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Biomedical subjects

Alain Fischer

Publications and source records attributed to Alain Fischer.

117 records · Page 7Linked to original sources
PubMed2002

Isoforms of the class II transactivator protein.

The class II transactivator (CIITA) controls both the constitutive and IFN-gamma inducible expression of HLA-D genes. In addition, through the squelching of another transactivator CREB-binding protein, CIITA was more recently shown to have a wider cellular function, including cell cycle control or cellular response to IFN-gamma and IL-4. However, due to its low expression level, its analysis mainly relies on the study of recombinant overexpressed forms of the protein. We report here the analysis of native CIITA in various cell types. We first show the precise timing of CIITA protein expression in a fibroblast cell line in response to IFN-gamma. This expression is observed 2 h after the cytokine addition with a peak of expression ranging from 16 to 24 h. We next show the existence of two major isoforms of the CIITA protein differentially expressed in fibroblast, B lymphocyte or melanoma cell lines. We present the first demonstration that these isoforms originate from alternative translation initiation codons. We finally show that CIITA isoforms translocate to the nucleus with an apparently similar efficiency. Our data therefore demonstrate the existence of CIITA isoforms whose respective ratio depends on the cell type examined. However, we present evidence for a modulation of this ratio in a melanoma cell line with an abnormal constitutive expression of MHC class II molecules.

Active Transport, Cell Nucleus↗
PubMed2002

Gene therapy of X-linked severe combined immunodeficiency.

This review addresses several questions in the light of the results recently obtained by a gene therapy trial for the treatment of X-linked severe combined immunodeficiency. This primary immunodeficiency, characterized by a complete absence of T and natural killer lymphocytes, appeared as a good model for the application of gene therapy, combining an expected selective advantage for transduced cells, an absence of immunological response to the vector and/or the therapeutic transgene together with accessibility to hematopoietic stem cells. After a brief description of the disease and its physiopathology we summarize the clinical results of the gene therapy trial putting them in perspective with those obtained following allogeneic hematopoietic stem cell transplantation. Definitive conclusions cannot be thrown due to the limited number of gene therapy-treated patients and their relatively short follow-up.

Bone Marrow Transplantation↗
PubMed2002

Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother.

A child with X-linked osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID) was recently reported. We report the clinical features of a second boy with this novel syndrome and his mother, who presented with signs of incontinentia pigmenti (IP). The child had mild osteopetrosis without neurosensory complications, unilateral lymphedema of the left leg, and characteristic features of anhidrotic ectodermal dysplasia with sparse hair, facial dysmorphy, delayed eruption of teeth, and sweat gland abnormalities. He died at 18 months of severe immunodeficiency with multiple infections caused by Gram-negative (Salmonella enteritidis) and Gram-positive (Streptococcus pneumoniae) bacteria, nontuberculous mycobacteria (Mycobacterium kansasii), and fungi (Pneumocystis carinii). His 30-year-old mother's medical history, together with residual cutaneous lesions, was highly suggestive of IP without neurologic impairment. In this patient with OL-EDA-ID, we detected the same NF-kappaB essential modulator stop codon hypomorphic mutation identified in the previous patient. The occurrence of the same clinical features in 2 unrelated patients with the same genotype demonstrates that OL-EDA-ID is a genuine clinical syndrome. The clinical and biological descriptions of the proband and his mother further corroborate the relationship between IP and EDA. Both syndromes are allelic and are associated with mutations in NF-kappaB essential modulator, with a genotype-phenotype correlation in hemizygous males. In contrast, loss-of-function mutations and hypomorphic mutations may cause IP in females.

Abnormalities, Multiple↗
PubMed2001

Molecular events associated with CD4-mediated Down-regulation of LFA-1-dependent adhesion.

We have previously shown that CD4 ligand binding inhibits LFA-1-dependent adhesion between CD4+ T cells and B cells in a p56(lck)- and phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. In this work, downstream events associated with adhesion inhibition have been investigated. By using HUT78 T cell lines, CD4 ligands were shown to induce a dissociation of LFA-1 from cytohesin, a cytoplasmic protein known to bind LFA-1 and to enhance the affinity/avidity of LFA-1 for its ligand ICAM-1. A dissociation of PI3-kinase from cytohesin is also observed. In parallel, we have found that CD4 ligand binding induced a redistribution of PI3-kinase and of the tyrosine phosphatase SHP-2 to the membrane and induced a transient formation of protein interactions including PI3-kinase; an adaptor protein, Gab2; SHP-2; and a SH2 domain-containing inositol phosphatase, SHIP. By using antisense oligonucleotides or transfection of transdominant mutants, down-regulation of adhesion was shown to require the Gab2/PI3-kinase association and the expression of SHIP and SHP-2. We therefore propose that CD4 ligands, by inducing these molecular associations, lead to sustained local high levels of D-3 phospholipids and possibly regulate the cytohesin/LFA-1 association.

CD4 Antigens↗
PubMedDate not supplied

Gene therapy of metabolic diseases.

This review surveys the potential application of gene therapy to metabolic diseases. Proof of principle has been achieved in the treatment of two inherited immunodeficiency conditions. A significant safety issue has also been observed. Several strategies are being experimentally tested for a number of metabolic diseases (more than 20) and may provide a rationale for the future development of clinical trials.

Gene Targeting↗
PubMedDate not supplied

[Defect in lytic granule exocytosis: several causes, a same effect].

An in vivo disturbance of lymphocyte homeostasis occurs during the course of the hemophagocytic syndrome (HS). HS is a severe and often fatal syndrome resulting from potent and uncontrolled activation and proliferation of T-lymphocytes, mainly polyclonal CD8 lymphocytes, leading to excessive macrophage activation, high level of proinflammatory cytokine production and multiple deleterious effects. The onset of HS characterizes several inherited disorders in humans. In most of these conditions, the molecular defect impairs the granule-dependent cytotoxic activity of lymphocytes, thus highlighting the determinant role of this function in driving back the immune system to a state of equilibrium following infection. Several lines of evidence suggest that an increase in the expansion phase rather than a decrease in the contraction phase of the CD8+ T cells population characterizes the HS. Failure to kill antigen presenting cells through a transaction mechanism of cytotoxic cells should favor a sustained response, although the mechanism may be more complex than simple decrease of antigen load. Defect in the granule dependent cytotoxic function of lymphocytes result from perforin mutation in familial hemophagocytic lymphohistiocytosis type 2, from Munc13-4 (UNC13D) mutation in familial hemophagocytic lymphohistiocytosis type 3, from Rab27a mutation in Griscelli syndrome type 2, and from CHS/LYST mutation in Chediak-Higashi syndrome. The characterization of the molecular causes leading to these conditions identified Rab27a and Munc13-4 as two critical effectors of the exocytic machinery, required for the terminal transport/docking or priming of the cytotoxic granules, respectively. Different members of the Rab and Munc13 family of proteins are also used in neurotransmitter release at the neurological synapse, highlighting the similarity of the mechanisms regulating both secretory pathways. Future investigations regarding HS will continue to elucidate this exocytic pathway machinery and improve our understanding of how it finely regulates the immune response, an area that is likely to be useful for therapeutic intervention.

Cytoplasmic Granules↗