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1.
J Immunol Res ; 2017: 8245879, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29094052

RESUMO

Objective: To investigate disease activity around and during pregnancy and pregnancy outcome in women with systemic lupus erythematosus (SLE) considering antiphospholipid antibody status. Moreover, differences between first and consecutive pregnancies were examined. Methods: Pregnancies > 16 weeks gestation of SLE patients receiving joint care from rheumatologists and gynecologists in two tertiary centers in the Netherlands between 2000 and 2015 were included. Disease activity, flare rate, and pregnancy outcomes and complications were assessed. Results: Ninety-six women (84% Caucasian) with 144 pregnancies were included. The median SLE(P)DAI score was 2 before, during, and after pregnancy. Flare rates were 6.3%, 20.1%, and 15.3%, respectively. Severe hypertensive disorder of pregnancy, intrauterine fetal death, preterm birth, and small-for-gestational age infants occurred in 18.1%, 4.1%, 32.7%, and 14.8%, respectively. Complication rates were similar in the first and consecutive pregnancies. Half of the women did not experience any pregnancy complication whereas 42.7% developed a complication during all pregnancies. Mean number of pregnancies was 2.4 and live births 1.7. Conclusion: In this SLE population with low disease activity, pregnancy complications were present irrespective of antiphospholipid antibody status. Furthermore, there were no differences in complication rates between the first and consecutive pregnancies as seen in healthy mothers. This information is useful for patient counseling.


Assuntos
Síndrome Antifosfolipídica/diagnóstico , Lúpus Eritematoso Sistêmico/diagnóstico , Adulto , Anticorpos Antifosfolipídeos/metabolismo , Estudos de Coortes , Aconselhamento , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Países Baixos , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Adulto Jovem
2.
Autoimmun Rev ; 16(7): 701-711, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28479488

RESUMO

OBJECTIVE: To analyze published data on the influence of maternal systemic lupus erythematosus (SLE) on different aspects of child development. METHODS: A systematic review was conducted using PubMed and Embase searches for SLE or SLE-related antibodies and physical, neurocognitive, psychiatric or motor development outcomes in children. RESULTS: In total 24 cohort and 4 case-control studies were included after initial screening of 1853 hits. Learning disorders (LD) were reported in 21.4-26% of SLE offspring, exceeding the prevalence in the general population. Four studies reported that dyslexia and reading problems were present in 14.3-21.6% of lupus offspring with a clear male predominance. Furthermore, a twofold increased rate of autism spectrum disorders (ASD) (n=1 study) and a two- to threefold increased risk for speech disorders (n=3 studies) were reported in lupus offspring compared to controls, although the latter was not statistically significant. More divergent results were found for attention deficit (n=5 studies) and behavior disorders (n=3 studies). In two large controlled studies attention disorders were more prevalent and a trend towards more behavior disorders was reported in 2 of 3 studies analyzing this subject. Finally, IQ and motor skills were not affected in respectively 7 and 5 studies. Cardiopulmonary functioning and mood disorders were scarcely investigated (both n=1). Maternal anti-SSA antibodies were associated with LD in offspring in one study. Other SLE-related antibodies were rarely studied. CONCLUSION: This systematic review suggests that maternal SLE is associated with LD (specifically dyslexia), ASD, attention deficit and probably speech problems in offspring. However, over half of the studies were assigned a low or moderate evidence level. Therefore, further research is necessary to substantiate the found evidence and expand the scope to lesser researched areas such as cardiopulmonary functioning.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Transtorno do Espectro Autista/etiologia , Lúpus Eritematoso Sistêmico/complicações , Distúrbios da Fala/etiologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Espectro Autista/epidemiologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Mães , Distúrbios da Fala/epidemiologia
3.
Clin Exp Rheumatol ; 35(3): 462-470, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28240588

RESUMO

OBJECTIVES: The current strategy for antinuclear antibody (ANA) analysis involves screening for presence with a subsequent detailed analysis of their specificity. The aim of this study is to compare the clinical and financial efficacy of this strategy between different commercial tests in a large cohort of unselected patients. METHODS: In all consecutive 1030 patients associations were defined between results from different ANA test systems and the pre-test probability for connective tissue disease (CTDs). Test systems were used for screening (ANA-IIF vs. CTD screen) and definition of their fine specificity (profile 3 line blot vs. CTD single analytes). RESULTS: Positive ANA-IIF and/or CTD screen results were found in 304 sera. Further analysis for ANA-specificity by profile 3 line blot and CTD single analytes showed 86 discrepant results of which more than a third are clinically relevant, with the CTD single analyte assay performing better than the line blot in supporting or confirming the presence of a CTD. Autoantigens present in one test but absent in the other were of minor practical use. The ANA screening and identification strategies currently employed are not cost-effective as 83% of tests were performed in order to find specific autoantibodies in patients without the fitting clinical signs or symptoms. This causes many unexpected positive results and subsequent confusion with regard to interpretation. CONCLUSIONS: We advocate that some autoantigens should be excluded from the line blot and CTD assays and propose the use of a cost-effective and selective ANA specificity testing purely based on clinical guidance.


Assuntos
Anticorpos Antinucleares/sangue , Doenças Autoimunes/diagnóstico , Doenças do Tecido Conjuntivo/diagnóstico , Kit de Reagentes para Diagnóstico , Testes Sorológicos , Especificidade de Anticorpos , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Biomarcadores/sangue , Doenças do Tecido Conjuntivo/sangue , Doenças do Tecido Conjuntivo/imunologia , Análise Custo-Benefício , Custos de Cuidados de Saúde , Humanos , Valor Preditivo dos Testes , Kit de Reagentes para Diagnóstico/economia , Reprodutibilidade dos Testes , Testes Sorológicos/economia
4.
Ann Rheum Dis ; 76(3): 554-561, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27884822

RESUMO

OBJECTIVES: Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE. METHODS: An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%. RESULTS: The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life. CONCLUSIONS: The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.


Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Corticosteroides/uso terapêutico , Anticorpos Antinucleares/sangue , Antimaláricos/uso terapêutico , Proteínas do Sistema Complemento/metabolismo , Consenso , DNA/imunologia , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/sangue , Quimioterapia de Manutenção , Indução de Remissão , Índice de Gravidade de Doença , Exacerbação dos Sintomas
6.
Rheumatology (Oxford) ; 55(5): 939-48, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26748351

RESUMO

OBJECTIVE: To determine relevant Fc-gamma receptor (FcγR) polymorphisms in relation to susceptibility to SLE and LN, and to determine the functional consequences of genetic associations found. METHODS: Using multiplex ligation-dependent probe amplification, copy number regions (CNRs) and relevant known functional single nucleotide polymorphisms of FcγRII and FcγRIII were determined in a LN-enriched cohort of 266 Dutch Caucasian SLE patients and 919 healthy Caucasian controls. Expression of FcγRs on leukocytes was assessed using flow cytometry. RESULTS: In multivariable analysis, low copy number of CNR1 (including FCGR3B; odds ratio (OR) 2.04; 95% CI: 1.29, 3.23), FCGR2A-131RR (OR 2.00; 95% CI: 1.33, 2.99), and the 2B.4 haplotype of FCGR2B (OR 1.59; 95% CI: 1.13, 2.24), but not FCGR2C open reading frame, were significantly (all P < 0.01) and independently associated with susceptibility to SLE. The 2B.4 haplotype was negatively associated with LN and led to surface expression of FcγRIIb on neutrophils and monocytes. CONCLUSION: This study is the first to investigate the most relevant and functional single nucleotide polymorphisms and copy number variations of FcγRII and FcγRIII polymorphisms in one study population, enabling the determination of the individual contribution of each polymorphism in multivariable analysis. Three polymorphisms were shown to be independently associated with susceptibility to SLE. The novel findings of a negative association of the 2B.4 haplotype with LN, and increased expression of FcγRIIb on neutrophils and monocytes as a result of this 2B.4 haplotype warrant future research in the role of these cells and FcγRs in the pathogenesis of SLE and LN.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Receptores de IgG/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Nefrite Lúpica/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex/métodos , Fases de Leitura Aberta
7.
Autoimmun Rev ; 15(1): 50-60, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26318678

RESUMO

The antiphospholipid syndrome (APS) is a systemic autoimmune disease that is characterized serologically by the presence of antiphospholipid antibodies (aPL) and clinically by vascular thrombosis and obstetric complications. The protein ß2 glycoprotein I (ß2GPI) is identified as the most important autoantigen in this syndrome. Activation of endothelial cells, thrombocytes and placental tissue by anti-ß2GPI antibodies relates to the clinical manifestations of APS. This review describes genetic and environmental factors in relation to APS and summarizes the current knowledge on abnormalities in components of both the innate and adaptive immune system in APS. The role of dendritic cells, T-cells, B-cells, monocytes, neutrophils and NK-cells as well as the complement system in APS are discussed. Several gaps in our knowledge on the pathophysiology of APS are identified and a plea is made for future extensive immune cell profiling by a systems medicine approach in order to better unravel the pathogenesis of APS, to gain more insight in the role of the immune system in APS as well as having the potential to reveal biomarkers or novel therapeutic targets.


Assuntos
Síndrome Antifosfolipídica/imunologia , Animais , Apresentação do Antígeno , Síndrome Antifosfolipídica/genética , Linfócitos B/imunologia , Células Dendríticas/imunologia , Humanos , Linfócitos T/imunologia
8.
NPJ Schizophr ; 1: 15013, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27336030

RESUMO

BACKGROUND: An increased prevalence of autoantibodies has been found in patients with schizophrenia, suggesting a role for autoimmunity in schizophrenia pathogenesis. METHODS: We examined the presence of antinuclear antibodies (ANAs), with further determination of specific antibodies, in 368 patients with a schizophrenia spectrum disorder and 283 healthy controls. RESULTS: No significant difference in prevalence of ANAs between patients (8%) and controls (11%) was found. CONCLUSION: We did not find an association between ANAs and schizophrenia spectrum disorders. We discuss potential reasons for the discrepancy with some previous studies, such as inclusion of patients using chlorpromazine, which can induce ANAs.

10.
Thromb Haemost ; 112(4): 736-42, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25008787

RESUMO

Coagulation factor deficiencies are thought to interfere with the detection of the phospholipid-dependent coagulation inhibitor known as lupus anticoagulant (LA). Treatment with vitamin K antagonists (VKA) in particular, is thought to preclude accurate LA assessment. For this reason, the procedure to detect LA includes a mixing test, in which coagulation factor deficiencies are corrected by mixing samples with an equal volume of normal plasma. Despite these mixing tests, interpretation of LA test results is considered difficult in patients receiving high intensity VKA treatment. As a result, VKA treatment is often temporarily discontinued to allow LA assessment. However, whether coagulation factor deficiencies influence LA test results is unclear. We found that neither deficiency of a single coagulation factor, nor a functional coagulation factor deficiency due to high intensity VKA treatment, resulted in false positive dRVVT- or APTT-based (silica clotting time; SCT) LA test results. LA was readily detected in unmixed samples from VKA-treated LA-positive patients with both dRVVT and SCT reagents. VKA treatment caused an underestimation of the strength of the LA with SCT reagents, but did not lead to misclassification of LA status. Although mixing with normal plasma during both screen and confirm tests allowed more accurate assessment of the strength of the LA with SCT reagents in samples with an international normalised >2.5, the mixing procedure itself lead to misclassification of LA in weakly positive samples from patients not treated with VKA. Based on these findings, we conclude that mixing studies are not necessary during LA-assessment.


Assuntos
Síndrome Antifosfolipídica/diagnóstico , Transtornos da Coagulação Sanguínea/diagnóstico , Fatores de Coagulação Sanguínea/imunologia , Testes de Coagulação Sanguínea/métodos , Inibidor de Coagulação do Lúpus/sangue , Vitamina K/antagonistas & inibidores , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Coagulação Sanguínea , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/imunologia , Testes de Coagulação Sanguínea/instrumentação , Técnicas de Laboratório Clínico , Reações Falso-Positivas , Feminino , Humanos , Coeficiente Internacional Normatizado , Inibidor de Coagulação do Lúpus/imunologia , Gravidez
11.
Ann Rheum Dis ; 73(6): 958-67, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24739325

RESUMO

The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.


Assuntos
Comitês Consultivos , Lúpus Eritematoso Sistêmico/terapia , Planejamento de Assistência ao Paciente , Gerenciamento Clínico , Humanos , Indução de Remissão/métodos , Prevenção Secundária/métodos
12.
PLoS One ; 8(10): e78459, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24205237

RESUMO

Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of systemic Lupus erythematosus (SLE), since netting neutrophils release potentially immunogenic autoantigens including histones, LL37, human neutrophil peptide (HNP), and self-DNA. In turn, these NETs activate plasmacytoid dendritic cells resulting in aggravation of inflammation and disease. How suppression of NET formation can be targeted for treatment has not been reported yet. Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1) is a surface molecule exclusively expressed on phagocytes. We recently identified SIRL-1 as a negative regulator of human neutrophil function. Here, we determine whether ligation of SIRL-1 prevents the pathogenic release of NETs in SLE. Peripheral blood neutrophils from SLE patients with mild to moderate disease activity and healthy donors were freshly isolated. NET release was assessed spontaneously or after exposure to anti-neutrophil antibodies or plasma obtained from SLE patients. The formation of NETs was determined by microscopic evaluation using DNA dyes and immunostaining of NET components, as well as by live cell imaging. We show that SLE neutrophils spontaneously release NETs. NET formation is enhanced by stimulation with antibodies against LL37. Inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and MEK-ERK signaling prevents NET release in response to these antibodies. Signaling via the inhibitory receptor SIRL-1 was induced by ligation with anti-SIRL-1 specific antibodies. Both spontaneous and anti-neutrophil antibody-induced NET formation is suppressed by engagement of SIRL-1. Furthermore, NET release by healthy neutrophils exposed to SLE plasma is inhibited by SIRL-1 ligation. Thus, SIRL-1 engagement can dampen spontaneous and anti-neutrophil antibody-induced NET formation in SLE, likely by suppressing NAPDH oxidase and MEK-ERK activity. Together, these findings reveal a regulatory role for SIRL-1 in NET formation, potentially providing a novel therapeutic target to break the pathogenic loop in SLE.


Assuntos
Armadilhas Extracelulares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Neutrófilos/imunologia , Receptores Imunológicos/imunologia , Adulto , Anticorpos/imunologia , Formação de Anticorpos/imunologia , Feminino , Humanos , Ligadura/métodos , Sistema de Sinalização das MAP Quinases/imunologia , Masculino , Pessoa de Meia-Idade , NADPH Oxidases/imunologia , Fagócitos/imunologia
13.
Autoimmun Rev ; 12(5): 617-28, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23232124

RESUMO

Systemic Lupus Erythematosus (SLE) is a clinically diverse, chronic autoimmune disease with inflammation in several organ systems. Its pathogenesis is complex, but includes many factors that can be influenced by glucocorticoids (GCs). Indeed, GCs constitute the corner-stone in SLE-treatment. However, guidelines for GC-treatment of the different disease manifestations are lacking and not every patient responds (sufficiently). The focus of this systematic review is to evaluate the differential glucocorticoid treatment of various SLE manifestations. In addition, some relevant mechanisms of glucocorticoid action as well as resistance are discussed.


Assuntos
Glucocorticoides/normas , Glucocorticoides/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Imunidade Adaptativa/efeitos dos fármacos , Autoanticorpos/biossíntese , Autoanticorpos/fisiologia , Autoantígenos/imunologia , Tolerância a Medicamentos/imunologia , Glucocorticoides/administração & dosagem , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/patologia , Tolerância a Antígenos Próprios/efeitos dos fármacos
14.
Ann Rheum Dis ; 71(6): 966-73, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22128082

RESUMO

OBJECTIVES: The objectives of this study are to analyse the long-term follow-up of a randomised controlled trial of induction treatment with azathioprine/methylprednisolone (AZA/MP) versus high-dose intravenous cyclophosphamide (ivCY) in patients with proliferative lupus nephritis (LN) and to evaluate the predictive value of clinical, laboratory and renal biopsy parameters regarding renal outcome. METHODS: 87 patients with biopsy-proven proliferative LN were treated with either AZA/MP (n=37) or ivCY (n=50), both with oral prednisone. After 2 years, renal biopsy was repeated, and all patients continued with AZA/oral prednisone. The primary study end point was sustained doubling of serum creatinine. Secondary end points included renal relapse, end-stage renal disease and mortality. RESULTS: After a median follow-up of 9.6 years, no significant differences between AZA/MP versus ivCY groups were found in the proportion of patients with sustained doubling of serum creatinine (n=6 (16%) vs n=4 (8%); p=0.313), end-stage renal disease (n=2 (5%) vs n=2 (4%); p=1.000) or mortality (n=6 (16%) vs n=5 (10%); p=0.388). Renal relapses occurred more often in the AZA/MP group (n=14 (38%) vs n=5 (10%); p=0.002, HR: 4.5). Serum creatinine, proteinuria and immunosuppressive treatment regimens at the last follow-up were comparable. Clinical and laboratory parameters at baseline and after 2 years, and renal biopsy parameters (only) at baseline predicted renal outcome. CONCLUSION: Induction treatment with ivCY was superior to AZA/MP in preventing renal relapses, but other parameters for renal function did not differ. AZA/MP can therefore serve as an alternative in patients with proliferative LN who wish to avoid gonadal toxicity of CY. Several prognostic factors of long-term renal outcome were identified.


Assuntos
Azatioprina/administração & dosagem , Ciclofosfamida/administração & dosagem , Imunossupressores/administração & dosagem , Nefrite Lúpica/tratamento farmacológico , Metilprednisolona/administração & dosagem , Adolescente , Adulto , Anti-Inflamatórios/administração & dosagem , Creatinina/sangue , Feminino , Seguimentos , Humanos , Falência Renal Crônica/mortalidade , Falência Renal Crônica/prevenção & controle , Nefrite Lúpica/sangue , Nefrite Lúpica/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteinúria/sangue , Proteinúria/tratamento farmacológico , Proteinúria/mortalidade , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
15.
Blood ; 117(4): 1408-14, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21119114

RESUMO

Antiphospholipid (aPL)/anti-ß(2) glycoprotein I (anti-ß(2)GPI) antibodies stimulates tissue factor (TF) expression within vasculature and in blood cells, thereby leading to increased thrombosis. Several cellular receptors have been proposed to mediate these effects, but no convincing evidence for the involvement of a specific one has been provided. We investigated the role of Apolipoprotein E receptor 2 (ApoER2') on the pathogenic effects of a patient-derived polyclonal aPL IgG preparation (IgG-APS), a murine anti-ß(2)GPI monoclonal antibody (E7) and of a constructed dimeric ß(2)GPI I (dimer), which in vitro mimics ß(2)GPI-antibody immune complexes, using an animal model of thrombosis, and ApoER2-deficient (-/-) mice. In wild type mice, IgG-APS, E7 and the dimer increased thrombus formation, carotid artery TF activity as well as peritoneal macrophage TF activity/expression. Those pathogenic effects were significantly reduced in ApoER2 (-/-) mice. In addition, those effects induced by the IgG-APS, by E7 and by the dimer were inhibited by treatment of wild-type mice with soluble binding domain 1 of ApoER2 (sBD1). Altogether these data show that ApoER2 is involved in pathogenesis of antiphospholipids antibodies.


Assuntos
Síndrome Antifosfolipídica/genética , Proteínas Relacionadas a Receptor de LDL/fisiologia , Trombose/genética , Animais , Anticorpos Antifosfolipídeos/efeitos adversos , Anticorpos Antifosfolipídeos/metabolismo , Anticorpos Antifosfolipídeos/farmacologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Fosfo-Específicos/administração & dosagem , Anticorpos Fosfo-Específicos/efeitos adversos , Anticorpos Fosfo-Específicos/farmacologia , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/patologia , Síndrome Antifosfolipídica/prevenção & controle , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Imunoglobulina G/farmacologia , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Trombose/etiologia , Trombose/patologia , beta 2-Glicoproteína I/imunologia
16.
J Rheumatol ; 38(2): 285-8, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21159832

RESUMO

OBJECTIVE: To compare the level and change of cortisol during the day of patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) with low and high erythrocyte sedimentation rate (ESR). METHODS: Saliva was collected in the real-life environment of 21 women with SLE, 16 women with pSS, and 30 age-matched healthy women at 9 fixed timepoints during 2 consecutive days. Repeated measures ANOVA was performed to examine whether cortisol levels during the day were different for the patients with low ESR (≤ 20 mm/h) versus those with high ESR (> 20 mm/h). RESULTS: The groups with low and high ESR showed the characteristic change of cortisol during the day (time-of-day effect, F = 124.9, p < 0.001). The cortisol awakening level was lower for patients with high ESR than for patients with low ESR (group*time effect, F = 3.1, p = 0.02). CONCLUSION: The cortisol awakening level differs for patients with low and high ESR, which indicates the usefulness of further studies of hypothalamic-pituitary-adrenal axis dynamics in patients with SLE and pSS.


Assuntos
Ritmo Circadiano/fisiologia , Hidrocortisona/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Saliva/metabolismo , Síndrome de Sjogren/metabolismo , Adulto , Idoso , Análise de Variância , Feminino , Humanos , Hidrocortisona/análise , Sistema Hipotálamo-Hipofisário/metabolismo , Imunoensaio , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/metabolismo , Saliva/química
17.
J Rheumatol ; 37(11): 2226-31, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20682662

RESUMO

OBJECTIVE: C-C chemokine receptor 5 (CCR5) plays an important role in inflammation. A 32 base-pair (Δ32) deletion in the CCR5 gene leads to a nonfunctional receptor. This deletion has been reported to have a protective effect on the development and progression of several autoimmune diseases. We investigated whether the Δ32 deletion is associated with disease susceptibility in a population of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and lupus nephritis (LN); and whether it is associated with disease severity. METHODS: DNA samples from 405 RA patients, 97 SLE patients, 113 LN patients, and 431 healthy controls were genotyped for the CCR5 Δ32 deletion. Differences in genotype frequencies were tested between patients and controls. Association of genotypes with disease severity was analyzed. RESULTS: Genotype frequencies of each group were in Hardy-Weinberg equilibrium. The genotype frequencies of patients did not differ significantly from controls (CCR5/Δ32, Δ32/Δ32: RA 18.3% and 1.2%, respectively; SLE 17.5% and 2.1%; LN 13.3% and 1.8%; controls 20.0% and 2.8%). However, there was a trend for lower Δ32 deletion allele frequency in LN patients compared to controls (p = 0.08). There was no significant association between the CCR5 status and disease severity in RA, SLE, or LN. CONCLUSION: Although an association with LN cannot be excluded, the CCR5 Δ32 deletion does not seem to be a disease susceptibility genotype for RA, SLE, or LN. No significant effect of the Δ32 deletion on disease severity was demonstrated.


Assuntos
Artrite Reumatoide/genética , Sequência de Bases , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Receptores CCR5/genética , Deleção de Sequência , Índice de Gravidade de Doença , Adulto , Idoso , Alelos , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estatísticas não Paramétricas
18.
Blood ; 116(8): 1336-43, 2010 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-20462962

RESUMO

The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies in blood of patients with thrombosis or fetal loss. There is ample evidence that beta(2)-glycoprotein I (beta(2)GPI) is the major antigen for antiphospholipid antibodies. The autoantibodies recognize beta(2)GPI when bound to anionic surfaces and not in solution. We showed that beta(2)GPI can exist in at least 2 different conformations: a circular plasma conformation and an "activated" open conformation. We also showed that the closed, circular conformation is maintained by interaction between the first and fifth domain of beta(2)GPI. By changing pH and salt concentration, we were able to convert the conformation of beta(2)GPI from the closed to the open conformation and back. In the activated open conformation, a cryptic epitope in the first domain becomes exposed that enables patient antibodies to bind and form an antibody-beta(2)GPI complex. We also demonstrate that the open conformation of beta(2)GPI prolonged the activated partial thromboplastin time when added to normal plasma, whereas the activated partial thromboplastin time is further prolonged by addition of anti-beta(2)GPI antibodies. The conformational change of beta(2)GPI, and the influence of the autoantibodies may have important consequences for our understanding of the antiphospholipid syndrome.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/metabolismo , beta 2-Glicoproteína I/química , Anticorpos Antifosfolipídeos/isolamento & purificação , Anticoagulantes/farmacologia , Síndrome Antifosfolipídica/patologia , Cardiolipinas/metabolismo , Humanos , Tempo de Tromboplastina Parcial , Conformação Proteica , Dobramento de Proteína , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Ressonância de Plasmônio de Superfície , beta 2-Glicoproteína I/genética
19.
Ann N Y Acad Sci ; 1173: 10-4, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19758125

RESUMO

Several initiatives have been undertaken, independent of the European Autoantibody Standardization Initiative (EASI), to standardize autoantibodies in The Netherlands. The Dutch EASI team has made an inventory of which initiatives on autoantibody standardization are already available and what future plans for autoantibody standardization exist. This inventory will subsequently be used to define what may be addressed by the Dutch EASI team. The Diagnostic Compass, initiated by the association of Dutch health insurance companies, describes methods and relevance of laboratory tests, including autoantibody tests. Recently, this initiative has been taken over by an independent publisher. There is also a national organization involved in developing guidelines in medicine, including guidelines for autoantibody testing. In addition, there is a national foundation for quality assessment in clinical laboratories (SKML). The quality assessment includes a wide array of autoantibodies. Samples are collected and thoroughly investigated by reference laboratories. Interpretation of results and advice to clinicians are part of the program. Feedback on the results of this proficiency testing is given in reports and during meetings to discuss trends, technical issues, and new developments. The last initiative that we discuss is the foundation Referentie Laboratorium Reuma Serologie (RELARES), which was founded to standardize serology in rheumatic diseases by preparing standard sera. Recently, RELARES has been combined with SKML. A new SKML working group, Standardization Autoimmune Serology, has been initiated to continue the work of RELARES. When comparing the already available Dutch initiatives to the international EASI goals, there appears to be a lack of harmonization in testing algorithms, and this issue is the most important topic to be addressed in the near future.


Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico , Técnicas de Laboratório Clínico/métodos , Técnicas de Laboratório Clínico/normas , Guias como Assunto , Humanos , Países Baixos , Padrões de Referência , Testes Sorológicos/métodos , Testes Sorológicos/normas
20.
Blood ; 114(17): 3656-61, 2009 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-19706887

RESUMO

von Willebrand factor (VWF) serves as adhesive surface for platelets to adhere to the vessel wall. We have recently found that beta2-glycoprotein I is able to inhibit platelet binding to VWF, indicating a role in the pathophysiology of arterial thrombosis. In the present study, we investigated whether differences in beta2-glycoprotein I plasma levels influence the risk of myocardial infarction. We have measured beta2-glycoprotein I and VWF antigen levels in 539 men with a first myocardial infarction and in 611 control subjects. Although we did not find a profound effect of beta2-glycoprotein I plasma levels on myocardial infarction in the overall population, we found a dose-dependent protective effect of increasing beta2-glycoprotein I plasma levels on myocardial infarction in men 60 years and older. In this age group, we found an odds ratio of 0.41 (95% confidence interval, 0.22-0.74) for high beta2-glycoprotein I levels compared with low levels. High plasma levels of beta2-glycoprotein I remained protective for myocardial infarction despite high levels of VWF. To conclude, high circulating levels of beta2-glycoprotein I appeared to be associated with a reduced risk of myocardial infarction in elderly men. In vivo experiments are needed to investigate the exact contribution of beta2-glycoprotein I on the pathophysiology of myocardial infarction.


Assuntos
Infarto do Miocárdio/sangue , beta 2-Glicoproteína I/sangue , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Países Baixos/epidemiologia , Prognóstico , Fatores de Risco , Adulto Jovem , Fator de von Willebrand/metabolismo
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