RESUMO
Rheumatoid arthritis (RA) is associated with an excess cardiovascular morbidity and mortality, related to systemic inflammation with endothelial dysfunction (ED) and impaired flow-mediated vasodilation (FMD). We assessed the FMD response to anti-TNF-alpha treatments in 28 RA patients, aged 49.8+/-15.3 years: an unpaired FMD was found in 66.7 percent of our cases and was restored after 6 weeks of anti-TNF-á treatment (13.5+/-5.3 percent vs 4.6+/-4.1 percent, p less than 0.05). Twenty-five percent of the infliximab patients demonstrated a long term response, compared with 60 percent of etanercept and 100 percent of adalimumab patients, after 2 years (p less than 0.01). Infections (3 cases), myocardial ischemia (1 case) or loss of response (4 cases) were associated with a worsened FMD, restored by shifting to adalimumab. The present study confirms that ED is an RA systemic disease marker, responsive to anti-TNF-alpha treatment and sensitive to clinical events or to a loss of response, underlying the biological coherence between synovial and endothelial inflammation.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Endotélio Vascular/fisiopatologia , Membrana Sinovial/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Artrite Reumatoide/sangue , Artrite Reumatoide/fisiopatologia , Artéria Braquial/fisiopatologia , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , VasodilataçãoRESUMO
OBJECTIVE: HIV-1 infection impairs a number of macrophage effector functions, but the mechanism is unknown. We studied the role of HIV-1 Nef in modulating phagocytosis by human monocytes and monocyte-derived macrophages (MDM). DESIGN AND METHODS: Using a flow cytometric assay, phagocytosis of Mycobacterium avium complex (MAC) by monocytes in whole blood of Sydney Blood Bank Cohort (SBBC) members infected with a nef-deleted (Delta nef) strain of HIV-1 was compared with that of monocytes from uninfected or wild-type (WT) HIV-infected subjects. The specific impact of Nef on phagocytosis by MDM was determined by either infecting cells in vitro with Delta nef strains of HIV-1 or electroporating Nef into uninfected MDM. RESULTS: MAC phagocytic capacity of monocytes from SBBC members was equivalent to that of cells from uninfected individuals (P = 0.81); it was greater than that of cells from individuals infected with WT HIV-1 (P < 0.0001), irrespective of CD4 counts and HIV viral load. In contrast, in vitro infection of MDM with either Delta nef or WT strains of HIV-1 resulted in similar levels of HIV replication and equivalent impairment of phagocytosis via Fc gamma and complement receptors. Electroporation of Nef into MDM did not alter phagocytic capacity. CONCLUSIONS: This study provides evidence demonstrating the complex indirect effect of Nef on phagocytosis by peripheral blood monocytes (infrequently infected with HIV-1) in vivo. Conversely, the fact that MDM infected with either Delta nef or WT HIV-1 in vitro (high multiplicity of infection) show comparably impaired phagocytosis, indicates that HIV-1 infection of macrophages can directly impair function, independent of Nef.
Assuntos
Genes nef , Infecções por HIV/imunologia , HIV-1/genética , Macrófagos/imunologia , Monócitos/imunologia , Fagocitose , Contagem de Linfócito CD4 , Estudos de Coortes , Eletroporação , Citometria de Fluxo , Fluoresceína-5-Isotiocianato , Corantes Fluorescentes , Deleção de Genes , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Immunoblotting , Técnicas In Vitro , Macrófagos/virologia , Monócitos/virologia , Carga ViralRESUMO
Monocytes from HIV-seronegative persons were analyzed for CD4 expression and susceptibility to infection with HIV-1 on the day of isolation and following 1, 2, and 7 days in culture. Although surface CD4 was readily detected on freshly isolated monocytes, these cells were relatively resistant to infection. After 1 to 2 days in culture, when surface expression of CD4 had decreased over 90% to near background levels, cells became susceptible to infection with HIV-1. CD4 expression on monocytes cultured for 7 days was more than four times higher than that on freshly isolated cells, and the cultured cells were fully permissive to infection. These observations suggest that the differing susceptibility of monocytes and monocyte-derived macrophages to infection with HIV-1 is not simply proportional to the level of surface CD4 expression.