Biomedical subjects

Stephanie Jennings

Publications and source records attributed to Stephanie Jennings.

4 recordsLinked to original sources

PubMed2007

To switch or not to switch--the opposing roles of TACI in terminal B cell differentiation.

The TNF superfamily ligands BAFF and APRIL and their three receptors BAFFR, BCMA, and TACI comprise a network that is critically involved in the development and function of humoral immunity. Failure of this complex system is associated with autoimmune disease, B lymphocyte tumours, and antibody deficiency. While BAFF:BAFFR interactions control peripheral B cell survival and homeostasis, BCMA function seems limited to the survival of long-lived bone marrow plasma cells. The functional activity of the third receptor TACI is, however, ambiguous: while TACI-/- mice predominantly develop autoimmunity and lymphoproliferation, TACI deficiency in humans primarily manifests itself as an antibody deficiency syndrome. An article in this issue of the European Journal of Immunology demonstrates a negative regulation via TACI in human B cells by using TACI specific antibodies. B cell proliferation, class switch recombination, and Ig production induced by various stimuli were inhibited via TACI. Within the BAFF/APRIL network, the expression of the receptors and ligands is spatially, as well as temporally, highly regulated at various stages of B cell development and function. Defining the exact contribution of TACI stimulation by specific triggers in vitro enables us to better understand the complex, context-dependent responses initiated by TACI in vivo.

Animals↗

PubMed2005

Thogoto virus ML protein suppresses IRF3 function.

The Thogoto virus (THOV) is a member of the family Orthomyxoviridae. It prevents induction of alpha/beta interferons (IFN) in cell culture and in vivo via the action of the viral ML protein. Phenotypically, the effect of THOV ML resembles that of the NS1 protein of influenza A virus (FLUAV) in that it blocks the expression of IFN genes. IFN expression depends on IFN regulatory factor 3 (IRF3). Upon activation, IRF3 forms homodimers and accumulates in the nucleus where it binds the transcriptional coactivator CREB-binding protein (CBP). Here, we show that expression of ML blocked the transcriptional activity of IRF3 after stimulation by virus infection. Further biochemical analysis revealed that ML acts by blocking IRF3 dimerization and association with CBP. Surprisingly, however, ML did not interfere with the nuclear transport of IRF3. Thus, the action of ML differs strikingly from that of FLUAV NS1 that prevents IFN induction by retaining IRF3 in the cytoplasm.

Animals↗

PubMed2004

Thogoto virus lacking interferon-antagonistic protein ML is strongly attenuated in newborn Mx1-positive but not Mx1-negative mice.

The Thogoto virus ML protein suppresses interferon synthesis in infected cells. Nevertheless, a virus mutant lacking ML remained highly pathogenic in standard laboratory mice. It was strongly attenuated, however, in mice carrying the interferon-responsive Mx1 gene found in wild mice, demonstrating that enhanced interferon synthesis is protective only if appropriate antiviral effector molecules are present. Our study shows that the virulence-enhancing effects of some viral interferon antagonists may escape detection in conventional animal models.

Animals↗

PubMed2003

Novel gene product of Thogoto virus segment 6 codes for an interferon antagonist.

Thogoto virus (THOV) is a tick-transmitted orthomyxovirus with a genome of six negative-stranded RNA segments. The sixth segment encodes two different transcripts: a spliced transcript that is translated into the matrix protein (M) and an unspliced transcript. Here, we report that the unspliced transcript encodes an elongated form of M named ML. A THOV isolate deficient in ML expression was an efficient interferon inducer, whereas ML-expressing wild-type strains were poor interferon inducers. These results were confirmed with recombinant THOVs rescued from cDNAs. Expression of ML efficiently suppressed activation of the beta interferon promoter by double-stranded RNA. These results indicate that ML is an accessory protein that functions as a potent interferon antagonist by blocking transcriptional activation of alpha/beta interferons.

Animals↗