Infection et auto-immunité : la piste des récepteurs Toll-like

Les mécanismes de tolérance immunitaire sont destinés à prévenir le développement des maladies auto-immunes. Concernant les lymphocytes B (LyB), les processus d’élimination décrits à ce jour (délétion clonale et anergie qui aboutissent à l’élimination de la cellule et édition du récepteur qui conduit à une perte de l’auto-réactivité) ne sont que partiellement efficaces [1]. En effet, les sujets sains possèdent de nombreux LyB auto-réactifs. Dans les conditions physiologiques, ils ne sont pas activés et coexistent « en paix » avec leur auto-antigène. Les mécanismes que nous-mêmes et d’autres avons proposés d’appeler « ignorance immunologique » sont imparfaitement élucidés [2]. La rupture de cet état est certainement un des mécanismes à l’origine des maladies auto-immunes. De nombreux facteurs génétiques influençant la susceptibilité aux maladies auto-immunes ont été identifiés. Néanmoins, ils apparaissent généralement insuffisants, suggérant un rôle important pour des facteurs environnementaux. Parmi ceux-ci, les infections jouent très probablement un rôle, suspecté de longue date, bien que les mécanismes physiopathologiques en restent mal connus [3]. Une hypothèse (la théorie dite antigène non-spécifique) formule que les dégâts tissulaires infligés par l’infection microbienne pourraient exposer des auto-antigènes aux lymphocytes auto-réactifs

The changing face of Parkinson's disease-associated psychosis: a cross-sectional study based on the new NINDS-NIMH criteria.

International audienceNew criteria for Parkinson's disease-associated psychosis (PDAP) were recently proposed by a NINDS-NIMH working group. We assessed 116 consecutive unselected outpatients with PD for the existence of psychotic symptoms during the previous month, using a structured questionnaire covering the whole spectrum of PDAP symptoms. Hallucinations occurred in 42% of the patients (visual: 16%; nonvisual: 35%), delusions in 4%, and minor symptoms in 45% (sense of presence, visual illusions, or passage hallucinations). The prevalence of PDAP was 43% when the usual definition was used (hallucinations and/or delusions) and 60% when the NINDS-NIHM criteria were used. Correlations between PDAP and patient characteristics varied with the definition of PDAP. These findings suggest that the epidemiology of PDAP should be re-evaluated with the new criteria. Minor symptoms and nonvisual hallucinations are an important part of the PDAP spectrum, which has commonly been restricted to visual hallucinations and delusions

Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer

Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies.acceptedVersionPeer reviewe

Discovery of 9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one (GLPG1205), a unique GPR84 negative allosteric modulator undergoing evaluation in a phase II clinical trial

GPR84 is a medium chain free fatty acid-binding G-protein-coupled receptor associated with inflammatory and fibrotic diseases. As the only reported antagonist of GPR84 (PBI-4050) that displays relatively low potency and selectivity, a clear need exists for an improved modulator. Structural optimization of GPR84 antagonist hit 1, identified through high-throughput screening, led to the identification of potent and selective GPR84 inhibitor GLPG1205 (36). Compared with the initial hit, 36 showed improved potency in a guanosine 5′-O-[γ-thio]triphosphate assay, exhibited metabolic stability, and lacked activity against phosphodiesterase-4. This novel pharmacological tool allowed investigation of the therapeutic potential of GPR84 inhibition. At once-daily doses of 3 and 10 mg/kg, GLPG1205 reduced disease activity index score and neutrophil infiltration in a mouse dextran sodium sulfate-induced chronic inflammatory bowel disease model, with efficacy similar to positive-control compound sulfasalazine. The drug discovery steps leading to GLPG1205 identification, currently under phase II clinical investigation, are described herein

Comprendre la trajectoire psychologique des personnes traitées pour une maladie de Parkinson évoluée (Une synthèse de recherches sur l'ajustement et la qualité de vie en fonction de l'option thérapeutique retenue, et de ses effets indésirables)

Cette thèse repose sur un ensemble de travaux visant à comprendre la trajectoire psychologique des personnes ayant une maladie de Parkinson (MP) évoluée, et traitées soit par dopathérapie, soit par stimulation cérébrale profonde (SCP). Les trois premières études, transversales, se consacrent aux critères de psychose parkinsonienne et aux hallucinations. Après avoir décrit et analysé comment celles-ci, et plus spécifiquement des phénomènes mineurs comme les sensations de présence, s expriment dans la MP, nous avons établi que les hallucinations s y manifestent selon un pattern différent de celui observé dans la population générale. L ensemble des données confère aux phénomènes mineurs une légitimité en tant que critères diagnostiques de psychose parkinsonienne. Nos deux études longitudinales montrent que la SCP améliore la qualité de vie (QdV) et la motricité des malades, que certaines composantes psychologiques préopératoires, telles que le coping et l humeur, prédisent en partie ces évolutions, mais aussi que la SCP permet une réduction du fardeau chez les plus jeunes conjoints, bien qu elle ne soit que rarement bénéfique à leur QdV. L ultime étude, rétrospective, objective le surcroît de risque suicidaire post-SCP. L ensemble de ces résultats suggère que, quelle que soit l option thérapeutique retenue, les hallucinations mineures ne doivent pas être négligées, et qu en cas de SCP, une attention particulière doit être portée aux personnes présentant avant l opération une impulsivité ou des éléments dépressifs importants. Ces patients pourront être aidés notamment par des psychothérapies centrées sur leurs stratégies d ajustement ou sur leurs buts personnels.This thesis is based on studies designed to understand psychological outcomes among patients with Parkinson's disease (PD) treated with either dopatherapy or deep brain stimulation (DBS). The first three cross-sectional studies focus on the diagnostic criteria for parkinsonian psychosis and on hallucinations. Following a phenomenological analysis of hallucinations in PD, and especially minor phenomena such as feelings of presence, we established that the patterns of hallucinations in PD are different to those observed in the general population. These minor phenomena could therefore be included among the diagnostic criteria for parkinsonian psychosis. Our two longitudinal studies show that DBS improves quality of life (QoL) and motor function in PD, and that certain presurgical psychological characteristics such as coping and mood, partly predict these outcomes. They also show that DBS reduces the care burden among younger spouses, even though their QoL is rarely improved. The last, retrospective study shows an increased risk of suicide after DBS. Several conclusions can be drawn from these findings. First, whatever the treatment option, minor hallucinations must not be neglected. Second, special attention must be paid to patient who, prior to DBS, show signs of impulsiveness or major depression. These patients may benefit from psychotherapy centered on their coping strategies or personal goals.BOULOGNE-BU Psych. Henri Pieron (920125201) / SudocSudocFranceF

Nanoscale chemical imaging of organo-mineral fractions of an andosol (La Martinique, France)

International audienc

Nanoscale chemical imaging of organo-mineral fractions of an andosol (La Martinique, France)

International audienc

Feeling of presence in Parkinson's disease.: Feeling of a presence in PD

International audienceBackground A feeling of presence (FP), that is, the vivid sensation that somebody (distinct from oneself) is present nearby, is commonly reported by patients with Parkinson's disease (PD), but its phenomenology has not been described precisely. The objective of this study was to provide a detailed description of FP in PD and to discuss its possible mechanisms. Patients and methods The authors studied 52 non-demented PD patients reporting FP in the preceding month (38 consecutive outpatients and 14 inpatients). FP characteristics were recorded with a structured questionnaire. The outpatients with FP were compared with 78 consecutive outpatients without FP. Results About half the patients said they recognised the 'identity' of the presence. More than 75% of patients said the FP were not distressing, were short-lasting, were felt beside and/or behind the patient, and occurred while indoors; most patients checked for a real presence, but their insight was generally preserved. In 31% of cases, the patients had an unformed visual hallucination simultaneously with the FP. A higher daily levodopa-equivalent dose and the presence of visual illusions or hallucinations were independently associated with FP. Discussion Although FP is not a sensory perception, projection of the sensation into the extrapersonal space, along with the frequent co-occurrence of elementary visual hallucinations and the strong association with visual hallucinations or illusions, supports its hallucinatory nature. FP may be viewed as a 'social' hallucination, involving an area or network specifically activated when a living being is present, independently of any perceptual clue