-1 and MASP-2 are able to cleave the coagulation factors prothrombin, fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor in vitro. In vivo studies also show that MASP-1 is involved in thrombogenesis. OBJECTIVES: To clarify the not yet identified mechanisms involved in triggering activation of the LP during thrombotic reactions. METHODS: Novel sandwich-ELISAs for detection of complexes between MASP-1 or MASP-2 and the serpins C1 inhibitor (C1-INH) or antithrombin (AT), were used to specifically detect and quantify the activated forms of MASP-1 and MASP-2. RESULTS: Activated platelets were shown by flow cytometry to bind Ficolin-1, -2 and -3 but not MBL, which was associated with activation of MASP-1 and MASP-2. We also demonstrated that fibrin and the plasmin-generated fibrin fragment DD in plasma, bind and activate MASP-1 and MASP-2. As demonstrated by the ELISA and SDS-PAGE/Western blotting, the fibrin-associated activation was reflected in a specific inactivation by AT during clotting without the assistance of heparin. In all other cases the MASPs were, as previously reported, inactivated by C1-INH. In systemic lupus erythematosus patients with thrombotic disease and in polytrauma patients, the levels of activated MASP-1 and MASP-2 in complex with both AT and C1-INH were associated with markers of thrombotic disease and contact/coagulation system activation. CONCLUSIONS: MASP-1 and MASP-2 are activated during blood clotting. This activation is triggered by activated platelets and by the generation of fibrin during thrombotic reactions in vitro and in vivo, and may represent a novel activation/amplification mechanism in thromboinflammation.
Assuntos
Coagulação Sanguínea , Plaquetas/enzimologia , Lectina de Ligação a Manose da Via do Complemento , Inflamação/enzimologia , Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo , Ativação Plaquetária , Trombose/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Antitrombina/metabolismo , Plaquetas/imunologia , Estudos de Casos e Controles , Proteína Inibidora do Complemento C1/metabolismo , Ativação Enzimática , Feminino , Fibrina/metabolismo , Humanos , Inflamação/sangue , Inflamação/imunologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/enzimologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Serina Proteases Associadas a Proteína de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Traumatismo Múltiplo/sangue , Traumatismo Múltiplo/enzimologia , Traumatismo Múltiplo/imunologia , Ligação Proteica , Transdução de Sinais , Trombose/sangue , Trombose/imunologia , Fatores de Tempo , Adulto JovemRESUMO
The complement system can be activated via the lectin pathway by the recognition molecules mannose-binding lectin (MBL) and the ficolins. Ficolin-2 exhibits binding against a broad range of ligands, including biomaterials in vitro, and low ficolin-2 levels are associated with increased risk of infections. Thus, we investigated the biocompatibility of the recognition molecules of the lectin pathway in two different types of cardiopulmonary bypass circuits. Bloods were drawn at five time-points before, during and postoperatively from 30 patients undergoing elective cardiac surgery. Patients were randomized into two groups using different coatings of cardiopulmonary bypass circuits, Phisio® (phosphorylcholine polymer coating) and Bioline® (albumin-heparin coating). Concentrations of MBL, ficolin-1, -2 and -3 and soluble C3a and terminal complement complex (TCC) in plasma samples were measured. Ficolin-3-mediated complement activation potential was evaluated with C4, C3 and TCC as output. There was no significant difference between the two circuit materials regarding MBL, ficolin-1 and -3. In the Bioline® group the ficolin-2 levels decreased significantly after initiation of surgery (P < 0.0001) and remained reduced throughout the sampling period. This was not seen for Phisio®-coated circuits. Ficolin-3-mediated complement activation potential was reduced significantly in both groups after start of operation (P < 0.0001), whereas soluble C3a and TCC in the samples were increased (P < 0.0001). Ficolin-2 was depleted from plasma during cardiac surgery when using heparin-coated bypass circuits and did not reach baseline level 24 h postoperation. These findings may have implications for the postoperative susceptibility to infections in patients undergoing extracorporeal circulation procedures.
Assuntos
Anticoagulantes , Ponte Cardiopulmonar , Lectina de Ligação a Manose da Via do Complemento , Stents Farmacológicos , Heparina , Lectinas/sangue , Proteínas do Sistema Complemento/metabolismo , Feminino , Glicoproteínas/sangue , Humanos , Masculino , Período Pós-Operatório , Fatores de Tempo , FicolinasRESUMO
BACKGROUND: The pattern recognition molecule pentraxin-3 (PTX3) is a novel potential marker of prognosis, as elevated levels are associated with both disease severity and mortality in patients with a wide range of conditions. However, the usefulness of PTX3 as a prognostic biomarker in a general hospital setting is unknown. PATIENTS AND METHODS: The study cohort consisted of 1326 unselected, consecutive patients (age >40 years) admitted to a community hospital in Copenhagen, Denmark. Patients were followed until death or for a median of 11.5 years after admission. The main outcome measure was all-cause mortality. Serum samples collected from patients at admission and from 192 healthy control subjects were quantified for PTX3 level by enzyme-linked immunosorbent assay. RESULTS: PTX3 was elevated in patients (median 3.7 ng mL(-1) , range 0.5-209.8) compared with healthy nonhospitalized subjects (median 3.5 ng mL(-1) , range 0.0-8.3; P = 0.0003). Elevated PTX3 levels, defined as above the 95th percentile of the concentration in healthy subjects, were associated with increased overall mortality during the study (P < 0.0001). This increase in mortality was greatest in the short term, with an unadjusted hazard ratio (HR) of 6.4 [95% confidence interval (CI) 3.8-11.0] at 28 days after admission, compared to 1.7 (95% CI 1.4-2.0) at the end of follow-up. These results were still significant after adjustment for age, gender and glomerular filtration rate: adjusted HR of 5.0 (95% CI 2.9-8.8) and 1.4 (95% CI 1.2-1.8), respectively. CONCLUSION: These results suggest that PTX3 could be a widely applicable marker of short-term mortality in hospitalized patients and may be useful in the initial risk stratification.
Assuntos
Proteína C-Reativa/metabolismo , Mortalidade Hospitalar , Componente Amiloide P Sérico/metabolismo , Idoso , Biomarcadores/metabolismo , Estudos de Casos e Controles , Dinamarca/epidemiologia , Feminino , Hospitalização/estatística & dados numéricos , Hospitais Comunitários , Humanos , Estimativa de Kaplan-Meier , Masculino , PrognósticoRESUMO
OBJECTIVES: To determine to what extent shared epitopes, smoking, and anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with disease activity and erosive disease in patients with rheumatoid arthritis (RA) at disease onset. METHOD: RA patients not previously treated with disease-modifying anti-rheumatic drugs (DMARDs) and with a disease duration of < 6 months (CIMESTRA study) were examined for shared epitopes, anti-CCP antibodies, immunoglobulin M rheumatoid factor (IgM-RF) and IgA-RF, radiographic erosive changes in hands and feet, and clinical disease activity. RESULTS: The study comprised 153 patients, of whom 104 (68%) were ever-smokers. The prevalence of patients with 0, 1, or 2 shared epitopes was 40 (48%), 71 (49%), and 33 (23%), respectively. Anti-CCP antibodies, IgM-RF, and IgA-RF were present in 89 (58%), 99 (65%), and 82 (54%) patients, respectively. Among smokers, erosive disease was associated with anti-CCP antibodies [odds ratio (OR) 3.9, 95% confidence interval (CI) 1.6-9.3], IgM-RF (OR 4.9, 95% CI 1.9-12), and IgA-RF (OR 2.8, 95% CI 1.2-6.4) but absent with regard to shared epitopes. Among never-smokers, erosive disease was not associated with either shared epitopes or antibodies. All antibody levels measured were associated with smoking and shared epitopes. CONCLUSIONS: Shared epitopes and smoking were associated with the production of anti-CCP antibodies and rheumatoid factors of IgM and IgA isotypes, which again were associated with erosive disease at presentation only in smokers. As shared epitopes and smoking were not directly associated with erosive disease, smoking may enhance the development of erosive disease in RA at different levels or through separate pathways.
Assuntos
Artrite Reumatoide/epidemiologia , Autoanticorpos/sangue , Peptídeos Cíclicos/imunologia , Fator Reumatoide/sangue , Fumar/epidemiologia , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Epitopos/imunologia , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Articulações/imunologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fator Reumatoide/imunologia , Fatores de Risco , Estudos Soroepidemiológicos , Fumar/imunologia , Adulto JovemRESUMO
The pattern recognition molecules of the lectin complement pathway are important components of the innate immune system with known functions in host-virus interactions. This paper summarizes current knowledge of how these intriguing molecules, including mannose-binding lectin (MBL), Ficolin-1, -2 and -3, and collectin-11 (CL-11) may influence HIV-pathogenesis. It has been demonstrated that MBL is capable of binding and neutralizing HIV and may affect host susceptibility to HIV infection and disease progression. In addition, MBL may cause variations in the host immune response against HIV. Ficolin-1, -2 and -3 and CL-11 could have similar functions in HIV infection as the ficolins have been shown to play a role in other viral infections, and CL-11 resembles MBL and the ficolins in structure and binding capacity.
Assuntos
Lectina de Ligação a Manose da Via do Complemento/imunologia , Infecções por HIV/imunologia , Lectina de Ligação a Manose da Via do Complemento/genética , Infecções por HIV/fisiopatologia , Humanos , Modelos Biológicos , Polimorfismo GenéticoRESUMO
OBJECTIVES: Autoimmunity may in part result from deficiencies in the processing of apoptotic debris. As mannose-binding lectin (MBL) is involved in such processes, we hypothesized that the variants in the MBL2 gene resulting in MBL deficiency confer an increased risk of nephritis in systemic lupus erythematosus (SLE). METHODS: A total of 171 SLE patients attending a Danish tertiary rheumatology referral center were included. Common variant alleles in exon 1 of the MBL2 gene (R52C, rs5030737; G54D, rs1800450; G57E, rs1800451) were genotyped. The normal allele and variant alleles are termed A and O, respectively. The follow-up period was defined as the time from fulfillment of the ACR 1987 classification criteria for SLE until the occurrence of an event (nephritis, end-stage renal disease (ESRD), or death) or end of follow-up. Cox regression analyses were controlled for gender, age and race. RESULTS: During a median follow-up of 5.7 years, nephritis developed in 94 patients, and ESRD developed in 16 of these patients. Twenty-seven patients died. The distribution of the MBL2 genotypes A/A, A/O and O/O was 58%, 35% and 7.0%, respectively. Compared to the rest, O/O patients had 2.6 times (95% CI: 1.2-5.5) higher risk of developing nephritis, and their risk of death after 10 years was 6.0 times increased (95% CI: 1.0-36). MBL serum levels below 100 ng/ml were associated with a 2.0 (95% CI: 1.2-3.4; p = 0.007) increased risk of developing nephritis. ESRD and histological class of nephritis were not associated with MBL deficiency. CONCLUSIONS: Genetically determined MBL deficiency was associated with development of nephritis in SLE patients, but not with histological class of nephritis or ESRD.
Assuntos
Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/genética , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/genética , Adolescente , Adulto , Idoso , Alelos , Criança , Dinamarca/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/epidemiologia , Masculino , Lectina de Ligação a Manose/genética , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Regressão , Fatores de Risco , Adulto JovemRESUMO
Cardiac arrest causes generalized ischaemia/hypoxia, and subsequent resuscitation inflicts reperfusion injury, the pathology of which is not fully understood. Moreover, predicting the prognosis of comatose, post-cardiac arrest patients is a complex clinical challenge. We hypothesized that the extent of complement activation might be a reliable predictor of mortality in this population. Forty-six comatose cardiac arrest patients were enrolled into our prospective cohort study, conducted in a tertiary care university clinic. All subjects were cooled to 32-34 °C body temperature for 24 h and then allowed to rewarm to normothermia. All patients underwent diagnostic coronary angiography. On admission, at 6 and 24 h, blood samples were taken from the arterial catheter. In these, complement products (C3a, C3, C4d, C4, SC5b9 and Bb) were measured by ELISA in blood samples. Patients were followed up for 30 days; 22 patients (47.8%) died by the end of this period. We observed that complement activation (determined as the C3a to C3 ratio) was higher in non-survivors than in survivors at each time point. In the multivariate Cox regression analysis, the C3a/C3 ratio determined 24 h after the initiation of therapeutic hypothermia predicted 30-day mortality regardless of age, sex and the APACHE II score. Complement activation occurs in post-cardiac arrest patients, and its extent correlates with 30-day survival. The C3a/C3 ratio might prove useful for estimating the prognosis of comatose post-cardiac arrest patients.
Assuntos
Ativação do Complemento , Parada Cardíaca/imunologia , Parada Cardíaca/mortalidade , APACHE , Idoso , Complemento C3/análise , Complemento C3a/análise , Humanos , Pessoa de Meia-Idade , PrognósticoRESUMO
Ficolin-1 is a recognition molecule of the lectin complement pathway. The ficolin-1 gene FCN1 is polymorphic, but the functional and clinical consequences are unknown.The concentration of ficolin-1 in plasma and FCN1 polymorphisms in positions -1981 (rs2989727), -791 (rs28909068), -542 (rs10120023), -271 (rs28909976), -144 (rs10117466) and +7918 (rs1071583) were determined in 100 healthy individuals. FCN1 expression by isolated monocytes and granulocytes and ficolin-1 levels in monocyte culture supernatants were assessed in 21 FCN1-genotyped individuals. FCN1 polymorphisms were determined in a cohort of 251 patients with systemic inflammation. High ficolin-1 plasma levels were significantly associated with the minor alleles in position -542 and -144. These alleles were also significantly associated with high FCN1 mRNA expression. The level of ficolin-1 in culture supernatants was significantly higher in individuals homozygous for the minor alleles at positions -542 and -144. Homozygosity for these alleles was significantly associated with fatal outcome in patients with systemic inflammation. None of the other investigated polymorphisms were associated with FCN1 and ficolin-1 expression, concentration or disease outcome. Functional polymorphic sites in the promoter region of FCN1 regulate both the expression and synthesis of ficolin-1 and are associated with outcome in severe inflammation.
Assuntos
Lectinas/genética , Polimorfismo de Nucleotídeo Único , Síndrome de Resposta Inflamatória Sistêmica/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Expressão Gênica , Frequência do Gene , Homozigoto , Humanos , Lectinas/biossíntese , Lectinas/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/biossíntese , Síndrome de Resposta Inflamatória Sistêmica/mortalidade , FicolinasRESUMO
C1q is the central pattern-recognition molecule in the classical pathway of the complement system and is known to have a key role in the crossroads between adaptive and innate immunity. Hereditary C1q deficiency is a rare genetic condition strongly associated with systemic lupus erythematosus and increased susceptibility to bacterial infections. However, the clinical symptoms may vary. For long, the molecular basis of C1q deficiency was ascribed to only six different mutations. In the present report, we describe five new patients with C1q deficiency, present the 12 causative mutations described till now and review the clinical spectrum of symptoms found in patients with C1q deficiency. With the results presented here, confirmed C1q deficiency is reported in 64 patients from at least 38 families.
Assuntos
Complemento C1q/deficiência , Complemento C1q/genética , Mutação , Substituição de Aminoácidos , Criança , Pré-Escolar , Feminino , Doenças Genéticas Inatas/diagnóstico , Genótipo , Humanos , Masculino , LinhagemRESUMO
Complement factor H (CFH) is a regulator of the alternative complement activation pathway. Mutations in the CFH gene are associated with atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II and C3 glomerulonephritis. Here, we report a 6-month-old CFH-deficient child presenting with endocapillary glomerulonephritis rather than membranoproliferative glomerulonephritis (MPGN) or C3 glomerulonephritis. Sequence analyses showed homozygosity for a novel CFH missense mutation (Pro139Ser) associated with severely decreased CFH plasma concentration (<6%) but normal mRNA splicing and expression. The father was heterozygous carrier of the mutation, but the mother was a non-carrier. Thus, a large deletion in the maternal CFH locus or uniparental isodisomy was suspected. Polymorphic markers across chromosome 1 showed homozygosity for the paternal allele in all markers and a lack of the maternal allele in six informative markers. This combined with a comparative genomic hybridization assay demonstrated paternal isodisomy. Uniparental isodisomy increases the risk of homozygous variations in other genes on the affected chromosome. Therefore, we analyzed other susceptibility genes on chromosome 1 and found no sequence variation in membrane cofactor protein, but homozygosity for the common deletion of CFH-related proteins 1 and 3, which may contribute to the early onset of disease.
Assuntos
Fator H do Complemento/deficiência , Fator H do Complemento/genética , Glomerulonefrite/genética , Glomerulonefrite/imunologia , Dissomia Uniparental/genética , Alelos , Proteínas Sanguíneas/genética , Cromossomos Humanos Par 1/genética , Proteínas Inativadoras do Complemento C3b/genética , Via Alternativa do Complemento/genética , Via Alternativa do Complemento/imunologia , Feminino , Regulação da Expressão Gênica , Variação Genética , Glomerulonefrite/patologia , Heterozigoto , Homozigoto , Humanos , Lactente , Proteína Cofatora de Membrana/genética , Proteína Cofatora de Membrana/imunologia , Mutação de Sentido Incorreto , RNA Mensageiro/genética , Análise de Sequência de DNARESUMO
Hereditary complete deficiency of complement component C1q is associated with a high prevalence of systemic lupus erythematosus and increased susceptibility to severe recurrent infections. An 11-year-old girl was screened for immunodeficiency due to a history of recurrent meningitis and pneumonia. Immunologic studies revealed absence of classic pathway hemolytic activity and undetectable levels of Clq. Exon-specific amplification of genomic DNA by polymerase chain reaction followed by direct sequence analysis revealed a novel homozygous missense mutation at codon 48 in the C1q C gene causing a glycine-to-arginine substitution affecting the collagen-like region of C1q. No changes were seen in the exons of the A and B chains. The mutation affected both the formation and the secretion of C1q variant molecules. We describe a novel mutation in the C1q C chain gene that leads to an interchange in amino acids resulting in absence of C1q in serum.
Assuntos
Complemento C1q/deficiência , Complemento C1q/genética , Criança , Complemento C1q/imunologia , Via Clássica do Complemento/genética , Via Clássica do Complemento/imunologia , DNA/química , DNA/genética , Feminino , Homozigoto , Humanos , Masculino , Mutação de Sentido Incorreto/imunologia , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , TurquiaRESUMO
Mannose-binding lectin (MBL) is a serum protein, which functions as an opsonin and initiator of the lectin pathway of complement. The serum concentration of MBL shows great interindividual variation because of common polymorphisms in the MBL2 gene. Although several quantitative MBL immunoassays have been developed more automated platforms for MBL analysis is urgently needed. To pursue this, we set out to develop a flexible bead-based MBL immunoassay. Serum was obtained from 98 healthy individuals and 50 patients investigated for possible immunodeficiencies. We used the Luminex xMAP bead array technology employing a mouse monoclonal anti-MBL antibody both for coating and detection. The assay was fast and reliable for measurements of MBL concentrations both in the lower and upper range. The lower detection limit was found to be 6.5 microg/l. The intra-assay coefficient and the interassay coefficient were found be 7.88% and 5.70%, respectively. A close correlation between the new assay and a reference MBL measurement ELISA was found (rho 0.9381, P < 0.0001). The bead-based assay was less sensitive to interfering anti-murine antibodies in the blood samples than when the antibodies employed were used in the reference polystyrene-based ELISA. The new assay could be performed in 3 h with less than 25 microl serum required of each sample. These results show that MBL can be measured readily using a bead-based platform, which may form an efficient basis for a multiplex approach to measure different antigens in the same sample.