56 research outputs found
Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency
In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)–related diseases. Three patients presented with EBV-associated Hodgkin’s lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal, but the proportions of memory B cells and EBV-specific effector memory CD8+ T cells were reduced. Furthermore, although T cell proliferation was normal, in vitro–generated EBV-specific cytotoxic T cell activity was reduced because of CD70 deficiency. This reflected impaired activation by, rather than effects during killing of, EBV-transformed B cells. Notably, expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8+ T cells from CD70-deficient individuals was reduced, consistent with their impaired killing of EBV-infected cells. Thus, autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70–CD27 interactions therefore play a nonredundant role in T and B cell–mediated immunity, especially for protection against EBV and humoral immunity
Molecular Cloning and Functional Characterization of a Unique Mammalian Cardiac Na v Channel Isoform with Low Sensitivity to the Synthetic Inactivation Inhibitor (Ϫ)-(S)-6-Amino-␣-[(4- diphenylmethyl-1-piperazinyl)-methyl]-9H-purine-9-ethanol (SDZ 211-939
ABSTRACT Cardiac voltage-dependent sodium channels (Na v ) are drug targets for synthetic inactivation inhibitors typified by (Ϯ)-4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxy propoxy]-1H-indole-2-carbonitrile (DPI 201-106), of which the molecular mode of action is not yet defined. The previous observation by Mevissen and coworkers in 2001 of the electrophysiological ineffectiveness of DPI 201-106 in the bovine heart, in contrast to other species, offers the opportunity for investigating these open questions. We now report about the molecular cloning, expression in Xenopus laevis oocytes, and electrophysiological characterization of a unique bovine heart sodium channel. Although the predicted 2022-amino acid bovine heart sodium channel (bH1) shares 92% identity with the rat and human isoforms and normal gating properties, it displays drastically reduced sensitivity to (Ϫ)-(S)-6-amino-␣-[(4-diphenylmethyl-1-piperazinyl)-methyl]-9H-purine-9-ethanol (SDZ 211-939). Experimental results with Anemonia sulcata toxin II (0.1-2.5 M) exclude the possibility of an overall insensitivity of this isoform to various sodium channel modulators. The binding of SDZ 211-939 seems to be largely unaffected (EC 50 of 10.3 and 10.6 M for bovine and rat isoforms, respectively) but the corresponding efficacy in bovine (V m of 0.15) is approximately 5 times smaller compared with the rat heart isoform (V m of 0.69). The comparison of the primary structure of bH1 to other sodium channels and the gating properties obtained in presence or absence of SDZ 211-939 revealed a high degree of similarity. Whether the mechanism of channel modulation depends on the interaction of synthetic modulators with some possibly voltageindependent part of the inactivation machinery needs to be determined
Guanfacine and Other Centrally Acting Drugs in Antihypertensive Therapy; Pharmacological and Clinical Aspects
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