Human Endogenous Retroviruses and Type 1 Diabetes.

PURPOSE OF THE REVIEW: The aim of this review is to discuss recent data pointing at an involvement of human endogenous retroviruses (HERVs) in type 1 diabetes (T1D) onset and progression. RECENT FINDINGS: The envelope protein of HERV-W family, named HERV-W-Env, was detected in pancreata from T1D patients and was shown to display pro-inflammatory properties and direct toxicity toward pancreatic beta cells. The etiopathogenesis of T1D remains elusive, even if conventional environmental viral infections have been recurrently involved. Nonetheless, a new category of pathogens may provide the missing link between genetic susceptibility and environmental factors long thought to contribute to T1D onset. A number of studies have now shown that HERV sequences, which are normally inactivated or repressed in the human genome, could be activated by environmental viruses. Thus, if similarly activated by viruses associated with T1D, disregarded HERV genes may underlie T1D genetic susceptibility. Moreover, once expressed, HERV elements may display broad pathogenic properties, which identify them as potential new therapeutic targets.

Serum induces a transcriptional activation of CYP1A1 gene in HepG2 independently of the AhR pathway.

CYP1A1 is largely implicated in carcinogenesis. To date, it is known that this gene is induced by xenobiotics such as polycyclic aromatic hydrocarbons. In this study, we evaluated the effect of serum in the regulation of CYP1A1 gene expression. CYP1A1 mRNA level is induced 1) in HepG2 and HT29-D4 cells by 3-methylcholanthrene 2) only in HepG2 after treatment by serum. The CYP1A1 mRNA induction in HepG2 is the consequence at least in part of a transcriptional activation as was demonstrated by evaluation of the hnRNA level. HepG2 cells were transfected by a plasmid containing the 7.5 Kb of the CYP1A1 promoter and the CAT reporter gene. No CAT stimulation was observed after serum treatment. These results demonstrated that CYP1A1 is induced at a transcriptional level by a physiological compound contained in serum independently of the Ah receptor and the 7.5 Kb promoter region.

Metabolism of carbamazepine by CYP3A6: a model for in vitro drug interactions studies.

Carbamazepine (CBZ) is widely used in the treatment of epilepsy. The drug is principally metabolized by CYPs to 10, 11-epoxy carbamazepine (CBZ-E) but this metabolite more toxic than the parent drug, does possess anticonvulsant properties. In humans, CYP3A4, CYP2C8 and CYP1A2 have been shown to be implicated in CBZ biotransformation. Our purpose was to establish an experimental model to determine the interaction of CBZ with other antiepileptic drugs. We first identified the CYP isoforms that metabolized CBZ in rabbit. We used liver microsomes from rabbit treated with various compounds known to induce principally some CYPs subfamilies. Having tested all the compounds we demonstrated that only the animals treated with CYP3A inducers were able to metabolize CBZ strongly. The CBZ biotransformation was inhibited by anti CYP3A antibodies. All the CYP3A subfamily substrates specifically decrease CBZ-E formation. In our experiment we did not observe any inhibition with CYP2C substrate. These data provide evidence that in rabbit the CYP3A subfamily is primarily involved in CBZ metabolism. Using this model we investigated the interaction of CBZ with phenobarbital, phenytoin, ethosuccimide, primidone, progabide, vigabatrin and lamotrigine.

Modulation of MDR1 and CYP3A expression by dexamethasone: evidence for an inverse regulation in adrenals.

A strong overlap exists between gp170 and CYP3A substrates and inducers. In order to investigate a putative coregulation of MDR and CYPA gene expression, we measured their transcripts in human liver and after dexamethasone treatment in HepG2 cells or in different mouse tissues. In human liver, we observed no correlation between MDR1 and CYP3A4 expression, whereas these genes were coinduced by dexamethasone in HepG2 cells. In mouse liver treated with dexamethasone, mdr1b and Cyp3a were induced (5- and 2-fold, respectively). In adrenals, the main expressing gp170 tissue, Cyp3a, was increased while mdr1b was repressed (-51%). The expression of mdr1b increased in heart, brain, and colon and decreased in lung and kidney but Cyp3a was not detectable. In conclusion, human hepatic CYP3A4 and MDR1 are not corregulated but are coinducible. In vivo murine mdr1b and Cyp3a are coregulated by dexamethasone in liver and inversely regulated in adrenals.

Association of deletion and homoplasmic point mutation of the mitochondrial DNA in an ocular myopathy.

The mitochondrial DNA of a 41 year old patient with ocular myopathy was explored. We found a deletion of 3540 base pair in about 50% of the mitochondrial genomes associated with a homoplasmic point mutation. The mutation at nucleotide pair 7444 converts stop codon AGA into lysine codon AAA (human mitochondrial genetic code). The synergistic effect between two point mutations has already been described in mitochondrial pathology but this is the first time that an association between a deletion and a point mutation is shown.

Epitope mapping of human thyroglobulin. Heterogeneous recognition by thyroid pathologic sera.

Thyroglobulin is the major Ag of the thyroid gland involved in autoimmune pathologies. Epitope mapping was carried out with a rabbit polyclonal immune serum against fusion proteins expressed in prokaryotic cells. After screening of an initial human thyroglobulin cDNA library and subcloning of immunoreactive clones, seven epitopes were characterized and localized on the human thyroglobulin monomeric molecule. One was close to each extremity of the molecule, and five others were concentrated in the middle, covering a sixth of this 2748-amino-acid chain. The immunoreactivities of 18 autoimmune sera from different thyroid pathologies were tested against the seven previously characterized epitopes. Those from Hashimoto's thyroiditis were the most immunoreactive. Immune responses were heterogeneous for sera from different pathologies as well as for those from the same pathology. The central epitopes and the near-C-terminal epitope, however, were the epitopes most often recognized by the immune sera. These findings show that some autoepitopes overlap accurately with some heteroepitopes characterized by a polyclonal immune serum directed against the mature protein.

Evidence for an alternate splicing in the thyroperoxidase messenger from patients with Graves' disease.

An initial lambda gt 11 cDNA library constructed from a human Graves' patient thyroid was screened with an immunopurified rabbit anti-human thyroperoxidase (hTPO) polyclonal antibody. A 869 bp clone was obtained. It presents a 130 bp deletion as compared to the published sequence and a 77 bp insertion in the 3' non-coding region. Screening of a pUC cDNA library from another Graves' patient thyroid exhibited the same 130 bp deletion in two other cDNA clones. PCR analysis of mRNA transcripts confirmed the presence of the two messengers in two other Graves' thyroid tissues. In all the cases, this new spliced mRNA species represents between 40% and 50% of the total hTPO mRNAs. With respect to the structure of the hTPO gene, the present deletion suggests an alternate splicing of exon 16. The juxtaposition of exon 17 to exon 15 encoding the transmembrane domain leads to a shift in the reading frame. By the use of a different stop codon, the spliced mRNA generates a modified 56 - COOH terminal aminoacids (aa) sequence.

[Structural heterogeneity of human thyroglobulin in relation to its messenger RNA maturation]. / Hétérogénéité structurale de la thyroglobuline humaine en relation avec la maturation de son ARN messager.

One human thyroglobulin cDNA clone present 192 nucleotides deletion which correspond to 64 amino-acid deletion on the protein molecule. We show that this fact figure the exon loss on the mRNA molecule using as template during cDNA synthesis by comparison between mRNA and genomic DNA nucleotide sequences. Different possibility can explain this fact. We retain mainly mistake in mRNA maturation fidelity. This type of event is not an exception and can be an explanation for some pathologies.

[Endoscopy of the maxillary sinus. Diagnostic and therapeutic value in chronic sinusitis]. / L'endoscopie du sinus maxillaire. Valeur diagnostique et thérapeutique dans les sinusites chroniques.

Sinus endoscopy is now well established as an essential exploratory procedure for the study of rhinosinus affections. By direct endocavitary observation, after identification and evacuation of possible secretions, it enables the anatomical and functional state of the mucosa to be studied, as well as that of the ostial region. For the maxillary sinus, the most easily accessible, direct endoscopic examination has become indispensable for a precise diagnosis of any chronic inflammatory or infections process, when associated with cyto-bacteriologic, colorimetric, manometric and possibly histologic investigations, completing clinical and radiologic findings when necessary. Endoscopy can also often act as the primary therapeutic gesture, its evacuating and aerating properties relieving ostial dyspermeability, the principal cause of chronic maxillary sinusitis. Diagnostic and therapeutic features in this particularly frequent affection are discussed with respect to the use of endoscopy.