Biomedical subjects

Fabienne Andris

Publications and source records attributed to Fabienne Andris.

6 recordsLinked to original sources

PubMed2006

Nicotinamide inhibits B lymphocyte activation by disrupting MAPK signal transduction.

Nicotinamide (NAm) represents both a pharmacological agent known to express cell preserving and anti-inflammatory properties, and a useful investigational tool to elucidate cellular pathways regulating a wide range of cellular functions. We demonstrate in this study that exogenous NAm, when used at pharmacological doses, inhibits activation of primary murine B lymphocytes in response to multiple ligands. NAm appears to affect a membrane proximal event leading to MAPKs activation, a transduction pathway shared by multiple receptors including the antigen-specific B cell receptor, CD38, CD40 and TLR4 receptors. NAm inhibited phospho-ERK accumulation, and only marginally affected phospho-p38 and phospho-JNK induction upon BCR stimulation of naive B lymphocytes. Accordingly, NAm also affected the expression of known targets of the MAPK ERK pathway such as CD69 and cyclin D2. Based on a comparison with well-characterized pharmacological inhibitors, we suggest in this work that NAm may inhibit a post-translational modification mediated by a yet unidentified mono(ADP-ribose)transferase. Collectively, our observations indicate that in addition to its previously described effect on cells of the innate immune system, NAm is able to modulate the activity of B lymphocytes suggesting a potential role of this vitamin in regulating antibody-mediated autoimmune disorders.

3-Iodobenzylguanidine↗

PubMed2006

CD4+ CD25+ regulatory T cells control the magnitude of T-dependent humoral immune responses to exogenous antigens.

CD4+ CD25+ T reg cells are critical for peripheral tolerance and prevention of autoimmunity. Here we show that CD4+ CD25+ T reg also regulate the magnitude of humoral responses against a panel of T-dependent antigens of foreign origin during both primary and secondary immune responses. Depletion of CD4+ CD25+ T cells leads to increased antigen-specific antibody production and affinity maturation but does not affect T-independent B cell responses, suggesting that CD4+ CD25+ T reg exert a feedback mechanism on non-self antigen-specific antibody secretion by dampening the T cell help for B cell activation. Moreover, we show that CD4+ CD25+ T reg also suppress in vitro B cell immunoglobulin production by inhibiting CD4+ CD25- T cell help delivery, and that blockade of TGF-beta activity abolishes this suppression.

Animals↗

PubMed2004

Naive T cells are resistant to anergy induction by anti-CD3 antibodies.

Anti-CD3 mAbs are potent immunosuppressive agents used in clinical transplantation. It has been generally assumed that one of the anti-CD3 mAb-mediated tolerance mechanisms is through the induction of naive T cell unresponsiveness, often referred to as anergy. We demonstrate in this study that naive T cells stimulated by anti-CD3 mAbs both in vivo and in vitro do not respond to the superantigen staphylococcal enterotoxin B nor to soluble forms of anti-CD3 mAbs and APC, but express increased reactivity to plastic-coated forms of the same anti-CD3 mAbs and to their nominal Ag/class II MHC, a finding that is difficult to rationalize with the concept of anergy. Phenotypic and detailed kinetic studies further suggest that a strong signal 1 delivered by anti-CD3 mAbs in the absence of costimulatory molecules does not lead to anergy, but rather induces naive T cells to change their mitogen responsiveness and acquire features of memory T cells. In marked contrast, Ag-experienced T cells are sensitive to anergy induction under the same experimental settings. Collectively, these studies demonstrate that exposure of naive T cells in vivo and in vitro to a strong TCR stimulus does not induce Ag unresponsiveness, indicating that sensitivity to negative signaling through TCR/CD3 triggering is developmentally regulated in CD4(+) T cells.

Animals↗

PubMed2003

Glucocorticoids alter the lipid and protein composition of membrane rafts of a murine T cell hybridoma.

Glucocorticoids (GC) are widely used anti-inflammatory agents known to suppress T cell activation by interfering with the TCR activation cascade. The attenuation of early TCR signaling events by these compounds has been recently attributed to a selective displacement of key signaling proteins from membrane lipid rafts. In this study, we demonstrate that GC displace the acyl-bound adaptor proteins linker for activation of T cells and phosphoprotein associated with glycosphingolipid-enriched microdomains from lipid rafts of murine T cell hybridomas, possibly by inhibiting their palmitoylation status. Analysis of the lipid content of the membrane rafts revealed that GC treatment led to a significant decrease in palmitic acid content. Moreover, we found an overall decrease in the proportion of raft-associated saturated fatty acids. These changes were consistent with a decrease in fluorescence anisotropy of isolated lipid rafts, indicating an increase in their fluidity. These findings identify the mechanisms underlying the complex inhibitory effects of glucocorticoids on early TCR signaling and suggest that some of the inhibitory properties of GC on T cell responses may be related to their ability to affect the membrane lipid composition and the palmitoylation status of important signaling molecules.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Reconstructing eukaryotic NAD metabolism.

In addition to its well-known role as a coenzyme in oxidation-reduction reactions, the distinct role of NAD as a precursor for molecules involved in cell regulation has been clearly established. The involvement of NAD in these regulatory processes is based on its ability to function as a donor of ADP-ribose; NAD synthesis is therefore required to avoid depletion of the intracellular pool. The rising interest in the biosynthetic routes leading to NAD formation and the highly conserved nature of the enzymes involved prompted us to reconstruct the NAD biosynthetic routes operating in distinct eukaryotic organisms. The evidence obtained from biochemical and computational analysis provides a good example of how complex metabolic pathways may evolve. In particular, it is proposed that the development of several NAD biosynthetic routes during evolution has led to partial functional redundancy, allowing a given pathway to freely acquire novel functions unrelated to NAD biosynthesis.

Adenosine Diphosphate Ribose↗

PubMed2002

Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis.

The murine homologue of the previously identified human "pre-B-cell colony-enhancing factor" (PBEF) gene coding for a putative cytokine has been identified by screening a subtractive library enriched in genes expressed in activated T lymphocytes. Unlike most cytokine genes known to date, the PBEF gene is ubiquitously expressed in lymphoid and non-lymphoid tissues and displays significant homology with genes from primitive metazoans (marine sponges) and prokaryotic organisms. Recently, a bacterial protein encoded by nadV, a gene from the prokaryote Haemophilus ducreyi displaying significant homology with PBEF, has been identified as a nicotinamide phosphoribosyltranferase (NAmPRTase), an enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis. Using a panel of antibodies to murine PBEF, we demonstrate in this work that, similarly to its microbial counterpart, the murine protein is a NAmPRTase, catalyzing the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. The role of PBEF as a NAmPRTase was further confirmed by showing that the mouse gene was able to confer the ability to grow in the absence of NAD to a NAmPRTase-defective bacterial strain. The present findings are in keeping with the ubiquitous nature of this protein, and indicate that NAD biosynthesis may play an important role in lymphocyte activation.

Amino Acid Sequence↗