Publications (8) View all
-
Article: B-cell activation induced microRNA-21 is elevated in circulating B cells preceding the diagnosis of AIDS-related non-Hodgkin lymphomas.
[show abstract] [hide abstract]
ABSTRACT: We show that microRNA-21 is significantly elevated in peripheral B cells of HIV-infected individuals who go on to develop AIDS-related non-Hodgkin lymphoma (n=13, <3 years prior to diagnosis) when compared with HIV-negative (n=18) or HIV-positive controls (n=21) (P<0.01). Moreover, miR-21 is overexpressed in activated B cells and can be induced by interleukin 4 alone, or with CD40 or immunoglobulin M co-stimulation, and lipopolysaccharides, suggesting that miR-21 may help maintain B-cell hyperactivation, contributing to lymphomagenesis.AIDS (London, England) 04/2012; 26(9):1177-80. · 4.91 Impact Factor -
Article: Overexpression of microRNAs from the miR-17-92 paralog clusters in AIDS-related non-Hodgkin's lymphomas.
[show abstract] [hide abstract]
ABSTRACT: Individuals infected by HIV are at an increased risk for developing non-Hodgkin's lymphomas (AIDS-NHL). In the highly active antiretroviral therapy (HAART) era, there has been a significant decline in the incidence of AIDS-associated primary central nervous system lymphoma (PCNSL). However, only a modest decrease in incidence has been reported for other AIDS-NHL subtypes. Thus, AIDS-NHLs remain a significant cause of morbidity and mortality in HIV infected individuals. Recently, much attention has been directed toward the role of miRNAs in cancer, including NHL. Several miRNAs, including those encoded by the miR-17-92 polycistron, have been shown to play significant roles in B cell tumorigenesis. However, the role of miRNAs in NHL in the setting of HIV infection has not been defined. We used quantitative realtime PCR to assess the expression of miRNAs from three different paralog clusters, miR-17-92, miR-106a-363, and miR-106b-25 in 24 cases of AIDS-NHLs representing four tumor types, Burkitt's lymphoma (BL, n = 6), diffuse large B-cell lymphoma (DLBCL, n = 8), primary central nervous system lymphoma (PCNSL, n = 5), and primary effusion lymphoma (PEL, n = 5). We also used microarray analysis to identify a differentiation specific miRNA signature of naïve, germinal center, and memory B cell subsets from tonsils (n = 4). miRNAs from the miR-17-92 paralog clusters were upregulated by B cells, specifically during the GC differentiation stage. We also found overexpression of these miRNA clusters in all four AIDS-NHL subtypes. Finally, we also show that select miRNAs from these clusters (miR-17, miR-106a, and miR-106b) inhibited p21 in AIDS-BL and DLBCL cases, thus providing a mechanistic role for these miRNAs in AIDS-NHL pathogenesis. Dysregulation of miR-17-92 paralog clusters is a common feature of AIDS-associated NHLs.PLoS ONE 01/2011; 6(6):e20781. · 4.09 Impact Factor -
Article: CD40 ligand (CD154) incorporated into HIV virions induces activation-induced cytidine deaminase (AID) expression in human B lymphocytes.
[show abstract] [hide abstract]
ABSTRACT: Most AIDS-associated non-Hodgkin's lymphoma (AIDS-NHL) arises from errors in immunoglobulin heavy-chain gene (IgH) class switch recombination (CSR) or somatic hypermutation (SHM), events that occur in germinal center (GC) B cells and require the activity of activation induced cytidine deaminase (AID). Several oncogenic viruses (EBV, HCV, HPV) can induce AID gene (AID) expression, and elevated AID expression is seen in circulating lymphocytes prior to AIDS-NHL diagnosis. Here, we report that HIV produced in peripheral blood mononuclear cells (PBMC) induced AID expression in normal human B cells. Since HIV produced in PBMC contains host cell CD40 ligand (CD40L) incorporated into the viral membrane, and CD40L is known to induce AID expression in human B cells, the role of virion-associated CD40L in HIV-induced AID expression was examined. Only viruses expressing functional CD40L were seen to induce AID expression; CD40L-negative HIV did not induce AID expression. The induction of AID expression by CD40L+ HIV was abrogated by addition of blocking anti-CD40L antibody. AID protein was detected in B cells exposed to CD40L+ HIV using intracellular multicolor flow cytometry, with most AID producing B cells expressing the CD71 activation marker on their surface. Therefore, HIV virions that express CD40L induce AID expression in B cells, and this induction appears to be due to a direct interaction between CD40L on these viruses and CD40 on B cells. These findings are consistent with a role for HIV in the direct stimulation of B cells, potentially leading to the accumulation of molecular lesions that have the potential to contribute to the development of NHL.PLoS ONE 01/2010; 5(7):e11448. · 4.09 Impact Factor -
Article: Urinary hepcidin in congenital chronic anemias.
[show abstract] [hide abstract]
ABSTRACT: Hepcidin, a regulator for iron homeostasis, is induced by inflammation and iron burden and suppressed by anemia and hypoxia. This study was conducted to determine the hepcidin levels in patients with congenital chronic anemias. Forty-nine subjects with anemia, varying degrees of erythropoiesis and iron burden were recruited. Eight children with immune thrombocytopenia were included as approximate age-matched controls. Routine hematologic labs and urinary hepcidin (uhepcidin) levels were assessed. For thalassemia major (TM) patients, uhepcidin was obtained pre- and post-transfusion. In TM, uhepcidin levels increased significantly after transfusion, demonstrated wide variance, and the median did not significantly differ from controls or thalassemia intermedia (TI). In both thalassemia syndromes, the hepcidin to ferritin ratio, a marker of the appropriateness of hepcidin expression relative to the degree of iron burden, was low compared to controls. In TI and sickle cell anemia (SCA), median uhepcidin was low compared to controls, P = 0.013 and <0.001, respectively. In thalassemia subjects, uhepcidin levels were positively associated with ferritin. In subjects with SCA, uhepcidin demonstrated a negative correlation with reticulocyte count. This study examines hepcidin levels in congenital anemias. In SCA, hepcidin was suppressed and inversely associated with erythropoietic drive. In thalassemic syndromes, hepcidin was suppressed relative to the degree of iron burden. Transfusion led to increased uhepcidin. In thalassemia, the relative influence of known hepcidin modifiers was more difficult to assess. In thalassemic syndromes where iron overload and anemia have opposing effects, the increased erythropoietic drive may positively influence hepcidin production.Pediatric Blood & Cancer 01/2007; 48(1):57-63. · 1.89 Impact Factor -
Article: Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor.
[show abstract] [hide abstract]
ABSTRACT: We found that sterile wounding of human skin induced epidermal expression of the antimicrobial (poly)peptides human beta-defensin-3, neutrophil gelatinase-associated lipocalin, and secretory leukocyte protease inhibitor through activation of the epidermal growth factor receptor. After skin wounding, the receptor was activated by heparin-binding epidermal growth factor that was released by a metalloprotease-dependent mechanism. Activation of the epidermal growth factor receptor generated antimicrobial concentrations of human beta-defensin-3 and increased the activity of organotypic epidermal cultures against Staphylococcus aureus. These data demonstrate that sterile wounding initiates an innate immune response that increases resistance to overt infection and microbial colonization.Journal of Clinical Investigation 08/2006; 116(7):1878-85. · 15.39 Impact Factor
