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Biomedical subjects

P Pierre

Publications and source records attributed to P Pierre.

At least 19 recordsLinked to original sources
PubMed2001

Polyploids require Bik1 for kinetochore-microtubule attachment.

The attachment of kinetochores to spindle microtubules (MTs) is essential for maintaining constant ploidy in eukaryotic cells. Here, biochemical and imaging data is presented demonstrating that the budding yeast CLIP-170 orthologue Bik1is a component of the kinetochore-MT binding interface. Strikingly, Bik1 is not required for viability in haploid cells, but becomes essential in polyploids. The ploidy-specific requirement for BIK1 enabled us to characterize BIK1 without eliminating nonhomologous genes, providing a new approach to circumventing the overlapping function that is a common feature of the cytoskeleton. In polyploid cells, Bik1 is required before anaphase to maintain kinetochore separation and therefore contributes to the force that opposes the elastic recoil of attached sister chromatids. The role of Bik1 in kinetochore separation appears to be independent of the role of Bik1 in regulating MT dynamics. The finding that a protein involved in kinetochore-MT attachment is required for the viability of polyploids has potential implications for cancer therapeutics.

Binding Sites↗
PubMed2001

[Proteases, natural protease inhibitors and activation of the machinery of antigen presentation in dendritic cells].

Dendritic cells play a central role in the immune response due to their exceptionally strong capacity for presenting antigens to naive T lymphocytes. Recent evidences have demonstrated that dendritic cells (DCs) exhibit a remarkable pattern of differentiation (maturation) that is accompanied by striking changes in morphology, organization and function. The hallmark of DC maturation is the major reorganization of the MHC class II molecule intracellular transport which is in part regulated by endosomal proteases activation. The central role of the endosomal proteases in generating antigenic peptides and controlling MHC class II traffic clearly defines these enzymes as an important area of investigation.

Animals↗
PubMed2000

Effect of naratriptan on myocardial blood flow and coronary vasodilator reserve in migraineurs.

BACKGROUND: Migraine drugs can produce adverse cardiac effects. The authors have demonstrated previously that ergotamine can lead to a significant reduction of hyperemic myocardial blood flow, but little is known about the effect of the newer serotonin analogues. Coronary artery constriction caused by serotonin or its analogues is mediated mainly by 5HT2 receptors. The selective 5HT1B/1D agonist naratriptan has no significant activity at 5HT2 receptors; however, like all 5HT1B/1D agonists developed for the acute treatment of migraine, naratriptan could potentially constrict coronary arteries by activation of 5HT1B receptors. METHODS: The effects on myocardial blood flow of subcutaneous naratriptan 1.5 mg compared with placebo were assessed under resting and hyperemic conditions with PET using oxygen-15 labeled water during two separate visits. This study was a randomized, double-blind, placebo-controlled crossover trial in 34 migraine subjects with no evidence of ischemic heart disease, studied outside a migraine attack. RESULTS: Naratriptan did not differ significantly from placebo in its effects on resting myocardial blood flow, but did evoke a small, significant fall in hyperemic myocardial blood flow (-13% versus placebo) and an increase in hyperemic coronary resistance (+19% versus placebo) without any signs or symptoms suggestive of myocardial ischemia. Naratriptan did not significantly affect the coronary vasodilator reserve (hyperemic/resting blood flow) compared with placebo. CONCLUSIONS: These results show that at therapeutic doses, naratriptan exerts only a minor effect on myocardial blood flow, coronary vasodilator reserve, or coronary resistance among subjects with no evidence of ischemic heart disease. These results should not be extrapolated to patients with coronary artery disease, in whom all 5HT1 agonists for migraine are contraindicated.

Adult↗
PubMed2000

Invariant chain controls H2-M proteolysis in mouse splenocytes and dendritic cells.

The association of invariant (Ii) chain with major histocompatibility complex (MHC) class II dimers is required for proper antigen presentation to T cells by antigen-presenting cells. Mice lacking Ii chain have severe abnormalities in class II transport, T cell selection, and B cell maturation. We demonstrate here that H2-M, which is required for efficient class II antigenic peptide loading, is unexpectedly downregulated in splenocytes and mature dendritic cells (DCs) from Ii(-/-) mice. Downregulation reflects an increased rate of degradation in Ii(-/-) cells. Degradation apparently occurs within lysosomes, as it is prevented by cysteine protease inhibitors such as E64, but not by the proteasome inhibitor lactacystin. Thus, Ii chain may act as a lysosomal protease inhibitor in B cells and DCs, with its deletion contributing indirectly to the loss of H2-M.

Animals↗
PubMed1999

Purification and analysis of authentic CLIP-170 and recombinant fragments.

We have purified authentic CLIP-170 (cytoplasmic linker protein of 170 kDa) and fragments comprising functional domains of the protein to characterize the structural basis of the function of CLIP-170. Analysis of authentic CLIP-170 and the recombinant fragments by electron microscopy after glycerol spraying/low angle rotary metal shadowing reveals CLIP-170 as a thin, 135-nm-long molecule with two kinks in its central rod domain, which are approximately equally spaced from the two ends of the protein. The central domain consisting of heptad repeats, which is alpha-helical in nature and forms a 2-stranded coiled-coil, mediates dimerization of CLIP-170. The rod domain harbors two kinks, each spaced approximately 37 nm from the corresponding end of the molecule, thus providing mechanical flexibility to the highly elongated molecule. The N-terminal domain of CLIP-170 binds to microtubules in vitro with a stoichiometry of one dimeric head domain per four tubulin heterodimers. Authentic CLIP-170 binds to microtubules with lower stoichiometry, indicating that the rod and tail domains affect microtubule binding of CLIP-170. These results document that CLIP-170 is a highly elongated polar molecule with the microtubule-binding domain and the organelle-interacting domains at opposite ends of the homodimer, thus providing a structural basis for the function of CLIP-170 as a microtubule-organelle linker protein.

Binding Sites↗
PubMed1999

Antigen capture, processing, and presentation by dendritic cells: recent cell biological studies.

Antigen uptake, processing and presentation by dendritic cells [DCs] have become amenable to cell biological approaches. The critical events occur in DCs that are undergoing maturation in response to inflammatory stimuli. Successful antigen presentation can be monitored directly using antibodies that are specific for particular MHC-peptide complexes. What a contrast to earlier times when it was difficult to visualize even the uptake of antigen into isolated DCs and DCs in the T cell areas of lymphoid organs! We emphasize here the efficiency of antigen capture and presentation by maturing DCs, especially for dying cells. This presentation of cellular antigens by DCs likely explains the phenomenon of cross priming in the setting of transplantation and other clinical states.

Animals↗
PubMed1998

Developmental regulation of invariant chain proteolysis controls MHC class II trafficking in mouse dendritic cells.

Dendritic cells (DCs) developmentally regulate their capacity for antigen presentation by controlling the transport and surface expression of MHC class II molecules. These events reflect a developmental regulation of invariant (Ii) chain cleavage, most likely by the cysteine protease cathepsin S. In immature DCs, inefficient Ii chain cleavage due to low cathepsin S activity leads to the transport of class II-Ii chain complexes to lysosomes, while in mature DCs, elevated cathepsin S activity results in efficient delivery of class II alphabeta dimers to the plasma membrane. Cathepsin S is not controlled transcriptionally but by a novel mechanism involving alterations in the expression and localization of an endogenous cathepsin S inhibitor cystatin C. Thus, the ratio of cystatin C to cathepsin S in developing DCs helps to determine the fate of newly synthesized MHC class II molecules.

Animals↗
PubMed1998

Exploring the mechanisms of antigen processing by cell fractionation.

It is becoming increasingly clear that most of the intracellular compartments that contain MHC class II products in antigen-presenting cells simply represent the conventional endosomes and lysosomes that are expressed in all cell types. Data from recent cell fractionation studies, however, predominantly those using electrophoresis techniques, show that a population of class-II-containing vesicles exists that may comprise a class of endosomes that are specialized for antigen processing. Strong support for this possibility comes from the observation that such specialized structures, designated class II vesicles (CIIV), are particularly abundant in mature dendritic cells.

Antigen Presentation↗
PubMed1998

Skin signs in the diagnosis of thallium poisoning.

A 45-year-old man developed a painful and rapidly progressive sensory-motor polyneuropathy associated with confusion and convulsions. This resulted in hypoventilation and led to respiratory failure and coma. A rapid and diffuse alopecia occurred after 3 weeks in the intensive care unit. Examination of hair roots under polarized light detected dystrophic anagen hairs with dark bands caused by empty spaces in the disorganized cortex. These dark zones were originally reported in patients with thallium poisoning and a toxicological investigation confirmed thallium exposure. The classical systemic symptoms and the various dermatological signs are reviewed, and the origins of contamination and physiopathology discussed.

Alopecia↗
PubMed1997

Developmental regulation of MHC class II transport in mouse dendritic cells.

Dendritic cells (DCs) have the unique capacity to initiate primary and secondary immune responses. They acquire antigens in peripheral tissues and migrate to lymphoid organs where they present processed peptides to T cells. DCs must therefore exist in distinct functional states, an idea that is supported by observations that they downregulate endocytosis and upregulate surface molecules of the class II major histocompatibility complex (MHC) upon maturation. Here we investigate the features of DC maturation by reconstituting the terminal differentiation of mouse DCs in vitro and in situ. We find that early DCs, corresponding to those found in peripheral tissues, exhibit a phenotype in which most class II molecules are intracellular and localized to lysosomes. Upon maturation, these cells give rise to a new intermediate phenotype in which intracellular class II molecules are found in peripheral non-lysosomal vesicles, similar to the specialized CIIV population seen in B cells. The intermediate cells then differentiate into late DCs which express almost all of their class II molecules on the plasma membrane. These variations in class II compartmentalization are accompanied by dramatic alterations in the intracellular transport of the new class II molecules and in antigen presentation. We found that although early DCs could not present antigen immediately after uptake, efficient presentation of the previously internalized antigen occurred after maturation, 24-48 hours later. By regulating class II transport and compartmentalization, DCs are able to delay antigen display, a property crucial to their role in immune surveillance.

Amino Acid Sequence↗
PubMed1996

HLA-DM is localized to conventional and unconventional MHC class II-containing endocytic compartments.

HLA-DM molecules remove invariant (Ii) chain peptides from newly synthesized MHC class II complexes. Their localization may thus delineate compartments, e.g., MIIC, specialized for loading peptides onto class II molecules. In murine A20 B cells, however, DM is not restricted to specialized endosomal class II-containing vesicles (CIIV). Although DM was found in CIIV, it was also found throughout the endocytic pathway, principally in lysosomes devoid of class II molecules. In human lymphoblasts, HLA-DM was found in structures indistinguishable from late endosomes or lysosomes, although in these cells the lysosomes contained MHC class II molecules. Thus, the distribution of HLA-DM does not necessarily identify specialized class II compartments. Many "MIIC" may represent conventional lysosomes that accumulate MHC class II and HLA-DM in a number of cell types.

Animals↗
PubMed1996

The anti-Hu syndrome: a clinical and immunological study of 7 cases.

The authors describe the clinical and biological data of seven patients with anti-Hu antibodies. Six of them displayed a small cell lung carcinoma (SCLC), but no cancer was detected in the 7th patient in spite of an extensive workup. The clinical heterogeneity of the anti-Hu syndrome is emphasized. The major symptoms were linked to a severe sensory neuropathy in three cases, to cerebellitis in two cases, to dysautonomia in one case, and to gastro-intestinal pseudo-obstruction in one case. One patient also displayed EMG abnormalities characteristic of the Lambert-Eaton myasthenic syndrome. Two patients developed opsoclonus or ocular flutter associated with severe confusion in the late stage of their disease. In four patients, the neurological signs and symptoms preceded the discovery of the SCLC, and in two cases the initial detection of anti-Hu antibodies prompted the successful search for this tumor. Immunopathological events injuring the peripheral and central nervous system are briefly discussed.

Aged↗
PubMed1995

Lonely MHC molecules seeking immunogenic peptides for meaningful relationships.

The association between antigenic peptides and MHC class II molecules represents a critical event in the initiation of the immune response to extracellular antigens. Understanding the molecular basis of antigen processing requires the characterization of the intracellular compartments, or 'singles bars', in which immunogenic peptides are generated and loaded onto class II molecules. In the past year, something of a breakthrough occurred with the identification of specialized compartments that host antigen processing and/or peptide loading, designated 'MHC class II compartment' and 'class II vesicles'. It is becoming increasingly clear, however, that these compartments are themselves heterogeneous and not always distinct from conventional endosomes and lysosomes.

Animals↗
PubMed1995

Headache at stroke onset: the Lausanne Stroke Registry.

Within 12 hours of stroke onset 2506 patients with first ever stroke admitted to the Lausanne Stroke Registry were questioned about headache. Eighteen per cent of the patients reported headache, 14% with anterior circulation stroke and 29% with posterior circulation stroke (p < 0.001). Headache was reported by 16% of the patients with infarct and 36% of those with haemorrhage (p < 0.001). The prevalence of headache was 9% with lacunar infarct, 15% with middle cerebral artery territory infarct, 37% with infratentorial haemorrhage, and 36% with supratentorial haemorrhage. The most common topography of pain was frontal (41%), followed by diffuse headache (27%; p < 0.001). Diffuse (41%) or occipital (30%) headache was particularly frequent with posterior circulation stroke, whereas frontal headache was associated with anterior circulation stroke (51%; p < 0.001). Headache in stroke may be explained in part by involvement of blood vessels (acute distention or distortion) and mechanical (stretch of haemorrhage) stimulation of intracranial nociceptive afferents. Stroke due to dissection was strongly associated with headache (p < 0.001), whereas embolic (cardiac, artery to artery) stroke was more common without headache (p < 0.001), emphasising the role of extracranial v intracranial arteries in the genesis of headache at stroke onset. Moreover, dual trigeminal-vascular and cervical-vascular system involvement in causing headache may explain the lack of correspondence with the "rules of referral" in up to 38% of the cases.

Adolescent↗
PubMed1994

Tissue-specific differences in the establishment of tolerance. Tolerogenic effects of lung allografts in rats.

With the increasing frequency of transplantation of two or more organs into a single recipient, it has become evident that different organs are rejected with different kinetics. In this study the kinetics of skin, lung, and heart allograft rejection were compared in a rodent model. To study the influence of different allografts on the recipient's immune system, simultaneous or sequential skin, lung, or heart transplants were performed in various combinations, using DA rats as recipients for PVG allografts. Recipients receiving primary allografts were treated postoperatively with ten doses of cyclosporine (CsA) or preoperatively with 4 doses of rabbit antirat thymocyte globulin (ATG). Subsequent transplants were performed a minimum of 40 days later without additional immunosuppression. All primary skin allografts and 60% of primary lung allografts were rejected, while 100% of the heart allografts were accepted indefinitely. Recipients of primary skin allografts rejected subsequent skin, lung, or heart allografts with accelerated kinetics. Recipients of primary heart allografts accepted subsequent skin, lung, and heart allografts indefinitely without further immunosuppression. Surprisingly, animals that had rejected a primary lung allograft accepted subsequent skin or heart allografts indefinitely. Simultaneously transplanted skin and lung allografts were concordantly rejected. However, these animals accepted a subsequent heart allograft indefinitely, suggesting a strong tolerizing effect of lung allografts. Our results indicate that tissue-specific differences are critical, not only in determining acceptance or rejection of a primary allograft but also in determining the fate of subsequent allografts.

Animals↗