Eczéma allergique de contact : Comment ré-induire une tolérance ?

L’eczéma allergique de contact est une dermatose inflammatoire fréquente, due à l’activation de lymphocytes T (LT) CD8+ cytotoxiques spécifiques d’haptènes en contact avec la peau. Les LT CD4+ sont, quant à eux, doués d’une fonction régulatrice et tolérogène, puisqu’ils limitent l’inflammation cutanée chez les patients (régulation) et préviennent le développement des LT effecteurs chez les individus sains (tolérance) : l’eczéma correspond donc à une rupture de la tolérance immunitaire aux haptènes présents dans l’environnement quotidien. Plusieurs sous-populations de LT CD4+ régulateurs (LT reg), parmi lesquelles celle des LT CD4+CD25+ naturels, sont impliquées dans la tolérance et la régulation de l’eczéma, via la production des cytokines immunosuppressives IL-10 (interleukine-10) et TGFβ (transforming growth factor β). Les travaux en cours ont pour objectif de ré-induire une tolérance immunitaire dans l’eczéma, soit en améliorant les méthodes existantes d’induction de tolérance aux haptènes (tolérance orale, tolérance à faibles doses, immunothérapie spécifique, tolérance induite par les rayons ultraviolets), soit en développant de nouvelles molécules capables d’activer les LT reg. Plus généralement, les données issues de ces travaux devraient pouvoir être appliquées au traitement des maladies auto-immunes ou allergiques, caractérisées par un déficit fonctionnel ou quantitatif en Ltreg à l’origine d’une rupture de la tolérance aux auto-antigènes ou aux allergènes de l’environnement.Allergic contact dermatitis (ACD) is a skin inflammatory disease mediated by activation of CD8+ cytotoxic T cells specific for haptens in contact with the skin. CD4+ T cells behave as both regulatory and tolerogenic cells since they down-regulate the skin inflammation in patients with ACD (regulation) and prevent the developement of eczema (tolerance) in normal individuals. Thus, ACD corresponds to a breakdown of immune tolerance to haptens in contact with the skin. Several regulatory CD4+ T cell subsets (Treg), especially CD4+CD25+ natural Treg cells, are involved in immunological tolerance and regulation to haptens through the production of the immunosuppressive cytokines IL-10 and TGF-β. Ongoing strategies to re-induce immune tolerance to haptens in patients with eczema include improvement of existing methods of tolerance induction (oral tolerance, low dose tolerance, allergen-specific immunotherapy, UV-induced tolerance) as well as development of new drugs able to activate IL-10 producing Treg cells in vivo. Ongoing and future progress in this area will open up new avenues for treatment of eczema and more generally autoimmune and allergic diseases resulting from a breakdown of tolerance to autoantigens and allergens, respectively

Fisiopatologia da dermatite de contato alérgica: papel das células T CD8 efetoras e das células T CD4 regulatórias Update on the pathophysiology with special emphasis on CD8 effector T cells and CD4 regulatory T cells

A dermatite de contato alérgica (DCA), também conhecida como hipersensibilidade de contato (HSC) é uma das dermatoses inflamatórias mais freqüentes, sendo caracterizada por eritema, pápulas e vesículas, seguidas de ressecamento e descamação. A DCA é induzida pelo contato da pele com substâncias químicas não protéicas denominadas haptenos, e corresponde a uma reação de hipersensibilidade cutânea do tipo tardio, mediada por células T hapteno-específicas. Durante a fase de sensibilização, tanto os precursores de células T CD4+ quanto os de CD8+ são ativados nos linfonodos de drenagem através da apresentação de peptídeos conjugados a haptenos pelas células dendríticas (CD) da pele. A subseqüente exposição de pele ao hapteno em um local a distância induz o recrutamento e ativação de células T específicas no local de provocação, levando à apoptose dos queratinócitos, recrutamento de células inflamatórias e desenvolvimento de sintomas clínicos. Estudos experimentais dos últimos 10 anos demonstraram que, em respostas normais de HSC a haptenos fortes, as células T CD8+ do tipo 1 são efetoras da HSC através de citotoxicidade e produção de IFNgama, enquanto que as células T CD4+ são dotadas de funções de regulação negativa. Estas últimas podem corresponder à população de células T regulatórias CD4+ CD25+ recentemente descritas. Entretanto, em algumas situações, especialmente naquelas em que há um pool deficiente de células T CD8, as células T CD4+ podem ser efetoras da HSC. Estudos em andamento deverão confirmar que a fisiopatologia da DCA em humanos é semelhante à HSC em camundongos, e que a resposta de HSC a haptenos fracos comuns, mais freqüentemente envolvidos na DCA em humanos, é semelhante à descrita para haptenos fortes.Allergic contact dermatitis (ACD) referred to as contact hypersensitivity (CHS) is one the most frequent inflammatory skin diseases characterized by redness, papules, and vesicles, followed by scaling and dry skin. ACD is elicited upon skin contact with non-protein chemicals called haptens and corresponds to a cutaneous delayed-type hypersensitivity reaction, mediated by hapten-specific T cells. During the sensitization phase, both CD4+ and CD8+ T cell precursors are activated in the draining lymph nodes by presentation of haptenated peptides by skin dendritic cells (DC). Subsequent hapten painting on a remote skin site induces the recruitment and activation of specific T cells at the site of challenge leading to apoptosis of keratinocytes, recruitment of inflammatory cells and development of clinical symptoms. Experimental studies from the last 10 years have demonstrated that, in normal CHS responses to strong haptens, CD8+ type 1 T cells are effector cells of CHS through cytotoxicity and IFNgamma, production while CD4+ T cells are endowed with down-regulatory functions. The latter may correspond to the recently described CD4+ CD25+ regulatory T cell population. However, in some instances, especially those where there is a deficient CD8 T cell pool, CD4+ T cells can be effector cells of CHS. Ongoing studies will have to confirm that the pathophysiology of human ACD is similar to the mouse CHS and that the CHS response to common weak haptens, most frequently involved in human ACD, is similar to that reported for strong haptens

Follicle-stimulating hormone does not impact male bone mass in vivo or human male osteoclasts in vitro.

Bone loss in the elderly is mainly caused by osteoclast-induced bone resorption thought to be causally linked to the decline in estrogen and testosterone levels in females and males. Recently, involvement of follicle stimulating-hormone (FSH) in this process has been suggested to explain in part the etiology of the disease in females, whereas its role in males has never been examined. In this study, the direct impact of FSH on bone mass of 16-week-old C57BL/6J male mice by either daily intermittent application of 6 or 60 mug/kg of FSH or continuous delivery via miniosmotic pump of a dose of 6 mug/kg over the course of a month was assessed. Femoral peripheral quantitative computed tomographic and microcomputed tomographic analyses at 0, 2, and 4 weeks of FSH-treated mice did not reveal any differences in cancellous and cortical bone compared to sham-treated mice. FSH functionality was verified by demonstrating cAMP induction and activation of a cAMP-response element-containing reporter cell line by FSH. Furthermore, osteoclastogenesis from human mononuclear cell precursors and from RAW 264.7 cells was not affected by FSH (3, 10, 30 ng/mL) compared to control. No direct effect of FSH on gene regulation was observed by Affymetrix Gene Array on RAW 264.7 cells. Lastly, no expression of FSH receptor (FSHR) mRNA or FSHR was observed by quantitative polymerase chain reaction and Western blot in either human male osteoclasts or RAW 264.7 cells. These data show that FSH does not appear to modulate male bone mass regulation in vivo and does not act directly on osteoclastogenesis in vitro

Analysis of independent microarray datasets of renal biopsies identifies a robust transcript signature of acute allograft rejection

Transcriptomics could contribute significantly to the early and specific diagnosis of rejection episodes by defining 'molecular Banff' signatures. Recently, the description of pathogenesis-based transcript sets offered a new opportunity for objective and quantitative diagnosis. Generating high-quality transcript panels is thus critical to define high-performance diagnostic classifier. In this study, a comparative analysis was performed across four different microarray datasets of heterogeneous sample collections from two published clinical datasets and two own datasets including biopsies for clinical indication, and samples from nonhuman primates. We characterized a common transcriptional profile of 70 genes, defined as acute rejection transcript set (ARTS). ARTS expression is significantly up-regulated in all AR samples as compared with stable allografts or healthy kidneys, and strongly correlates with the severity of Banff AR types. Similarly, ARTS were tested as a classifier in a large collection of 143 independent biopsies recently published by the University of Alberta. Results demonstrate that the 'in silico' approach applied in this study is able to identify a robust and reliable molecular signature for AR, supporting a specific and sensitive molecular diagnostic approach for renal transplant monitoring

Mutations in MAPKBP1 cause late onset cilia-independent nephronophthisis

Nephronophthisis (NPH), an autosomal recessive tubulointerstitial nephritis, is the most common cause of heriditary end-stage renal disease in the first three decades of life. Since most NPH gene products (NPHP) function at the primary cilium, NPH is classified as ciliopathy. We identified mutations in a novel candidate gene in 10 individuals from 6 families presenting late onset NPH with massive renal fibrosis. This gene encodes MAPKBP1, a poorly characterized scaffolding protein for JNK signaling. Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects indicating that MAPKBP1 may represent a new family of NPHP not involved in cilia-associated functions. Instead, MAPKBP1 is recruited to mitotic spindle poles (MSPs) during the early phases of mitosis where it colocalizes with its paralog WDR62, which plays a key role at MSP. Detected mutations compromise recruitment of MAPKBP1 to the MSP and/or its interaction with JNK2 or WDR62. Additionally, we show increased DNA damage response signaling in patients fibroblasts and upon knockdown of Mapkbp1 in murine cell lines, a phenotype previously associated with NPH. In conclusion, we identified mutations in MAPKBP1 as a genetic cause of late onset and cilia-independent NPH and propose “NPHP21” as an alias for MAPKBP1

Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization

Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies