Rôle des chimiokines dans le développement des réactions allergiques (apport des modèles murins)

Les chimiokines sont des cytokines produites constitutivement par les tissus, ou inductibles en situation inflammatoire. Elles permettent le recrutement spécifique de certaines populations leucocytaires vers le lieu de développement de l'inflammation, mais ont également des fonctions immunes plus fines, en contrôlant l'état d'activation et la survie de différentes populations du système immunitaire. Ces protéines ont un rôle essentiel dans l'homéostasie tissulaire, et sont à l'origine de l'orchestration cellulaire des réactions inflammatoires. Les maladies allergiques sont caractérisées par une réponse immune adaptative orientée vers la voie Th2, avec production d'IgE spécifiques, et activation tissulaire de granulocytes par contact avec l'allergène (principalement les mastocytes, puis les polynucléaires éosinophiles). Ces pathologies ont connu au cours des 20 dernières années une recrudescence très forte, avec une prévalence plus importante dans les pays industrialisés. Parmi ces pathologies, l'asthme allergique fait en France plus de 1000 morts par an. Malgré l'amélioration des connaissances des mécanismes physiopathologiques menant à l'altération des tissus ou de la fonction respiratoire, les mécanismes immunologiques à l'origine du développement de ces pathologies restent incomplètement élucidés. Une plus grande compréhension de ces mécanismes, et en particulier du contrôle de l'inflammation par les chimiokines peut permettre d'identifier de nouvelles cibles thérapeutiques. Pour mettre en évidence ces voies de régulation chimiokiniques, plusieurs modèles animaux ont été utilisés. Le premier consiste en une greffe de peau et de cellules mononucléés humaines chez la souris SCID immunodéficiente. Ce type d'approche permet d'évaluer in vivo le recrutement chimiokinique de cellules humaines vers un tissu humain. Ce modèle a permis de mettre en évidence que l'administration intradermique de CCL17 est à l'origine du recrutement vers les ganglions drainant de lymphocytes TCD4+ mémoires et de cellules dendritiques, et d'un recrutement spécifique vers la peau de cellules polarisée in vitro vers la voie Th2, mais pas Th1. Ces résultats suggèrent l'implication forte de l'axe CCL17/CCR4 dans le développement de pathologies allergiques cutanées, et souligne son potentiel thérapeutique dans des pathologies comme la dermatite atopique. Ce même modèle de xénogreffe cutanée a par ailleurs déjà été utilisé par notre équipe pour évaluer les conséquences de la neutralisation in vivo d'un récepteur chimiokinique, CCR5, à l'aide d'un anticorps. Ce traitement a permis d'abroger le recrutement de lymphocytes T mémoires, et plus particulièrement des lymphocytes polarisés Th1, et de monocytes/macrophages. Ces résultats démontrent l'efficacité in vivo de la neutralisation d'un tel axe chimiokinique. La seconde approche est un modèle murin d'asthme allergique, induit par l'ovalbumine chez la souris Balb/cBYJ. Celui-ci a été utilisé pour l'étude d'une chimiokine humaine originale, CCL18, dont l'implication dans l'asthme allergique chez l'homme à été récemment suggérée par notre équipe. D'un point de vue fonctionnel, l'administration de CCL18 recombinant par voie intratrachéale à des animaux rendu préalablement expérimentalement allergiques permet d'inhiber le développement de la réaction asthmatique, en diminuant l'inflammation pulmonaire (réduction de l'infiltration éosinophilique, inhibition de la production locale de cytokines Th2) et protège ces derniers contre l'altération de leur fonction respiratoire (protection contre l'hyperréactivité bronchique, avec inhibition de l'hypersécrétion de mucus). Toutefois, les mécanismes cellulaires à l'origine de cette protection sont encore actuellement à l'étude, et semblent indépendants de grandes voies de régulation de la réaction allergique comme les lymphocytes T régulateurs. L'ensemble de ces données permet de mettre en évidence l'importance de certaines voies chimiokiniques dans le contrôle des pathologies Th2, et de démontrer les conséquences fonctionnelles de leur ciblage spécifique (par neutralisation, ou administration), révélant ainsi leur potentiel thérapeutique.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Additional Layer of Regulation via Convergent Gene Orientation in Yeasts

International audienc

Diesel exhaust exposure favors TH2 cell recruitment in nonatopic subjects by differentially regulating chemokine production.

The prevalence of allergic diseases has increased in the last 20 years, and a number of studies have shown that diesel exhaust particle-associated polyaromatic hydrocarbons can exacerbate the allergic reaction. Much less is known about their potential capacity to generate a T(H)2-type allergic reaction in nonatopic subjects.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Involvement of CCL18 in allergic asthma.

Allergic asthma is associated with a pulmonary recruitment of Th type 2 cells, basophils, and eosinophils, mainly linked to chemokine production. CCL18 is a chemokine preferentially expressed in the lung, secreted by APCs, induced by Th2-type cytokines, and only present in humans. Therefore, CCL18 may be involved in allergic asthma. PBMC from asthmatics allergic to house dust mite cultured in the presence of Dermatophagoides pteronyssinus 1 (Der p 1) allergen secreted CCL18, 48 and 72 h after stimulation, whereas those from healthy donors did not. Part of CCL18 was directly derived from Der p 1-stimulated plasmacytoid dendritic cells, whereas the other part was linked to monocyte activation by IL-4 and IL-13 produced by Der p 1-stimulated T cells. In bronchoalveolar lavages from untreated asthmatic allergic patients, CCL18 was highly increased compared with controls. Functionally, CCL18 preferentially attracted in vitro-polarized Th2 cells and basophils, but not eosinophils and Th1 cells, and induced basophil histamine and intracellular calcium release. These data show a new function for CCL18, i.e. the recruitment of Th2 cells and basophils, and suggest that CCL18 may play a predominant role in allergic asthma.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Splicing Patterns in SF3B1 -Mutated Uveal Melanoma Generate Shared Immunogenic Tumor-Specific Neoepitopes

International audienceAbstract Disruption of splicing patterns due to mutations of genes coding splicing factors in tumors represents a potential source of tumor neoantigens, which would be both public (shared between patients) and tumor-specific (not expressed in normal tissues). In this study, we show that mutations of the splicing factor SF3B1 in uveal melanoma generate such immunogenic neoantigens. Memory CD8+ T cells specific for these neoantigens are preferentially found in 20% of patients with uveal melanoma bearing SF3B1-mutated tumors. Single-cell analyses of neoepitope-specific T cells from the blood identified large clonal T-cell expansions, with distinct effector transcription patterns. Some of these expanded T-cell receptors are also present in the corresponding tumors. CD8+ T-cell clones specific for the neoepitopes specifically recognize and kill SF3B1-mutated tumor cells, supporting the use of this new family of neoantigens as therapeutic targets. Significance: Mutations of the splicing factor SF3B1 in uveal melanoma generate shared neoantigens that are uniquely expressed by tumor cells, leading to recognition and killing by specific CD8 T cells. Mutations in splicing factors can be sources of new therapeutic strategies applicable to diverse tumors. This article is highlighted in the In This Issue feature, p. 186

CCR5 usage by CCL5 induces a selective leukocyte recruitment in human skin xenografts in vivo.

CCR5 is one of the major inflammatory chemokine receptors with potential therapeutical applications in humans. However, the redundancy of chemokines and their receptors, and the species specificity of chemokine receptor antagonists pose challenges to understanding of the role they play in pharmacological situations. To address this question, we used a humanized severe combined immunodeficient mouse model grafted with human skin and autologous leukocytes, and evaluated the effect of a blocking antibody against human CCR5, on CCL5-induced cutaneous leukocyte recruitment in vivo. At baseline, CCL5 induced a significant recruitment of T cells mainly of the memory phenotype, of monocytes/macrophages, eosinophils, and IFN-gamma(+) but not IL-4(+) and IL-5(+) cells. In vivo, anti-CCR5 antibody was able to almost completely inhibit the recruitment of monocytes/macrophages and T-helper (Th)1-type cells to inhibit partially the attraction of memory T cells, but had no effect on eosinophil infiltration, although all these cell types express other CCL5 binding chemokine receptors than CCR5. These results indicate that the in vivo environment regulates target cell specificity of CCL5 leading to differential cell recruitment, suggesting that antagonizing CCR5 receptor may be of therapeutic value in diseases such as acquired immuno deficiency syndrome, where CCL5/CCR5, monocytes, and Th1-type cells play a predominant role

Improving the primary care physicians' decision making for fibromyalgia in clinical practice: Development and validation of the Fibromyalgia Detection (FibroDetect®) screening tool

Background: Fibromyalgia diagnosis is a challenging and long process, especially among primary care physicians (PCPs), because of symptom heterogeneity, co-morbidities and clinical overlap with other disorders. The purpose was to develop and validate a screening tool in French (FR), German (DE) and English (UK) to help PCPs identify patients with fibromyalgia. Methods: The FibroDetect questionnaire was simultaneously developed in FR, DE and UK based on information obtained from a literature review, focus groups conducted with clinicians, and face-to-face interviews with fibromyalgia patients (FR, DE and UK, n = 23). The resulting tool was comprehension-tested in patients with diagnosed or suspected fibromyalgia (n = 3 and n = 2 in each country, respectively). Acceptability and applicability were assessed and the tool modified accordingly, then assessed in clinical practice. A scoring method was created using an iterative process based on statistical and clinical considerations with American College of Rheumatology + (ACR+) patients and ACR- patients (n = 276), and validated with fibromyalgia and non-fibromyalgia patients (n = 312). Results: The FibroDetect included 14 questions assessing patients' pain and fatigue, personal history and attitudes, symptoms and impact on lives. Six questions were retained in the final scoring, demonstrating satisfactory discriminative power between ACR + and ACR- patients with area under the Receiver Operating Characteristic curve of 0.74. The predictive accuracy of the tool increased to 0.86 for fibromyalgia and non-fibromyalgia patient detection, with a sensitivity of 90% and a specificity of 67% for a cut-off of 6 on the score. Conclusions: The FibroDetect is a self-administered tool that can be used as a screening classification surrogate to the ACR criteria in primary care settings to help PCPs detect potential fibromyalgia patients among a population complaining of chronic widespread pain.SCOPUS: ar.jinfo:eu-repo/semantics/publishe