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1.
Arthritis Rheumatol ; 69(10): 2052-2061, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28666081

RESUMO

OBJECTIVE: Both environmental and genetic factors are important in the development of antiphospholipid antibodies (aPL) in patients with antiphospholipid syndrome (APS). Currently, the only available data on predisposing genetic factors have been obtained from epidemiologic studies, without mechanistic evidence. Therefore, we studied the influence of major histocompatibility complex (MHC) class II alleles on the production of aPL in a mouse model of APS. METHODS: Three groups of mice, MHC class II-deficient (MHCII-/- ) mice, MHCII-/- mice transgenic for human HLA-DQ6 (DQ6), DQ8, or DR4 alleles, and the corresponding wild-type (WT) mouse strains were immunized; half were immunized with human ß2 -glycoprotein I (ß2 GPI), and the other half were immunized with control ovalbumin (OVA) protein. Thrombus formation in vivo, tissue factor activity in carotid and peritoneal macrophages, and serum levels of tumor necrosis factor (TNF), IgG anticardiolipin (aCL), antibodies, and anti-OVA antibodies were determined. RESULTS: Immunization with ß2 GPI induced significant production of aCL and anti-ß2 GPI in WT mice compared with control mice immunized with OVA (P < 0.001) but diminished aCL (P < 0.001) and anti-ß2 GPI (P = 0.016) production in MHCII-/- mice. Anti-ß2 GPI production was fully restored in DQ6 and DQ8 mice, while levels of anti-ß2 GPI in DR4 mice and aCL in all transgenic lines were only partially restored (P < 0.001 to P < 0.046). Thrombus size in WT mice was twice that in MHCII-/- mice (P < 0.001) but similar to that in all transgenic lines. Carotid and peritoneal macrophage tissue factor levels decreased by >50% in MHCII-/- mice compared with wild-type B6 mice and were restored in DQ8 mice but not DR4 mice or DQ6 mice. TNF levels decreased 4-fold in MHCII-/- mice (P < 0.001) and were not restored in transgenic mice. CONCLUSION: Our mechanistic study is the first to show that MHC class II alleles influence not only quantitative aPL production but also the pathogenic capacity of induced aPL.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Genes MHC da Classe II/genética , Antígenos HLA-DQ/genética , Antígeno HLA-DR4/genética , Alelos , Animais , Anticorpos Anticardiolipina/imunologia , Artérias Carótidas/imunologia , Modelos Animais de Doenças , Humanos , Imunização , Imunoglobulina G/imunologia , Macrófagos/imunologia , Macrófagos Peritoneais/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ovalbumina/imunologia , Índice de Gravidade de Doença , Trombose , Fator de Necrose Tumoral alfa/imunologia , beta 2-Glicoproteína I/imunologia
2.
Ann N Y Acad Sci ; 1173: 736-45, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19758223

RESUMO

Fluvastatin has been shown to revert proinflammatory/prothrombotic effects of antiphospholipid antibodies (aPL) in vitro and in mice. Here, we examined whether fluvastatin affects the levels of proinflammatory/prothrombotic markers in antiphospholipid syndrome (APS) patients. Vascular endothelial growth factor (VEGF), soluble tissue factor (sTF), tumor necrosis factor-alpha (TNF-alpha), soluble intercellular adhesion molecule-1 (sICAM-1), sE-selectin (E-sel), C-reactive protein (CRP), and soluble vascular cell adhesion molecule (sVCAM-1), were measured in the sera of 93 APS patients and 60 controls and in the sera of nine patients with APS before and after 30 days of treatment with fluvastatin. Elevated levels of VEGF, sTF, and TNF-alpha were found in APS patients. Fluvastatin significantly reduced those markers in the majority of treated subjects. The data from this study show that statins may be beneficial in aPL-positive patients and warrant larger clinical trials to confirm the efficacy of the drug for the treatment of APS clinical manifestations.


Assuntos
Síndrome Antifosfolipídica/tratamento farmacológico , Biomarcadores/sangue , Ácidos Graxos Monoinsaturados/uso terapêutico , Indóis/uso terapêutico , Adulto , Idoso , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Proteína C-Reativa/metabolismo , Selectina E/sangue , Feminino , Fluvastatina , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Molécula 1 de Adesão Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Tromboplastina/metabolismo , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/sangue
3.
J Rheumatol ; 34(12): 2446-50, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17918782

RESUMO

OBJECTIVE: Venous thrombotic events (VTE), including both deep venous thrombosis and pulmonary emboli, are now recognized as an important complication of Wegener's granulomatosis (WG), but the mechanism(s) of this occurrence is unclear. The frequency of anticardiolipin antibodies (aCL), anti-beta2-glycoprotein antibodies (anti-beta2-GP), and several genetic hypercoagulable factors were examined in a large cohort of patients with WG. METHODS: One hundred eighty patients with active WG had serum and DNA samples collected upon entry into a clinical trial. Of the 180 patients, 29 patients had VTE -- 13 before trial entry, 16 during trial. aCL (IgG, IgM, and IgA) and anti-beta2-GP (IgG and IgM) were evaluated in 176 patients. Factor V Leiden (FVL), the prothrombin gene mutation (G20210A, PGM), and methylenetetrahydrofolate reductase (MTHFR) gene mutation were tested in the 29 patients with thrombotic events, and 36 patients without. RESULTS: aCL occurred with increased frequencies in patients with WG when compared to the general population (1%-5%): 12% had aCL and 3% had anti-beta2-GP. There was no difference in the prevalences of aCL or anti-beta2-GP based on clotting status. The prevalence of the genetic hypercoagulable factors examined in patients with WG was comparable to the reported rates in the general population. CONCLUSION: Although the incidence of clinically significant VTE is increased in patients with WG, this increased risk is not explained by increased prevalences of aCL, anti-beta2-GP, FVL, or mutations in PGM or MTHFR. These observations suggest a need to search for new genetic or acquired prothrombotic abnormalities to account for the increased thrombotic event rate in patients with active WG.


Assuntos
Anticorpos Anticardiolipina/sangue , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/genética , Embolia Pulmonar/sangue , Trombofilia/genética , Trombose Venosa/sangue , Feminino , Predisposição Genética para Doença , Granulomatose com Poliangiite/complicações , Humanos , Masculino , Mutação , Embolia Pulmonar/genética , Fatores de Risco , Trombofilia/sangue , Trombose Venosa/genética
4.
J Rheumatol ; 34(5): 1027-31, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17444585

RESUMO

OBJECTIVE: Previous studies in small cohorts of patients with Wegener's granulomatosis (WG) or antineutrophil cytoplasmic antibody (ANCA) associated vasculitis have yielded conflicting data regarding the prevalence of antiendothelial cell antibodies (AECA), ranging from 8% to 100%, and the use of AECA as a measure of disease activity. We examined a large, well-characterized cohort of patients with WG and active disease for the presence of AECA. METHODS: Serum from subjects with WG who participated in a clinical therapeutic trial was collected at baseline, when all subjects had active disease. Clinical manifestations and disease activity were documented using the Birmingham Vasculitis Activity Score for WG (BVAS/WG). Serum AECA (IgG) was measured by cyto-ELISA using unfixed human umbilical vein endothelial cells (HUVEC). The AECA positivity cutoff was determined using 71 healthy control samples. Statistical analyses utilized Student's t test, chi-square and Fisher's exact tests, and linear regression. RESULTS: AECA were detected in 34 of 173 (20%) evaluated serum samples. Mean BVAS/WG did not differ between patients with (7.3 +/- 3.2) or without AECA (7.0 +/- 3.3) (p = 0.58). Among the 34 patients positive for AECA, the antibody titer did not correlate with disease activity (BVAS/WG; r = 0.09, p = 0.60). There were no statistically significant differences in the frequency of major clinical manifestations between patients with or without AECA. CONCLUSION: AECA, as measured using HUVEC, are not highly prevalent among patients with active WG, are not associated with specific clinical manifestations, and do not correlate with level of disease activity.


Assuntos
Autoanticorpos/sangue , Biomarcadores/sangue , Endotélio Vascular/imunologia , Granulomatose com Poliangiite/imunologia , Células Cultivadas , Endotélio Vascular/citologia , Granulomatose com Poliangiite/patologia , Granulomatose com Poliangiite/fisiopatologia , Humanos , Veias Umbilicais/citologia
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