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1.
Nat Commun ; 8(1): 1282, 2017 11 03.
Article de Anglais | MEDLINE | ID: mdl-29101363

RÉSUMÉ

Infectious pathogens contribute to the development of autoimmune disorders, but the mechanisms connecting these processes are incompletely understood. Here we show that Plasmodium DNA induces autoreactive responses against erythrocytes by activating a population of B cells expressing CD11c and the transcription factor T-bet, which become major producers of autoantibodies that promote malarial anaemia. Additionally, we identify parasite DNA-sensing through Toll-like receptor 9 (TLR9) along with inflammatory cytokine receptor IFN-γ receptor (IFN-γR) as essential signals that synergize to promote the development and appearance of these autoreactive T-bet+ B cells. The lack of any of these signals ameliorates malarial anaemia during infection in a mouse model. We also identify both expansion of T-bet+ B cells and production of anti-erythrocyte antibodies in ex vivo cultures of naive human peripheral blood mononuclear cells (PBMC) exposed to P. falciprum infected erythrocyte lysates. We propose that synergistic TLR9/IFN-γR activation of T-bet+ B cells is a mechanism underlying infection-induced autoimmune-like responses.


Sujet(s)
Anémie hémolytique auto-immune/étiologie , Anémie hémolytique auto-immune/immunologie , Sous-populations de lymphocytes B/immunologie , Sous-populations de lymphocytes B/parasitologie , ADN des protozoaires/immunologie , Paludisme à Plasmodium falciparum/complications , Paludisme à Plasmodium falciparum/immunologie , Plasmodium falciparum/immunologie , Récepteur-9 de type Toll-like/métabolisme , Anémie hémolytique auto-immune/parasitologie , Animaux , Autoanticorps/biosynthèse , Érythrocytes/immunologie , Érythrocytes/parasitologie , Femelle , Humains , Activation des lymphocytes , Paludisme à Plasmodium falciparum/parasitologie , Souris , Souris de lignée C57BL , Souris knockout , Plasmodium falciparum/pathogénicité , Récepteur interféron/déficit , Récepteur interféron/génétique , Récepteur interféron/métabolisme , Protéines à domaine boîte-T/déficit , Protéines à domaine boîte-T/génétique , Protéines à domaine boîte-T/métabolisme , Récepteur-9 de type Toll-like/déficit , Récepteur-9 de type Toll-like/génétique ,
2.
J Biol Chem ; 276(32): 30188-98, 2001 Aug 10.
Article de Anglais | MEDLINE | ID: mdl-11402028

RÉSUMÉ

Reactive oxygen species (ROS) are important second messengers generated in response to many types of environmental stress. In this setting, changes in intracellular ROS can activate signal transduction pathways that influence how cells react to their environment. In sepsis, a dynamic proinflammatory cellular response to bacterial toxins (e.g. lipopolysaccharide or LPS) leads to widespread organ damage and death. The present study demonstrates for the first time that the activation of Rac1 (a GTP-binding protein), and the subsequent production of ROS, constitutes a major pathway involved in NFkappaB-mediated tumor necrosis factor-alpha (TNFalpha) secretion following LPS challenge in macrophages. Expression of a dominant negative mutant of Rac1 (N17Rac1) reduced Rac1 activation, ROS formation, NFkappaB activation, and TNFalpha secretion following LPS stimulation. In contrast, expression of a dominant active form of Rac1 (V12Rac1) mimicked these effects in the absence of LPS stimulation. IKKalpha and IKKbeta were both required downstream modulators of LPS-activated Rac1, since the expression of either of the IKK dominant mutants (IKKalphaKM or IKKbetaKA) drastically reduced NFkappaB-dependent TNFalpha secretion. Moreover, studies using CD14 blocking antibodies suggest that Rac1 induces TNFalpha secretion through a pathway independent of CD14. However, a maximum therapeutic inhibition of LPS-induced TNFalpha secretion occurred when both CD14 and Rac1 pathways were inhibited. Our results suggest that targeting both Rac1- and CD14-dependent pathways could be a useful therapeutic strategy for attenuating the proinflammatory cytokine response during the course of sepsis.


Sujet(s)
Éthidium/analogues et dérivés , Lipopolysaccharides/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Oxydoréduction , Protein-Serine-Threonine Kinases/métabolisme , Espèces réactives de l'oxygène , Facteur de nécrose tumorale alpha/métabolisme , Protéine G rac1/métabolisme , Adenoviridae/génétique , Animaux , Technique de Western , Catalase/métabolisme , Lignée cellulaire , Noyau de la cellule/métabolisme , Cytokines/métabolisme , Relation dose-effet des médicaments , Régulation négative , Spectroscopie de résonance de spin électronique , Activation enzymatique , Éthidium/pharmacologie , Régulation de l'expression des gènes , Gènes dominants , Glutathione transferase/métabolisme , Humains , I-kappa B Kinase , Antigènes CD14/métabolisme , Luciferases/métabolisme , Souris , Modèles biologiques , Mutation , Liaison aux protéines , Isoformes de protéines , ARN messager/métabolisme , RT-PCR , Transduction du signal , Superoxydes/métabolisme , Facteurs temps , Régulation positive
3.
Jpn J Ophthalmol ; 45(1): 1-4, 2001.
Article de Anglais | MEDLINE | ID: mdl-11163039

RÉSUMÉ

PURPOSE: The reproducibility of functional magnetic resonance imaging (fMRI) has been studied on 1.5 Tesla (T) (high field strength) scanners. We report the reproducibility of visual activation in fMRI at 4 T (very high field strength). METHODS: Five healthy subjects were scanned twice in the same session with a 4 T scanner during binocular flashing visual stimulation. The activated areas during the first and second acquisition were compared. RESULTS: Activation of the visual cortex was observed in all subjects and activation of lateral geniculate nucleus was also detected in four subjects. The ratio of overlapping activated voxels in the first and second acquisition was 0.81 +/- 0.05. CONCLUSIONS: Reproducibility of visual activation using fMRI at 4 T was found to be acceptable, and the results from 4T scanners show a reliability similar to those at 1.5 T.


Sujet(s)
Imagerie par résonance magnétique , Vision binoculaire/physiologie , Cortex visuel/physiologie , Voies optiques/physiologie , Adulte , Femelle , Humains , Mâle , Adulte d'âge moyen , Reproductibilité des résultats
4.
Arch Ophthalmol ; 115(11): 1429-35, 1997 Nov.
Article de Anglais | MEDLINE | ID: mdl-9366675

RÉSUMÉ

BACKGROUND: Mutations in the RPGR gene at the RP3 locus have been found to cause x-linked retinitis pigmentosa in some families. OBJECTIVES: To identify a previously undescribed 2-base pair insertion in codon 99 of the RPGR gene and to describe the phenotype in a well-characterized family with X-linked retinitis pigmentosa. DESIGN: Case reports with clinical features, fluorescein angiography, kinetic perimetry, electrophysiological studies, and molecular genetics. SETTING: University medical centers. PATIENTS: Eight members of the family were screened for the codon 99 insertion in the RPGR gene. RESULTS: Three affected males were found to be hemizygous for the 2-base pair insertion; 2 carriers were heterozygous. This insertion creates a frameshift that would be expected to cause a premature arrest of translation after only 132 amino acids (683 amino acids less than the normal protein). The affected males had typical retinitis pigmentosa with visual field contraction and abnormal findings on electroretinograms with little to no rod activity, profoundly subnormal residual cone responses to single flash and 30-Hz flicker stimuli, and prolonged b-wave implicit times. The electroretinogram of a 49-year-old carrier showed amplitudes that were roughly half of normal. Carrier women did not show a tapetallike fundus reflex but showed asymmetrical patchy pigmentary disturbances consistent with lyonization. CONCLUSION: A frameshifting 2-base pair insertion at codon 99 of the RPGR gene produced typical retinitis pigmentosa and carrier findings (but no tapetallike reflex) in this family.


Sujet(s)
Protéines de transport/génétique , Codon/génétique , Protéines de l'oeil , Liaison génétique/génétique , Mutagenèse par insertion , Protéines/génétique , Rétinite pigmentaire/génétique , Chromosome X/génétique , Adolescent , Adulte , Analyse de mutations d'ADN , Amorces ADN/composition chimique , Éléments transposables d'ADN/génétique , Électrorétinographie , Femelle , Angiographie fluorescéinique , Mutation avec décalage du cadre de lecture , Humains , Mâle , Adulte d'âge moyen , Pedigree , Polymorphisme de conformation simple brin , Rétine/anatomopathologie , Rétine/physiopathologie , Rétinite pigmentaire/anatomopathologie , Rétinite pigmentaire/physiopathologie , Acuité visuelle , Tests du champ visuel , Champs visuels
5.
Ophthalmology ; 104(2): 299-306, 1997 Feb.
Article de Anglais | MEDLINE | ID: mdl-9052636

RÉSUMÉ

PURPOSE: To evaluate the clinical and electrophysiologic findings in a family with two heterozygous sequence changes in the peripherin-retinal degeneration slow (RDS) gene. METHODS: A family study was done of a pedigree obtained by screening for rhodopsin, peripherin/RDS, or rom-1 gene mutations in probands from families with hereditary retinal diseases. The patients consisted of three affected and four unaffected members from a family with cone dystrophy. Ophthalmoscopy, visual field testing, electroretinography, and DNA analysis were performed. RESULTS: Denaturing gradient gel electrophoresis showed the presence of two different sequence changes in the RDS genes of this family. In three members with a retinal disease, the authors observed the substitution of phenylalanine for serine in codon 27 (serine-27-phenylalanine). The clinical and functional findings in these three patients were most consistent with autosomal-dominant cone dystrophy. Three other family members, unaffected with retinal disease, were found to show a substitution of serine for cysteine in codon 72 of the peripherin protein. CONCLUSION: A peripherin/RDS sequence change may produce a cone dystrophy with minimal ophthalmoscopic changes in the macula and limited peripheral degenerative changes. Caution is warranted to avoid ascribing nondisease-causing sequence polymorphisms in candidate genes as responsible for determining the development of a retinal disease phenotype.


Sujet(s)
Protéines de l'oeil/génétique , Protéines de filaments intermédiaires/génétique , Glycoprotéines membranaires , Protéines de tissu nerveux , Phénylalanine/génétique , Mutation ponctuelle , Cellules photoréceptrices en cône de la rétine/anatomopathologie , Dégénérescence de la rétine/génétique , Sérine/génétique , Adulte , Sujet âgé , ADN/analyse , Électrophorèse sur gel d'agar , Électrorétinographie , Fond de l'oeil , Humains , Mâle , Pedigree , Périphérines , Réaction de polymérisation en chaîne , Cellules photoréceptrices en cône de la rétine/physiopathologie , Dégénérescence de la rétine/anatomopathologie , Dégénérescence de la rétine/physiopathologie , Analyse de séquence , Champs visuels
6.
J R Coll Gen Pract ; 39(327): 423-4, 1989 Oct.
Article de Anglais | MEDLINE | ID: mdl-2560025

RÉSUMÉ

The Essex faculty of the Royal College of General Practitioners organized a collaborative study for trainees in Essex between October 1986 and July 1988. Of the trainees in post during the study period, 28 (46%) participated. The study was performed not only as an educational exercise for trainees in their practice year but also to assess the feasibility of collaborative study as a research tool in general practice. The authors feel that facilitating collaborative research is a faculty activity worthy of consideration.


Sujet(s)
Enseignement médical , Rougeole/prévention et contrôle , Humains , Recherche , Royaume-Uni
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