RESUMO
Cryopyrin-associated periodic syndrome (CAPS) is characterized by dysregulated inflammation with excessive interleukin (IL)-1ß activation and secretion. Neonatal-onset multi-system inflammatory disease (NOMID) is the most severe form. We explored cytokine responses in 32 CAPS patients before and after IL-1ß blocking therapy. We measured cytokines produced by activated peripheral blood monuclear cells (PBMCs) from treated and untreated CAPS patients after stimulation for 48 h with phytohaemagglutinin (PHA), PHA plus IL-12, lipopolysaccharide (LPS) or LPS plus interferon (IFN)-γ. We measured IL-1ß, IL-6, IL-10, tumour necrosis factor (TNF), IL-12p70 and IFN-γ in the supernatants. PBMCs from three untreated CAPS patients were cultured in the presence of the IL-1ß blocker Anakinra. Fifty healthy individuals served as controls. CAPS patients had high spontaneous production of IL-1ß, IL-6, TNF and IFN-γ by unstimulated cells. However, stimulation indexes (SIs, ratio of stimulated to unstimulated production) of these cytokines to PHA and LPS were low in NOMID patients compared to controls. Unstimulated IL-10 and IL-12p70 production was normal, but up-regulation after PHA and LPS was also low. LPS plus IFN-γ inadequately up-regulated the production of IL-1ß, IL-6, TNF and IL-10 in CAPS patients. In-vitro but not in-vivo treatment with Anakinra improved SIs by lowering spontaneous cytokine production. However, in-vitro treatment did not improve the low stimulated cytokine levels. Activating mutations in NLRP3 in CAPS are correlated with poor SIs to PHA, LPS and IFN-γ. The impairment in stimulated cytokine responses in spite of IL-1ß blocking therapy suggests a broader intrinsic defect in CAPS patients, which is not corrected by targeting IL-1ß.
Assuntos
Síndromes Periódicas Associadas à Criopirina/metabolismo , Citocinas/metabolismo , Adolescente , Adulto , Proteínas de Transporte/genética , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/genética , Humanos , Lactente , Interleucina-1beta/antagonistas & inibidores , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , Mutação/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR , Adulto JovemRESUMO
Mendelian defects in interferon-gamma (IFN-gamma) signaling most commonly lead to infection with nontuberculous mycobacteria. Mutations have been identified in the genes encoding IFN-gamma-receptor-1, IFN-gamma-receptor-2 and Stat-1. Partial and complete deficiencies in signaling are found, leading to parallel clinical, pathological, and cellular phenotypes. These rare defects have led to better molecular and mechanistic understanding of the role of IFN-gamma in the human immune system.
Assuntos
Interferon gama/imunologia , Infecções por Mycobacterium/genética , Mycobacterium , Animais , Núcleo Celular/metabolismo , Predisposição Genética para Doença , Humanos , Imunidade Celular , Imunidade Inata , Interferon gama/metabolismo , Camundongos , Mutação , Infecções por Mycobacterium/imunologia , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Recidiva , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Ativação Transcricional , Receptor de Interferon gamaRESUMO
OBJECTIVE: To determine the effect of lamivudine on HBV co-infection in HIV-infected patients. DESIGN: Retrospective METHOD: The HBsAg status and the use of lamivudine were determined retrospectively in a cohort of 800 HIV-infected patients under treatment at the Infectious Diseases outpatient clinic of the University Medical Centre in Utrecht, The Netherlands. In the group of HBsAg-positive patients using lamivudine 150 mg twice daily as part of highly active antiretroviral therapy (HAART), the HBV-DNA was measured quantitatively in the remaining plasma. In addition, the HBsAg, HBeAg, activity of alanineaminotransferase (ALAT) and CD4-count were obtained from the patient records. RESULTS: The study identified 29 (3.6%) HIV-infected patients to be HBsAg-positive. Plasma samples of 14 of these 29 patients were positive for HBV-DNA before the start of the therapy. Ten of these 14 patients had CD4 counts of at least 200 x 10(6) cells/l, while four patients had less than 200 x 10(6) cells/l. In contrast to the group with less than 200 x 10(6) cells/l, a significant decrease in HBV-DNA load was seen after six months of therapy in the patients with at least 200 x 10(6) CD4-cells/l (t-test for repeated measurements; p = o.oo1). The difference between the two groups in the effect of lamivudine was statistically significant (p = 0.021). At final evaluation after a mean follow-up of 32 and 13 months, respectively, HBV-DNA could no longer be detected in 7 patients; ALAT normalised in 9 patients (64%). CONCLUSION: In this retrospective study, lamivudine was effective in the therapy of HIV-infected patients with a HBV co-infection. The decrease in the amount of circulating HBV was associated with the number of CD4 cells.