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Biomedical subjects

L Pelletier

Publications and source records attributed to L Pelletier.

At least 19 recordsLinked to original sources
PubMed2006

A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott-Rallison syndrome.

Mutations in the EIF2AK3 gene have been identified in patients with Wolcott-Rallison syndrome - a rare autosomal recessive disorder associated with permanent neonatal insulin-dependent diabetes. Despite the fact that different mutations have been observed in every single unrelated case reported so far, most patients presented with similar characteristics, such as osteopenia, epiphyseal dysplasia as well as hepatic and/or renal dysfunction. The EIF2AK3 gene was analyzed using a PCR-based sequencing approach in two Wolcott-Rallison patients and their parents. We report two cases from different families carrying the same and novel truncating nonsense mutation in the EIF2AK3 gene that encodes the pancreatic eukaryotic initiation factor 2alpha kinase 3. This mutation clearly displays different clinical characteristics in the two patients we examined. Remarkably, the onset of diabetes was different for the two patients, and there was also heterogeneity in other clinical manifestations. These cases illustrate the important role of alternative pathways that could, to some extent, take over or supplement a defective metabolic pathway. This supports the idea that there is no simple relationship among clinical manifestations and EIF2AK3 mutations.

Amino Acid Sequence↗
PubMed2006

Toxoplasma gondii in human astrocytes in vitro: interleukin (IL)-12 and IL-10 do not influence cystogenesis.

Interleukin (IL)-12, IL-10, and interferon (IFN)-gamma are major cytokines involved in the immune response against Toxoplasma gondii. Nevertheless, the role of IL-12 and IL-10 in the control of parasite replication and cytogenesis is not known yet, whereas the importance of IFN-gamma is documented. Furthermore, it is of paramount importance to study the interaction between T. gondii and cells from the central nervous system, e.g., astrocytes. In this study, we report that IL-12 and IL-10 have no effect on penetration, replication, or cystogenesis of the T. gondii Prugniaud strain in human astrocytes in vitro and do not antagonize the role of IFN-gamma on cystogenesis.

Animals↗
PubMed2003

Apoptosis participates to liver damage in HSV-induced fulminant hepatitis.

BACKGROUND: HSV fulminant hepatitis is a rare pathology. Rapid hepatic failure, as a consequence of extended liver damage, has generally been attributed to necrosis. As apoptosis can constitute another way for hepatocytes to die, we decided to investigate whether programmed cell death took place during HSV fulminant hepatitis. METHODS: Liver sections were obtained from two cases of fulminant herpetic hepatitis as well as from hepatitis B virus and Rickettsia-infected livers. Herpes simplex virus infection was confirmed using in situ hybridization. Apoptosis was assessed by histopathological examination, p53, activated-caspase 3 and Fas immunohistochemistry and TUNEL labeling. RESULTS: We report that the number of cells expressing activated-caspase 3 was largely increased in fulminant herpes simplex virus hepatitis, when compared to livers chronically infected by hepatitis B virus or from a Rickettsial acute hepatitis. Apoptosis of hepatocytes was confirmed by a positive double-staining for activated-caspase 3 and hepatocytes. Finally, the apoptotic process has progressed beyond the step of nuclear DNA cleavage as demonstrated by TUNEL labeling. CONCLUSION: These data as a whole show that apoptosis is responsible, at least partially, for liver damage during HSV fulminant hepatitis.

Apoptosis↗
PubMed2001

Gold is a T cell polyclonal activator in BN and LEW rats but favors IL-4 expression only in autoimmune prone BN rats.

Gold salts are beneficial in the treatment of rheumatoid arthritis but may induce immune-mediated disorders in predisposed patients. Gold salts induce Th2-dependent autoimmunity in Brown-Norway (BN) rats but not in Lewis (LEW) rats. The aim of this study was to define molecular targets of gold salts and to approach why LEW rats are resistant. Gold salts act on early steps of transduction in T cells from BN and LEW rats since they trigger tyrosine phosphorylation of numerous proteins including p56(lck) and a calcium signal which results in IL-4 and IFN-gamma expression by BN and LEW T cells. However, the IL-4 response was favored in BN spleen cells in vitro and in vivo. IFN-gamma, produced in part by CD8(+) cells, contributes to the resistance of LEW rats since gold salt-injected LEW rats receiving anti-CD8 or anti-IFN-gamma mAb displayed the parameters characteristics of gold salt-induced Th2 autoimmunity although to a lesser extent than in BN rats. Gold salts transduce a signal in BN and LEW spleen cells resulting in IL-4 and IFN-gamma gene transcription with a preferential IL-4 response in BN rats, a Th2-prone strain, while IFN-gamma contributes to the resistance of LEW rats.

Animals↗
PubMed2001

Weak TCR stimulation induces a calcium signal that triggers IL-4 synthesis, stronger TCR stimulation induces MAP kinases that control IFN-gamma production.

Th1 and Th2 cells produce different cytokines and have distinct functions. Th1/Th2 cell differentiation is influenced, among other factors, by the nature of TCR-MHC interactions. However, how the TCR transduces a signal resulting in IFN-gamma or IL-4 production is a matter of debate. For example, some authors reported a loss of calcium signaling pathway in Th2 cells. We used a T cell hybridoma producing IL-4 upon weak TCR stimulation and both IL-4 and IFN-gamma for strong TCR engagement as a model to study how TCR signaling pathways are differentially activated in both conditions of stimulation and how this influences the production of cytokines. We show that: (1) the calcium response is identical following weak and strong TCR stimulation; (2) mitogen-activated protein kinase(MAPK) activation is a gradual phenomenon depending upon the strength of TCR activation; (3) a calcium response, even weak, triggers IL-4 expression; (4) IFN-gamma synthesis requires not only a calcium response but also MAPK activation. The MAPK pathway is dispensable for IL-4 production, although it amplifies IL-4 synthesis upon strong TCR stimulation; (5) TCR-induced IL-4 production also depends on calcium signaling in Th2 cells, while IFN-gamma synthesis is dependent, in addition, on MAPK activation in Th1 cells.

Animals↗
PubMed2001

Induction of autoimmunity through bystander effects. Lessons from immunological disorders induced by heavy metals.

Autoreactive T cells exist in healthy individuals and represent a potential reservoir of pathogenic effectors which, when stimulated by microbial adjuvants, could trigger an autoimmune disease. Experimental studies have indicated that xenobiotics, well defined from a chemical point of view, could promote the differentiation of autoreactive T cells towards a pathogenic pathway. It is therefore theoretically possible that compounds present in vaccines such as thiomersal or aluminium hydroxyde can trigger autoimmune reactions through bystander effects. Mercury and gold in rodents can induce immunological disorders with autoimmune reactions. In vitro, both activate signal transduction pathways that result in the expression of cytokines, particularly of IL-4 and IFNgamma. In a suitable microenvironment heavy metals could therefore favour the activation of autoreactive T cells. In that respect, genetic background is of major importance. Genome-wide searches in the rat have shown that overlapping chromosomal regions control the immunological disorders induced by gold salt treatment, the development of experimental autoimmune encephalomyelitis and the CD45RC(high)/CD45RC(low)CD4(+)T cells balance. The identification and functional characterization of genes controlling these phenotypes may shed light on key regulatory mechanisms of immune responses. This should help to improve efficacy and safety of vaccines.

Adjuvants, Immunologic↗
PubMed2001

Self major histocompatibility complex class-II-specific regulatory CD4 T cells prevent both Th1- and Th2-mediated autoimmune diseases in the rat.

It is clear that functional heterogeneity of T cells may be explained by differential cytokine production. The aim of this paper was to review evidence for regulatory cells, generated after HgCl(2)-exposure. They differ from classical Th1 and Th2 cells, produce transforming growth factor-beta and interleukin-10 and exert their regulatory functions in a Th1/Th2-unrestricted fashion.

Animals↗
PubMed2001

Cellular and genetic factors involved in the difference between Brown Norway and Lewis rats to develop respectively type-2 and type-1 immune-mediated diseases.

The understanding of the mechanisms of immune tolerance and the unravelling of the pathophysiology of autoimmune diseases rely on animal models. In this respect, BN and LEW rats represent models of choice to study immune-mediated diseases from the cellular and genetic points of view. Indeed, BN and LEW rats are extremes with respect to their polarisation of the immune response as well as their susceptibility to autoimmune diseases. LEW rats are susceptible to Th1-mediated autoimmune diseases while BN rats are highly susceptible to Th2-mediated autoimmune disease. Comparison of the T cell compartment between LEW and BN rats revealed several important differences. 1) A MHC-dependent quantitative difference that is due to a defect in the CD8 T cell compartment in BN rats. 2) A qualitative MHC-independent difference that is related to a high frequency of CD45RClow CD4 and CD8 T cell subsets, producing IL-4, IL-13, IL-10 and TGF-beta in BN rats as compared to LEW rats. 3) Interestingly, the genetic studies showed that susceptibility to Th1-mediated experimental autoimmune encephalomyelitis, and to Th2-mediated disorders triggered by gold salts as well as the difference in the CD4SRChigh/CD45RClow ratio between LEW and BN rats are genetically determined by regions on chromosomes 9, 10 and 20.

Animals↗
PubMed2001

[Calcium-dependent pathways involved in the production of cytokines in lymphocytes].

CD4+ T lymphocytes are divided in Th1 cells producing IFN gamma and Th2 cells that synthetize IL-4. This paper describes signaling pathways activated following T cell receptor (TCR) engagement and emphasizes differences that can account for differential cytokine production. This paper focuses on a new signaling pathway involved in IL-4 synthesis. This pathway couples the TCR to PKC that controls a calcium entry through dihydropyridine sensitive calcium channels. The calcium response is sufficient to initiate IL-4 gene transcription. Differing from that of IL-4, IFN gamma gene expression always requires MAP-kinase activation in addition to a calcium signal.

Calcium↗
PubMed2000

Invasive pneumococcal infections in Canadian children, 1991-1998: implications for new vaccination strategies. Canadian Paediatric Society/Laboratory Centre for Disease Control Immunization Monitoring Program, Active (IMPACT).

We reviewed 2040 consecutive cases of invasive pneumococcal infection that were seen at 11 pediatric centers across Canada during 1991-1998 to determine if such infections could be prevented by new conjugate vaccines. Isolates from 1528 cases were serotyped. Most cases (61.5%) occurred in patients aged >2 years. Underlying medical conditions were present in 23.2% of case patients. Serotypes in the 7-valent conjugate vaccine matched isolates as follows: 85.8% of tested isolates from children aged 6 months to 5 years, but significantly fewer isolates in younger and older children; 72.9% of isolates from non-healthy children, but 83.9% of isolates from previously healthy children; and 95.4% of isolates with high-level penicillin resistance, but only 72.7% of those with intermediate-level resistance. Significant natural variation in the proportion of isolates matching 7-valent vaccines occurred from year to year and among centers. New conjugate vaccines have great potential but their effectiveness and limitations require ongoing study.

Bacteremia↗
PubMed2000

The effect of Golgi depletion on exocytic transport.

Here we evaluate the idea that the Golgi is in dynamic equilibrium with the endoplasmic reticulum (ER). In cytoplasts that lack the Golgi apparatus, no regrowth of the Golgi is observed, nor is any transport from the ER to the cell surface detected. However, introduction of the smallest measurable amount of Golgi (equivalent to a few per cent per cell) yields significant exocytic transport. Our results indicate that the steady-state levels of Golgi in the ER are far smaller than the 30% that has been postulated, and that the Golgi may be an independent organelle and not simply an extension of the ER.

Animals↗
PubMed2000

An in vitro model for the study of human bone marrow angiogenesis: role of hematopoietic cytokines.

This study describes a human bone marrow endothelial cell culture in which endothelial cells are organized into capillary tubes. These endothelial cells were positive for von Willebrand Factor, expressed CD34, CD31, and L-fucose residues, took up acetylated low-density lipoproteins, contained Weibel-Palade bodies, and were ensheathed in a basal lamina (which included laminin beta1, EDa+ and EDb+ fibronectin, and collagen type iv). Pericytes expressing alpha-smooth muscle (alpha-SM) actin were spatially associated with the capillary tubes and there was a highly significant correlation between the number of capillary tubes and pericytes. In this model, basal angiogenesis was found to be vascular endothelial growth factor (VEGF)-dependent, because neutralization of endogenous VEGF induced a dramatic regression in the number of tubes. However, the presence of alpha-SM actin-expressing pericytes in the linings of endothelial tubes partially prevented the VEGF-neutralized tube regression. We also observed that nitric oxide production contributed to basal angiogenesis and that upregulation of nitric oxide increased the number of tubes. Tube numbers also decreased when antibodies neutralizing the integrin alphavbeta5 were applied to the cultures. Moreover, addition of any of the hematopoietic cytokines, erythropoietin, stem cell factor, granulocytic colony stimulating factor, or granulomonocytic colony stimulating factor induced a highly significant increase in tube formation. When erythropoietin and granulocytic colony stimulating factor were added, this increase was larger than the maximum increase observed with VEGF. Thus, we have described an in vitro model for human bone marrow angiogenesis in which pericytes and basal lamina matrix were associated with endothelial cells and formed fully organized capillary tubes. In this model, cytokines known to regulate hematopoiesis also seemed to be mediators of angiogenesis. This culture system may therefore prove to be a valuable tool for the study of hematopoietic cytokines on angiogenesis.

Bone Marrow↗