Search

Background Vitiligo is an autoimmune skin disorder characterized by loss of melanocytes. Protease-mediated disruption of junctions between keratinocytes and/or keratinocyte intrinsic dysfunction may directly contribute to melanocyte loss. House dust mite (HDM), an environmental allergen with potent protease activity, contributes to respiratory and gut disease but also to atopic dermatitis and rosacea. Objective To verify if HDM can contribute to melanocyte detachment in vitiligo and if so, by which mechanism(s). Methods Using primary human keratinocytes, human skin biopsies from healthy and vitiligo patients, and 3D reconstructed human epidermis, we studied the effect of HDM on cutaneous immunity, tight and adherent junction expression and melanocyte detachment. Results HDM increased keratinocyte production of vitiligo-associated cytokines and chemokines and increased expression of TLR-4. This was associated with increased in situ MMP-9 activity, reduced cutaneous expression of adherent protein E-cadherin, increased soluble E-cadherin in culture supernatant and significantly increased number of supra-basal melanocytes in the skin. This effect was dose-dependent and driven by cysteine protease Der p1 and MMP-9. Selective MMP-9 inhibitor, Ab142180 restored E-cadherin expression and inhibited HDM-induced melanocyte detachment. Keratinocytes from vitiligo patients were more sensitive to HDM-induced changes than healthy keratinocytes. All results were confirmed in 3D model of healthy skin and in human skin biopsies. Conclusions Our results highlight that environmental mite may act as an external source of PAMPs in vitiligo and topical MMP-9 inhibitors may be useful therapeutic targets. Whether HDM contributes to onset of flares in vitiligo remains to be tested in carefully controlled trials.

Background: Clinical factors associated with vitiligo in patients receiving anti–programmed cell death-1 (PD-1) remain unknown. Objective: To better characterize the occurrence of vitiligo in patients receiving anti–PD-1. Methods: The present single-center ambispective cohort study included patients with melanoma treated with anti–PD-1. Progression-free survival, overall survival, and objective tumor response were compared between patients with and those without vitiligo using Kaplan-Meier curves and the log-rank test. Demographic and clinical factors associated with vitiligo were evaluated using multivariate logistic regression. Results: Of the 457 patients included in the study, vitiligo developed in 85 patients. The clinical presentation of vitiligo consisted of the presence of ovalar and multiple flecked white macules, mainly located on chronic sun-exposed areas. The presence of vitiligo was associated with a significant improvement in overall survival and progression-free survival (P

The use of immune checkpoint inhibitors (ICI), such as anti-programmed cell death-1 (PD-1) antibodies, has profoundly changed melanoma prognosis. However, only 35% to 45% of patients experience durable responses, highlighting the need to improve our understanding of the mechanisms underlying clinical benefit from anti-PD-1 therapy.1 The extent to which PD-1 blockade boosts CD8+ T-effector cell responses, particularly at the invasive tumor margin, is a critical determinant of anti-PD-1 efficacy.

Vitiligo, the most common depigmenting disorder of the skin, is undergoing a period of intense advances in both disease understanding and therapeutic possibilities leading the way to the beginning of a new era for the disorder. Its pathophysiology has gathered the attention of researchers for years, and many advances have been made in the clarification of the interaction between different factors that result in depigmented macule formation. The complex interplay between non-immunological and immunological factors in vitiligo is key for the development of the disease, and the participation of cells other than melanocytes, such as keratinocytes, fibroblasts, natural killer cells, and innate lymphoid cells, has been shown. Recent advances have also brought to the understanding of the complex part played by a specific subtype of T cells: T-resident memory cells. This review analyzes some of the most recent insights in vitiligo pathogenesis underlining the interactions between different cell types, which are the basis for the therapeutic approaches under development.

International audience; No abstract available

BACKGROUND Vitiligo is a chronic inflammatory skin disorder characterized by the loss of melanocytes. While a T helper cell (Th)1/cytotoxic T cell (Tc)1-skewed immune response is now well demonstrated in vitiligo, recent data suggest that the T-cell component could be more complex, involving different combinatorial T-cell subsets. OBJECTIVES To analyse the phenotype and function of circulating CD4+ and CD8+ memory T-cell subsets in patients with stable and active vitiligo, in comparison with patients with psoriasis and healthy controls. METHODS This is a monocentric, prospective, descriptive and exploratory study. Multiparametric flow cytometry analyses were performed to evaluate the surface expression of homing and T-cell-subset markers together with intracellular cytokine production in peripheral blood mononuclear cells from 60 patients with vitiligo, 25 patients with psoriasis and 28 healthy donors. RESULTS Vitiligo peripheral blood circulating effector and central memory T cells expressed similar proportions of skin-homing markers. Decrease in the frequencies of circulating CD4+ and CD8+ Th1/Tc1, Th17/Tc17, and Th1/Th17 or Tc1/Tc17 effector memory T-cell subsets were observed in patients with vitiligo compared with healthy donors. Similar observations were made in psoriasis. In contrast, vitiligo circulating T cells showed a similar capacity for proinflammatory cytokine production compared with those in psoriasis and healthy controls. CONCLUSIONS The decreased frequencies of circulating Th1/Tc1, Th17/Tc17 and Th1/Th17-Tc1/Tc17 cells suggest a possible migration of these T-cell subsets into the skin of patients with vitiligo. These could be targeted to prevent flares of the disease. What is already known about this topic? Vitiligo is a chronic inflammatory skin disorder associated with the loss of melanocytes. Vitiligo is characterized by a T helper cell (Th)1/cytotoxic T cell (Tc)1-skewed immune response in the skin. What does this study add? A thorough analysis of the phenotype and function of circulating memory T cells suggests the migration of Th1/Tc1, Th17/Tc17 and Th1/Th17-Tc1/Tc17 cell subsets in the skin. What is the translational message? A better understanding of the different immune T-cell subsets involved in vitiligo could lead to better therapeutic options. Linked Comment: Matos. Br J Dermatol 2020; 183:803.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by barrier dysfunction, dysregulated immune response, and dysbiosis with increased

Vitiligo is an autoimmune disease characterized by the presence of several autoantibodies, some of which are directed against melanocyte components and have been shown to be associated with the progression of the disease. However, the mechanism involved in the production of autoantibodies remains unclear. Follicular helper CD4+ T cells (TFH) are specialized in B-cell activation and antibody production, especially the TFH cell subsets type 2 and type 17. To date, TFH cell subsets have not been studied in human vitiligo. This study in 44 vitiligo patients and 19 healthy controls showed an increase in circulating TFH cells associated with disease clinical progression. A more precise analysis of TFH cell phenotype demonstrated that vitiligo is characterized by populations of peripheral TFH cells responsible for helping B-cell function, such as TFH type 2 and type 17 which produce Th2- and TH17-related cytokines, respectively. These findings suggest a new mechanism involving TFH cell subsets in the pathogenesis of human vitiligo and leading to the production of autoantibodies and disease.

The understanding of the immune mechanisms of vitiligo has profoundly improved over the past years. The recent discovery of a new population of antigen-experienced memory T cells called resident memory T cells (TRM ) has changed the concept of immune surveillance in peripheral tissue as skin, and the presence of melanocyte-specific TRM is clearly demonstrated in vitiligo, a disease that could be now seen such as a memory skin disease. This review summarizes the recent knowledge on skin TRM and their role in vitiligo. Future management or therapies for this disease will have the goal to block their migration/differentiation, to dampen their activation and/or their accumulation in the vitiligo skin to prevent flare-up or to promote repigmentation.

Vitiligo is a T cell-mediated inflammatory skin disorder characterized by the loss of epidermal melanocytes. However, the contribution of melanocytes to the physiopathology of the disease in response to the T-cell microenvironment remains unclear. Here, using NanoString technology and multiplex ELISA, we show that active vitiligo perilesional skin is characterized by prominent type 1 and 2 associated immune responses. The vitiligo skin T-cell secretome downregulated melanocyte function and adhesion while increasing melanocyte mitochondrial metabolism and expression of inflammatory cytokines and chemokines by epidermal cells. The Jak1/2 inhibitor ruxolitinib strongly inhibited such effects on epidermal cells. Our data highlight that vitiligo is more complex than previously thought, with prominent combined activities of both T helper type 1- and T helper type 2-related cytokines inducing inflammatory responses of epidermal cells. Melanocytes do not appear only to be a target of T cells in vitiligo but could actively contribute to perpetuate inflammation. Jak inhibitors could prevent the impact of T cells on epidermal cells and pigmentation, highlighting their potential clinical benefit in vitiligo.

Vitiligo is an autoimmune disease that results from the loss of melanocytes, associated with skin infiltration of CD8+ effector memory T cells with a Tc1 skewed immune response. NKG2D is an activating receptor found on immune cells, in particular natural killer and activated CD8+ T cells, that are able to produce a high amount of IFN-γ. Here we found that NKG2D expression was increased in vitiligo skin CD8+ effector memory T cells and was promoted by IL-15. Phenotypic and functional analyses showed that NKG2D+ CD8+ skin effector memory T cells displayed an activated phenotype and produced elevated levels of both IFN-γ and tumor necrosis factor-α. Additional experiments revealed that vitiligo skin dendritic cells expressed the NKG2D ligands MICA-MICB, and in vitro experiments showed that these ligands could be induced on dendritic cells by IFN-α. Cultures of IFN-α–stimulated dendritic cells with skin NKG2D+ CD8+ T cells potentiated the production of type 1 cytokines, which was next inhibited by blocking the NKG2D/MICA-MICB interaction. These data show that NKG2D is a potential marker of pathogenic skin CD8+ effector memory T cells during vitiligo. Therefore, targeting NKG2D could be an attractive strategy in vitiligo, a disease for which there is a strong need of innovative treatments.

Loss of melanocytes is the pathological hallmark of vitiligo, a chronic inflammatory skin depigmenting disorder induced by exaggerated immune response, including autoreactive CD8 T cells producing high levels of type 1 cytokines. However, the interplay between this inflammatory response and melanocyte disappearance remains to be fully characterized. Here, we demonstrate that vitiligo skin contains a significant proportion of suprabasal melanocytes, associated with disruption of E-cadherin expression, a major protein involved in melanocyte adhesion. This phenomenon is also observed in lesional psoriatic skin. Importantly, apoptotic melanocytes were mainly observed once cells were detached from the basal layer of the epidermis, suggesting that additional mechanism(s) could be involved in melanocyte loss. The type 1 cytokines IFN-γ and TNF-α induce melanocyte detachment through E-cadherin disruption and the release of its soluble form, partly due to MMP-9. The levels of MMP-9 are increased in the skin and sera of patients with vitiligo, and MMP-9 is produced by keratinocytes in response to IFN-γ and TNF-α. Inhibition of MMP-9 or the JAK/STAT signaling pathway prevents melanocyte detachment in vitro and in vivo. Therefore, stabilization of melanocytes in the basal layer of the epidermis by preventing E-cadherin disruption appears promising for the prevention of depigmentation occurring in vitiligo and during chronic skin inflammation.

Vitiligo is a chronic autoimmune depigmenting skin disorder that results from a loss of melanocytes. Multiple combinatorial factors have been involved in disease development, with a prominent role of the immune system, in particular T cells. After repigmentation, vitiligo frequently recurs in the same area, suggesting that vitiligo could involve the presence of resident memory T cells (TRM). We sought to perform a thorough characterization of the phenotype and function of skin memory T cells in vitiligo. We show that stable and active vitiligo perilesional skin is enriched with a population of CD8 TRM expressing both CD69 and CD103 compared with psoriasis and control unaffected skin. CD8 TRM expressing CD103 are mainly localized in the epidermis. Expression of CXCR3 is observed on most CD8 TRM in vitiligo, including the population of melanocyte-specific CD8 T cells. CD8 TRM displayed increased production of IFN-γ and tumor necrosis factor-α with moderate cytotoxic activity. Our study highlights the presence of functional CD8 TRM in both stable and active vitiligo, reinforcing the concept of vitiligo as an immune memory skin disease. The CD8 TRM that remain in stable disease could play a role during disease flares, emphasizing the interest in targeting this cell subset in vitiligo.

Introduction Le pronostic du melanome metastatique s’est considerablement ameliore ces dernieres annees grâce aux avancees dans le domaine de l’immunotherapie. L’apparition de lesions a type de vitiligo au cours du traitement par anticorps anti-PD-1 semble associee a une meilleure reponse therapeutique. Ces lesions s’averent etre differentes de celles classiquement decrites dans le cadre du vitiligo, cependant les facteurs associes a son developpement n’ont jamais ete etudies en detail ni correles a la reponse antitumorale. Materiel et methodes Decrire les caracteristiques demographiques et cliniques associees a l’apparition d’un vitiligo survenant chez des patients atteints de melanome avance traites par anti-PD-1 et evaluer leur correlation a la reponse antitumorale. Etude monocentrique ambispective, incluant tous les patients atteints de melanome stade III inoperable ou stade IV recevant un traitement par anti-PD-1. Resultats Une population de 457 patients traites par anti-PD-1 pour un melanome ont ete inclus d’avril 2014 a decembre 2019. Parmi eux, 85 ont developpe un vitiligo (18,6 %). Le delai median de survenue du vitiligo apres le debut du traitement par anti-PD-1 etait de 6,9 mois [1,0-35,5]. La disposition photodistribuee des lesions de vitiligo etait retrouvee chez 84,7 % des patients. La presence d’une leucotrichie ou de halo-metastases etait trouvee chez 34 % (n = 29) et 12 % (n = 10) des patients respectivement, avec dans ces sous-groupes un taux de mortalite de 10,3 % (n = 3) et de 0 % (aucun patient decede) respectivement. En analyse multivariee, le sexe masculin etait associe de maniere significative a la survenue d’un vitiligo (OR 1,66 [1,00-2,78]). Au contraire, la presence de metastases pulmonaires etait un facteur protecteur de survenue d’un vitiligo sous anti-PD-1 (OR 0,50 [0,3-0,8]). Une amelioration significative de la survie globale et de la survie sans progression etait observee dans le groupe de patients presentant un vitiligo comparativement au groupe sans vitiligo (p Discussion Le genre masculin est associe a la survenue d’un vitiligo alors que les metastases pulmonaires apparaissent etre un facteur protecteur de la survenue d’un vitiligo. La presence d’une leucotrichie ou de halo-metastases pourrait etre associee a une meilleure survie chez les patients developpant un vitiligo sous anti-PD-1. Ces donnees necessitent d’etre prise en compte comme piste de reflexion pour des etudes physiopathologiques. Notre cohorte confirme que le vitiligo survenant sous anti-PD-1 est un signe clinique associe a une meilleure reponse antitumorale, temoignant d’une immunite anti-melanocytaire.

Vitiligo is an acquired chronic depigmenting disorder of the skin, with an estimated prevalence of 0.5% of the general population, characterized by the development of white macules resulting from a loss of epidermal melanocytes. The nomenclature has been revised after an extensive international work within the vitiligo global issues consensus conference, and vitiligo (formerly non-segmental vitiligo) is now a consensus umbrella term for all forms of generalized vitiligo. Two other subsets of vitiligo are segmental vitiligo and unclassified/undetermined vitiligo, which corresponds to focal disease and rare variants. A series of hypopigmented disorders may masquerade as vitiligo, and some of them need to be ruled out by specific procedures including a skin biopsy. Multiple mechanisms are involved in melanocyte disappearance, namely genetic predisposition, environmental triggers, metabolic abnormalities, impaired renewal, and altered inflammatory and immune responses. The auto-immune/inflammatory theory is the leading hypothesis because (1) vitiligo is often associated with autoimmune diseases; (2) most vitiligo susceptibility loci identified through genome-wide association studies encode immunomodulatory proteins; and (3) prominent immune cell infiltrates are found in the perilesional margin of actively depigmenting skin. However, other studies support melanocyte intrinsic abnormalities with poor adaptation of melanocytes to stressors leading to melanocyte instability in the basal layer, and release of danger signals important for the activation of the immune system. Recent progress in the understanding of immune pathomechanisms opens interesting perspectives for innovative treatment strategies. The proof of concept in humans of targeting of the IFNγ /Th1 pathway is much awaited. The interplay between oxidative stress and altered immune responses suggests that additional strategies aiming at limiting type I interferon activation pathway as background stabilizing therapies could be an interesting approach in vitiligo. This review covers classification and clinical aspects, pathophysiology with emphasis on immunopathogenesis, and promising therapeutic approaches.

Background The use of anti-programmed cell death (PD)-1 therapies in metastatic tumors is associated with cutaneous side effects including vitiligo-like lesions. Objective We sought to characterize clinically and biologically vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies by studying a case series of 8 patients with metastatic tumors and 30 control subjects with vitiligo. Methods Eight patients receiving anti-PD-1 therapies with features of vitiligo-like lesions seen in our department were recruited. Clinical features and photographs were analyzed. For some patients, skin and blood samples were obtained. Results were compared with the vitiligo group. Results All patients developed lesions localized on photoexposed areas with a specific depigmentation pattern consisting of multiple flecked lesions without Koebner phenomenon. In contrast to vitiligo, patients receiving anti-PD-1 therapies who developed vitiligo-like lesions did not report any personal or family histories of vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin samples revealed increased C-X-C motif ligand 10 levels in serum of patients developing vitiligo-like lesions, associated with skin infiltration of CD8 T-cells expressing C-X-C motif receptor 3 and producing elevated levels of interferon-γ and tumor necrosis factor-alfa. Limitations This cross-sectional study concerned a single center. Conclusions Clinical and biological patterns of vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism.

Le vitiligo est une dermatose inflammatoire chronique caracterisee par la perte des melanocytes et associee a une reponse exageree du systeme immunitaire, avec production locale de cytokines inflammatoires, en particulier l’IFNγ et le TNFα, produites notamment par les lymphocytes T residents memoires (LTRM) cutanes. Cependant l’impact des facteurs solubles produits par les LT cutanes infiltrant la peau perilesionnelle sur la reponse epidermique reste a ce jour mal evalue. Nous montrons que les LT cutanes perilesionnels de patient vitiligo produisent non seulement des cytokines de type Th1 mais egalement de type Th2. Le secretome de ces LT induit une forte expression de genes associes a l’inflammation par le melanocyte, une deregulation de l’activite metabolique et l’apparition d’un stress oxydatif, demontrant un role majeur du melanocyte lui-meme dans cette pathologie. Enfin, le ruxolitinib, un inhibiteur de JAK1/JAK2, permet d’inhiber les effets des secretomes sur la reponse melanocytaire. Ainsi, nos resultats mettent en evidence le role du melanocyte, de la voie JAK/STAT et la complexite des cytokines produites au cours du vitiligo, permettant d’envisager une voie therapeutique grâce aux inhibiteurs de JAK dans cette pathologie encore orpheline de traitement.

Antibody-based therapeutics targeting programmed cell death 1 (PD-1) have shown strong efficacy in the treatment of metastatic cancers as melanoma. However, restoring the immune function with these therapies to target cancer cells leads to immune side effects including immune cutaneous events. Vitiligo-like lesions in patients receiving anti-PD-1 is one of the most common skin adverse event reported and the incidence seems to be higher than in patients receiving other immune-checkpoints therapies. Initially described in patients with metastatic melanoma, vitiligo-like lesions have now been reported in other metastatic cancers treated with anti-PD-1. Several reports suggest that this side effect could be different from spontaneously occurring vitiligo and could be associated with increased response to the therapy and patients' survival. The aim of this review is to provide an overview of the clinical presentation of vitiligo-like lesions occurring in patients receiving anti-PD-1, and the hypothesis to explain the mechanism involved in the development of these lesions.

Psoriasis is one of the most common skin inflammatory diseases worldwide. The vitamin D3 analog calcipotriol has been used alone or in combination with corticosteroids in treating plaque psoriasis, but how it suppresses psoriatic inflammation has not been fully understood. Using an experimental mouse psoriasis model, we show that topical calcipotriol inhibited the pivotal IL-23/IL-17 axis and neutrophil infiltration in psoriatic skin, and interestingly, such effects were mediated through the vitamin D receptor (VDR) in keratinocytes (KCs). We further reveal that IL-36α and IL-36γ, which have recently emerged as key players in psoriasis pathogenesis, were effectively repressed by calcipotriol via direct VDR signaling in mouse KCs. Accordingly, calcipotriol treatment suppressed IL-36α/γ expression in lesional skin from patients with plaque psoriasis, which was accompanied by a reduced IL-23/IL-17 expression. In contrast, dexamethasone indirectly reduced IL-36α/γ expression in mouse psoriatic skin through immune cells. Furthermore, we demonstrate that calcipotriol and dexamethasone, in combination, synergistically suppressed the expression of IL-36α/γ, IL-23, and IL-17 in the established mouse psoriasis. Our findings indicate that the combination of calcipotriol and corticosteroid efficiently disrupts the IL-36 and IL-23/IL-17 positive feedback loop, thus revealing a mechanism underlying the superior efficacy of calcipotriol and corticosteroid combination therapy for psoriasis.

The development of immunotherapies has remarkably improved the efficacy of treatment of patients with metastatic melanoma, as observed for example with immune checkpoint therapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death-1 (PD-1). Nonetheless, reinstatement of an effective antitumor immune response also contributes to the development of immune-related adverse events, including vitiligo-like depigmentation. This review aims to discuss special considerations in vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies from a clinical and physiopathological perspective.

The epidermis and its main constituents, keratinocytes, produce a vast repertoire of cytokines, including interleukins (IL), growth factors, colony-stimulating factors, and chemokines. Under normal circumstances most of them are not synthesized or not released, but a number of external stimuli and stressors, e.g., infections, chemicals, trauma, or ultraviolet radiation, are capable of inducing production and release of such molecules from keratinocytes. IL-6 and TNF are paracrine inhibitors of human melanocyte proliferation and melanogenesis, eliciting a dose-dependent decrease in tyrosinase activity of cultured normal human melanocytes and inhibiting melanocyte proliferation, while IFN-γ impedes maturation of the key organelle melanosome by concerted regulation of pigmentation genes. Interestingly, a higher expression of these cytokines has been demonstrated by various authors in the affected skin of vitiligo patients at both protein and transcript levels.

Introduction Le vitiligo est une maladie inflammatoire chronique depigmentante touchant 0,5 a 1 % de la population. Le traitement du vitiligo reste a ce jour difficile et repose sur une double strategie : bloquer l’inflammation par l’utilisation de la corticotherapie locale ou systemique ou les inhibiteurs de la calcineurine et stimuler la regeneration melanocytaire par l’utilisation de la phototherapie. Des etudes recentes suggerent que le methotrexate (MTX) pourrait etre efficace seul ou en association avec la corticotherapie generale pour bloquer l’evolution de la maladie. Objectif Evaluer l’efficacite et la tolerance du MTX pour la prise en charge du vitiligo. Materiel et methodes Etude retrospective, monocentrique, incluant des patients ayant recu un traitement par MTX pour la prise en charge d’un vitiligo non segmentaire. Les caracteristiques cliniques et demographiques etaient recueillies ainsi que les traitements concomitants utilises. L’evaluation de l’efficacite etait realisee aux mois 6 et 12 par les scores objectifs : (1) le score VES (Vitiligo Extent Score) permettant d’evaluer la surface cutanee atteinte, et (2) le score VIDA (VItiligo Disease Activity), permettant d’evaluer l’activite de la maladie. Les effets indesirables etaient repertories. Resultats Un total de 26 patients ont ete inclus (16 femmes et 10 hommes) avec une moyenne d’âge de 47,5 ans. La duree moyenne d’evolution de la maladie etait de 16,04 ans. La dose de MTX recue etait de 10 mg (n = 2), 15 mg (n = 18) et 20 mg (n = 6) par semaine. La duree moyenne de traitement etait de 21,6 mois. Les traitements associes etaient : la phototherapie NB-UVB (46,2 %), la corticotherapie systemique (30,8 %) et les inhibiteurs topiques de la calcineurine (26,9 %). Une diminution significative des scores VES et VIDA a ete observee a 6 et 12 mois. La tolerance globale du traitement etait bonne, deux patients ont arrete le traitement pour effets secondaires. Discussion Nos resultats suggerent que le MTX en combinaison a d’autres therapeutiques comme la corticotherapie generale et la phototherapie pourrait permettre non seulement de limiter la progression mais egalement induire une repigmentation. Une recente etude a ainsi observe que le MTX pouvait etre aussi efficace que la corticotherapie generale pour bloquer la progression de la maladie. Une etude plus recente suggere que son utilisation en association a une corticotherapie generale pouvait permettre l’obtention d’une meilleure reponse que l’utilisation du MTX ou de la corticotherapie generale en monotherapie. Conclusion Le methotrexate pourrait etre une option pour la prise en charge du vitiligo a confirmer au cours d’un essai clinique randomise.

Natural Killer (NK) Group 2D (NKG2D) est un corecepteur activateur exprime notamment par les Lymphocytes T (LT) CD8+, les cellules NK et NKT et dont l’expression exageree est demontree dans differents modeles de maladies auto-immunes, potentialisant ainsi l’activite cytotoxique ou pro-inflammatoire majoritairement de type 1 (IFNY et TNF-α). Le vitiligo est une maladie auto-immune caracterisee par la perte des melanocytes epidermiques associee a une forte production d’IFNY et de TNF-α par les LT CD8+ effecteurs memoires (TEM) infiltrant la peau peri-lesionnelle. Nos travaux demontrent une sur-expression de NKG2D par les LTEM CD8 + peri-lesionnels chez le patient actif, correlant a l’activite de la maladie et dont l’expression est induite par l’IL-15. Les LTEM CD8 + NKG2D+ peri-lesionnels sont specifiques d’antigenes melanocytaires et presentent un phenotype active, avec un profil cytokinique de type 1, faiblement cytotoxique. De plus, les ligands de NKG2D (MICA-MICB) sont fortement exprimes par les cellules dendritiques myeloides cutanees chez le patient actif et sont induits par l’IFN-α, et potentialisent la production de cytokines inflammatoires par les LTEM CD8 + NKG2D+ cutanes. L’ensemble de ces resultats demontre l’importance de l’axe NKG2D Ligand-NKG2D chez le malade, qui pourrait etre envisage comme une cible therapeutique de choix.

Folliculitis decalvans (FD) is a chronic inflammatory disease leading to scarring alopecia with poorly defined pathogenesis. The aim of this study was to investigate the expression of markers associated with the activation of innate immune signals, such as inflammasome (NALP1 and NALP3), interleukin (IL)-1β and IL-8 and type I interferon (MxA). A retrospective monocentric study was conducted and included 17 patients with FD with available biopsies. Disease activity (stable vs. active) was defined clinically and histologically. Immunostaining was performed using antibodies directed against NALP1, NALP3, IL-1β, IL-8, and MxA on FD skin biopsies. Results were compared with normal controls and lichen planopilaris. Eleven patients had active disease and 6 had stable disease. NALP1, NALP3, and IL-1β expression were significantly increased in hair follicles in FD compared with controls and lichen planopilaris. This study highlights the predominant immune signal associated with inflammasome activation in FD, suggesting the use of IL-1β blockade in FD.

Understanding the mechanisms leading to melanocyte loss in vitiligo is a mandatory step to improve the overall management of vitiligo patients. In vitro strategies to study vitiligo range from the analysis of the whole skin to different skin cell subsets, individually, using different techniques that will be described in this review: primary cell cultures (melanocytes, keratinocytes, or fibroblasts), three-dimensional skin models to reproduce the in vivo network, and isolation of blood or skin mononuclear cells to identify inflammatory cells that are involved in disease development. Cell culture models are useful to investigate the differences between healthy and vitiligo cells and to test potential treatment options in a cell-focusing approach. Beyond the study of vitiligo pathomechanisms or therapies using unmodified patient's cells, in vitro approaches can be also adapted to generate melanocyte-specific silencing or overexpression of putative target genes or, in a further step, to design animal models using melanocyte-specific expression of modified genes.

Introduction Le dupilumab est un anticorps monoclonal ciblant la sous-unite alpha du recepteur de l’interleukine IL-4 commune a deux cytokines IL-4 et IL-13 dont l’efficacite est desormais clairement demontree pour le traitement de la dermatite atopique (DA) moderee a severe. La DA est classiquement associee a d’autres pathologies auto-immunes comme la pelade, une maladie encore orpheline de therapeutique efficace. Ainsi nous rapportons de facon surprenante l’efficacite du dupilumab sur les deux conditions, notamment une repousse complete du cuir chevelu. Observation Un homme de 28 ans nous etait adresse pour la prise en charge d’une DA severe ayant debutee dans l’enfance, associee a un asthme. Depuis un an et demi, il presentait egalement une pelade universelle. Pour sa DA, le patient avait recu successivement de la ciclosporine et du methotrexate, avec un controle seulement partiel. Ces deux traitements n’avaient eu aucun effet sur l’evolution de sa pelade. Ainsi etait debute en relais le dupilumab (1 injection sous-cutanee initiale de 600 mg, puis 300 mg tous les 15 jours). A 6 mois, les scores d’activite de la DA etaient significativement ameliores (Δ total SCORAD : −22 ; Δ score EASI : −8,4). Par ailleurs, il etait constate une repousse spectaculaire des cheveux, des cils et des sourcils, debutant des 3 mois, quasi-complete a 6 mois (Δ score SALT : −80,4). La tolerance du dupilumab etait excellente, sans conjonctivite ( Fig. 1 ). Discussion Alors que son efficacite dans la DA moderee a severe est desormais bien demontree, l’action spectaculaire du dupilumab sur la pelade confirme les avancees recentes dans la comprehension de cette pathologie. Jusque-la, les etudes sur sa physiopathologie etaient majoritairement conduites sur des modeles murins et s’attachaient a decrire le role de la reponse immune Th1 et de l’IFNg, amenant a l’utilisation recente des inhibiteurs de JAK. Il a ete ainsi montre chez l’homme des polymorphismes des genes codant pour l’IL-4 et l’IL-13 associes a un risque accru de pelade. Chez des patients atteints de pelade, des etudes transcriptomiques sur tissu cutane ont revele une augmentation de l’expression des genes associes a la reponse Th2, ainsi qu’une augmentation des taux d’IL-13 dans le serum. Enfin, des donnees recentes suggerent que le blocage des cytokines impliquees dans la voie Th2 pourrait induire un passage des follicules pileux en phase anagene. L’ensemble de ces resultats suggere que le blocage de cette voie pourrait etre une therapeutique efficace, au moins dans le sous-groupe de patients touches par ces deux comorbidites : DA et pelade. Conclusion Nous rapportons ainsi le premier cas d’efficacite du dupilumab dans la pelade chez un patient atteint egalement de DA. Cette efficacite semble etre supportee par des donnees montrant l’implication de la voie Th2 au cours de la pelade et justifie des essais cliniques pilotes afin de preciser son efficacite reelle.

The extension and severity of vitiligo guide diagnosis, prognosis, and therapeutic choices. However, to date, the lack of a standardized method for measuring vitiligo is responsible for the high variability in vitiligo assessment. van Geel et al. introduce a clinical scoring called the Vitiligo Extent Score with a strong interest in clinical practice and clinical research in vitiligo.

Vitiligo is a common, chronic skin disorder characterized by loss of epidermal melanocytes and progressive depigmentation. Vitiligo has complex immune, genetic, environmental, and biochemical etiology, but the exact molecular mechanisms of vitiligo development and progression, particularly those related to metabolic control, are poorly understood. Here we characterized the human vitiligo cell line PIG3V and the normal human melanocytes, HEM-l by RNA-sequencing (RNA-seq), targeted metabolomics, and shotgun lipidomics. Melanocyte-enriched miR-211, a known metabolic switch in non-pigmented melanoma cells, was severely downregulated in vitiligo cell line PIG3V and skin biopsies from vitiligo patients, while its predicted targets transcriptional co-activator PGC1-α (PPARGC1A), ribonucleotide reductase regulatory subunit M2 (RRM2), and serine-threonine protein kinase TAO1 (TAOK1) were reciprocally upregulated. miR-211 binds to PGC1-α 3’UTR locus and represses it. Although mitochondrial numbers were constant, mitochondrial complexes I, II, and IV and respiratory responses were defective in vitiligo cells. Nanoparticle-coated miR-211 partially augmented the oxygen consumption rate in PIG3V cells. The lower oxygen consumption rate, changes in lipid and metabolite profiles, and increased reactive oxygen species production observed in vitiligo cells appear to be partly due to abnormal regulation of miR-211 and its target genes. These genes represent potential biomarkers and therapeutic targets in human vitiligo.

SummaryBackground Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells specialized in the production of type I interferon (IFN-α/β) and involved in various cutaneous inflammatory and autoimmune disorders, such as cutaneous lupus erythematosus (CLE) and vitiligo. Heat shock proteins (HSPs) are molecular chaperones essential for maintaining cellular functions, but they can act as a danger signal during inflammation. Objectives To decipher the role of HSP70 in the production of IFN-α by pDCs in CLE and vitiligo. Methods Expression of HSP70 and CD123+ pDCs was analysed by immunohistochemistry or immunofluorescence in CLE and vitiligo skin samples. Flow cytometry was performed to analyse expression of HSP70 receptors, activation markers on pDCs and DNA uptake by pDCs in the presence of HSP70. The impact of HSP70 on DNA-induced IFN-α secretion by pDCs was evaluated by enzyme-linked immunosorbent assay (ELISA). The effect of IFN-α on chemokine (C-X-C motif) ligand 9 (CXCL9)/10 gene and protein expression by keratinocytes was determined by real-time polymerase chain reaction and ELISA. Results Infiltration of pDCs in CLE and progressive vitiligo was primarily located in the epidermis, close to keratinocytes expressing HSP70. In vitro experiments revealed that the pDCs expressing HSP70 receptor Lox-1 (lectin-like oxidized low-density lipoprotein-receptor-1) were able to aggregate HSP70. Exogenous HSP70 induced activation of pDCs and increased the uptake of exogenous DNA. Furthermore, HSP70 potentiated DNA-induced IFN-α production by pDCs. Finally, IFN-α induced expression of CXCL9 and CXCL10 by keratinocytes. Conclusions These data demonstrate that interaction between HSP70 and pDCs in CLE and vitiligo is a prerequisite for the enhancement of IFN-α production, and could be an interesting target.

The international vitiligo community had last December its first "vitiligo only" research meeting in the Eternal City. Vitiligo is a well-recognized but poorly addressed public health concern worldwide. The Vitiligo International Symposium (VIS) is a strong signal for the medical world of the coming of age of vitiligo as a major research field. Because of the gathering of the majority of world experts, the meeting was preceded by a clinical research methodology workshop held at the San Gallicano Institute. This report gives a combined account of the two parts. This article is protected by copyright. All rights reserved

Immune-mediated responses are consistently observed in progressing vitiligo at the edge of depigmenting patches. Besides the role of the adaptive immune system, the profile of the innate immune response is now at the center of the stage. We report that plasmacytoid dendritic cells (pDC), which are the major interferon (IFN)-alpha-producing cells, are part of the infiltrate of progressive vitiligo with local production of MxA (a protein induced by IFNα). MxA was associated with expression of the type I IFN-inducible ligand CXCL9 and correlated with the recruitment of CXCR3(+) immune cells. Interestingly, strong MxA expression was observed in perilesional skin in close apposition to remaining melanocytes, surrounded by a prominent T-cell infiltrate. In contrast, MxA was not detectable in lesional skin, suggesting that IFN-α production is an early event in the progression of the disease. Our data highlight a new innate immune pathway leading to progression of vitiligo.