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

Novel Insights into NDP52 Autophagy Receptor Functioning

International audienceNDP52/CALCOCO2 makes multiple contributions to selective autophagy. By interacting with cargos and LC3, NDP52 directs autophagy targets to autophagosomes. In addition, NDP52 promotes autophagosomes fusion with endolysosomes by connecting autophagosomes to MYOSIN VI. Recent studies reveal that Rab35 GTPase controls NDP52 recruitment to its targets and that NDP52 triggers MYOSIN VI (MYO6) motility

Autophagy during Early Virus-Host Cell Interactions

International audienceAutophagy refers to the conserved, multi-step mechanism that delivers cytosolic cargoes to vesicles of the endo-lysosomal system for degradation. It maintains cellular homeostasis by ensuring the continuous degradation of misformed/senescent intracellular components and the associated recycling of nutrients. Autophagy also represents an important cell-intrinsic defense mechanism against invasion by intracellular pathogens, including viruses. Autophagy might oppose viral invasion by targeting viral particles or viral components for degradation. It can also promote the interaction of viral constituents with receptors specialized in the activation of innate immunity pathways or facilitate the activation of anti-viral adaptive immunity. In response to such pressures, viruses have evolved various sophisticated strategies to avoid anti-viral autophagic responses or to manipulate the autophagic machinery to promote their own replication. This review focuses on our current knowledge of autophagy-related events that take place at early stages during interaction of viruses with host cells as well as on their associated consequences in terms of virus replication and cell fate

Autophagy in Measles Virus Infection

Autophagy is a biological process that helps cells to recycle obsolete cellular components and which greatly contributes to maintaining cellular integrity in response to environmental stress factors. Autophagy is also among the first lines of cellular defense against invading microorganisms, including viruses. The autophagic destruction of invading pathogens, a process referred to as xenophagy, involves cytosolic autophagy receptors, such as p62/SQSTM1 (Sequestosome 1) or NDP52/CALCOCO2 (Nuclear Dot 52 KDa Protein/Calcium Binding And Coiled-Coil Domain 2), which bind to microbial components and target them towards growing autophagosomes for degradation. However, most, if not all, infectious viruses have evolved molecular tricks to escape from xenophagy. Many viruses even use autophagy, part of the autophagy pathway or some autophagy-associated proteins, to improve their infectious potential. In this regard, the measles virus, responsible for epidemic measles, has a unique interface with autophagy as the virus can induce multiple rounds of autophagy in the course of infection. These successive waves of autophagy result from distinct molecular pathways and seem associated with anti- and/or pro-measles virus consequences. In this review, we describe what the autophagy–measles virus interplay has taught us about both the biology of the virus and the mechanistic orchestration of autophagy

Autophagie et co-infection: « C’est double plaisir que de tromper le trompeur »

International audienceNo abstract availabl

Selective Autophagy Receptors in Antiviral Defense

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Regulation of anti-microbial autophagy by factors of the complement system

International audienceThe complement system is a major component of innate immunity that participates in the defense of the host against a myriad of pathogenic microorganisms. Activation of complement allows for both local inflammatory response and physical elimination of microbes through phagocytosis or lysis. The system is highly efficient and is therefore finely regulated. In addition to these well-established properties, recent works have revealed that components of the complement system can be involved in a variety of other functions including in autophagy, the conserved mechanism that allows for the targeting and degradation of cytosolic materials by the lysosomal pathway after confining them into specialized organelles called autophagosomes. Besides impacting cell death, development or metabolism, the complement factors-autophagy connection can greatly modulate the cell autonomous, antimicrobial activity of autophagy: xenophagy. Both surface receptorligand interactions and intracellular interactions are involved in the modulation of the autophagic response to intracellular microbes by complement factors. Here, we review works that relate to the recently discovered connections between factors of the complement system and the functioning of autophagy in the context of host-pathogen relationship

TGF-β down-regulates both IL-22 and IL-21 production by naïve CD4⁺T cells.

<p>Purified migratory skin DCs were cultured with allogeneic naïve CD4⁺T cells in the presence of exogeneous human TGF-β (50 ng/ml) or anti-human TGF-β mAb (10 µg/ml). Culture medium was RPMI 1640 supplemented with 10% human AB serum or (B, left panel) serum free medium. After 6 days cells were restimulated with phorbol myristate acetate (PMA) and ionomycin. Cell supernatants were harvested after 24 hours and (A) IL-22 or (B) IL-21 secretion was measured by ELISA. Each marker illustrates experiments carried out with different donors.</p