JAK inhibition in Aicardi-Goutières syndrome: a monocentric multidisciplinary real-world approach study

International audienceThe paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery

Implication de la voie Hedgehog dans la mastocytose : apport de l'étude génétique de formes rares de mastocytoses à début pédiatrique

Introduction. Mastocytosis is a neoplastic condition characterized by the accumulation of mast cells (MCs) in one or more organs. Adults tend to have persistent, systemic mastocytosis, whereas MC infiltration in children is usually limited to the skin and classically regresses after several years. In more than 85% of both adult and pediatric patients, KIT mutations are identified, the KIT D816V mutation being present in most affected adults but in only half of affected children. All attempts to demonstrate the oncogenic effect of the D816V mutation alone have failed – suggesting that other pathogenic factors cooperate with KIT in the context of mastocytosis. Objectives. i- To identify the clinical, biological and molecular factors associated with the regression of cutaneous mastocytosis (CM) in children and ii-to identify, in rare forms of congenital mastocytosis, primitive genetic events acting in synergy with the KIT mutation, in order to analyze the underlying pathophysiological mechanisms and test them in sporadic forms. Results. Through the study of a cohort of 272 children with mastocytosis, we showed that congenital mastocytosis and the KIT D816V mutation were associated with a regression of CM. Thus, the mutational differences between children and adults (especially the high prevalence of KIT D816V mutation in adults) cannot alone explain the outcome of CM. Then, through the observation of 3 patients from 2 unrelated families, presenting with i-a Greig cephalopolysyndactyly syndrome (GCPS) - a rare polymalformative syndrome caused by a loss-of- function mutation in GLI3 gene coding for the main repressive transcription factor of the Hedgehog (Hh) signaling pathway (GLI3R) and ii-a congenital mastocytosis, we showed that Hh is overactive in neoplastic MCs from patients with aggressive systemic mastocytosis (ASM). Hedgehog pathway inhibitors suppressed MC proliferation, induced the apoptosis of neoplastic MCs, and significantly extended the survival time of mice with ASM. We showed that MCs derived from the bone marrow of Gli3Xt+/- mice (a mouse model of GCPS) and transduced with the KIT-D816V vector proliferated much more than controls - confirming the synergistic tumorigenic effects of GLI3 and KIT mutations on the onset of mastocytosis. Ectopic expression of GLI3R rapidly induced the death of pathological MCs - highlighting the protein’s tumor suppressor activity and therapeutic potential in this model. Conclusion. Our study i- opens up new hypotheses with regard to the spontaneous regression of CM in pediatric patients and ii- highlights, a new mechanism contributing to the pathogenesis of ASM and suggests new therapeutic targets in this pathology.Introduction. Les mastocytoses sont caractérisées par une accumulation clonale de mastocytes dans un ou plusieurs organe(s). Alors que la majorité des mastocytoses à début pédiatrique sont cutanées pures (MC) et spontanément régressives, les mastocytoses adultes sont plus souvent systémiques et persistantes. Des mutations somatiques du gène KIT responsables d’une activation constitutive du récepteur à activité tyrosine kinase KIT ont été identifiées chez la majorité des patients. La mutation D816V est la plus fréquente (85% des adultes et 42% des enfants). D’autres mutations, hors codon 816, sont retrouvées chez un peu plus de 40% des enfants. Toutes les tentatives de démonstration de l'effet oncogène de la mutation KIT D816V seule ont échoué. D'autres facteurs interviennent donc dans la genèse de la maladie. Objectifs. Nos deux objectifs étaient i- d’étudier les facteurs cliniques, biologiques et moléculaires associés à la régression de la mastocytose chez l’enfant et ii- d’identifier dans des formes rares de mastocytoses congénitales des évènements génétiques primitifs agissant en synergie avec la mutation de KIT dans l’apparition de la mastocytose. Résultats. À partir d’une cohorte de 272 enfants atteints de mastocytose, nous avons montré, pour la première fois, qu'une régression spontanée des lésions cutanées était statistiquement associée au caractère congénital de la mastocytose, et à la mutation KIT D816V. Ainsi, contrairement à l’adulte, la mutation KIT D816V est associée de façon significative à la régression de la mastocytose chez l’enfant. Les différences mutationnelles dans le gène KIT n’expliquent donc pas à elles seules les différences phénotypiques observées entre ces deux populations. A partir de 3 patients appartenant à 2 familles indépendantes qui présentaient l’association d’une mastocytose congénitale et une céphalopolysyndactylie de Greig (MIM175700) – syndrome malformatif lié à des mutations hétérozygotes perte de fonction dans le gène GLI3 codant pour le principal répresseur de la voie de signalisation Hedgehog (Hh), GLI3R, nous avons montré que i) la voie Hh était constitutivement hyperactivée dans les mastocytes néoplasiques de patients atteints de mastocytoses agressives, ii) l'utilisation d'inhibiteurs de la voie de signalisation Hh inhibait la prolifération et induisait l'apoptose des mastocytes néoplasiques de patients, et retardait significativement la mort chez les souris présentant une mastocytose agressive KITD816V+ , iii) les mastocytes dérivés de moelle de souris Gli3Xt+/-, modèle murin du syndrome de Greig, et transduits avec le vecteur KIT-D816V avaient un fort potentiel prolifératif par rapport aux témoins, confirmant la coopération oncogénique entre les voies Hh et KIT. Enfin, nous avons montré que l'expression ectopique de GLI3R induisait rapidement la mort des mastocytes pathologiques, démontrant son rôle de suppresseur de tumeur dans ce modèle. Conclusion. Notre étude a permis d’identifier un nouveau mécanisme contribuant à la pathogénèse des mastocytoses agressives et suggérant ainsi des de nouvelles cibles thérapeutiques dans cette pathologie. De nouvelles hypothèses expliquent la régression de la mastocytose à début pédiatrique

Involvement of the Hedgehog Pathway in Mastocytosis : Contribution of the Genetic Study of Rare Forms of Pediatric Mastocytosis

Introduction. Les mastocytoses sont caractérisées par une accumulation clonale de mastocytes dans un ou plusieurs organe(s). Alors que la majorité des mastocytoses à début pédiatrique sont cutanées pures (MC) et spontanément régressives, les mastocytoses adultes sont plus souvent systémiques et persistantes. Des mutations somatiques du gène KIT responsables d’une activation constitutive du récepteur à activité tyrosine kinase KIT ont été identifiées chez la majorité des patients. La mutation D816V est la plus fréquente (85% des adultes et 42% des enfants). D’autres mutations, hors codon 816, sont retrouvées chez un peu plus de 40% des enfants. Toutes les tentatives de démonstration de l'effet oncogène de la mutation KIT D816V seule ont échoué. D'autres facteurs interviennent donc dans la genèse de la maladie. Objectifs. Nos deux objectifs étaient i- d’étudier les facteurs cliniques, biologiques et moléculaires associés à la régression de la mastocytose chez l’enfant et ii- d’identifier dans des formes rares de mastocytoses congénitales des évènements génétiques primitifs agissant en synergie avec la mutation de KIT dans l’apparition de la mastocytose. Résultats. À partir d’une cohorte de 272 enfants atteints de mastocytose, nous avons montré, pour la première fois, qu'une régression spontanée des lésions cutanées était statistiquement associée au caractère congénital de la mastocytose, et à la mutation KIT D816V. Ainsi, contrairement à l’adulte, la mutation KIT D816V est associée de façon significative à la régression de la mastocytose chez l’enfant. Les différences mutationnelles dans le gène KIT n’expliquent donc pas à elles seules les différences phénotypiques observées entre ces deux populations. A partir de 3 patients appartenant à 2 familles indépendantes qui présentaient l’association d’une mastocytose congénitale et une céphalopolysyndactylie de Greig (MIM175700) – syndrome malformatif lié à des mutations hétérozygotes perte de fonction dans le gène GLI3 codant pour le principal répresseur de la voie de signalisation Hedgehog (Hh), GLI3R, nous avons montré que i) la voie Hh était constitutivement hyperactivée dans les mastocytes néoplasiques de patients atteints de mastocytoses agressives, ii) l'utilisation d'inhibiteurs de la voie de signalisation Hh inhibait la prolifération et induisait l'apoptose des mastocytes néoplasiques de patients, et retardait significativement la mort chez les souris présentant une mastocytose agressive KITD816V+ , iii) les mastocytes dérivés de moelle de souris Gli3Xt+/-, modèle murin du syndrome de Greig, et transduits avec le vecteur KIT-D816V avaient un fort potentiel prolifératif par rapport aux témoins, confirmant la coopération oncogénique entre les voies Hh et KIT. Enfin, nous avons montré que l'expression ectopique de GLI3R induisait rapidement la mort des mastocytes pathologiques, démontrant son rôle de suppresseur de tumeur dans ce modèle. Conclusion. Notre étude a permis d’identifier un nouveau mécanisme contribuant à la pathogénèse des mastocytoses agressives et suggérant ainsi des de nouvelles cibles thérapeutiques dans cette pathologie. De nouvelles hypothèses expliquent la régression de la mastocytose à début pédiatrique.Introduction. Mastocytosis is a neoplastic condition characterized by the accumulation of mast cells (MCs) in one or more organs. Adults tend to have persistent, systemic mastocytosis, whereas MC infiltration in children is usually limited to the skin and classically regresses after several years. In more than 85% of both adult and pediatric patients, KIT mutations are identified, the KIT D816V mutation being present in most affected adults but in only half of affected children. All attempts to demonstrate the oncogenic effect of the D816V mutation alone have failed – suggesting that other pathogenic factors cooperate with KIT in the context of mastocytosis. Objectives. i- To identify the clinical, biological and molecular factors associated with the regression of cutaneous mastocytosis (CM) in children and ii-to identify, in rare forms of congenital mastocytosis, primitive genetic events acting in synergy with the KIT mutation, in order to analyze the underlying pathophysiological mechanisms and test them in sporadic forms. Results. Through the study of a cohort of 272 children with mastocytosis, we showed that congenital mastocytosis and the KIT D816V mutation were associated with a regression of CM. Thus, the mutational differences between children and adults (especially the high prevalence of KIT D816V mutation in adults) cannot alone explain the outcome of CM. Then, through the observation of 3 patients from 2 unrelated families, presenting with i-a Greig cephalopolysyndactyly syndrome (GCPS) - a rare polymalformative syndrome caused by a loss-of- function mutation in GLI3 gene coding for the main repressive transcription factor of the Hedgehog (Hh) signaling pathway (GLI3R) and ii-a congenital mastocytosis, we showed that Hh is overactive in neoplastic MCs from patients with aggressive systemic mastocytosis (ASM). Hedgehog pathway inhibitors suppressed MC proliferation, induced the apoptosis of neoplastic MCs, and significantly extended the survival time of mice with ASM. We showed that MCs derived from the bone marrow of Gli3Xt+/- mice (a mouse model of GCPS) and transduced with the KIT-D816V vector proliferated much more than controls - confirming the synergistic tumorigenic effects of GLI3 and KIT mutations on the onset of mastocytosis. Ectopic expression of GLI3R rapidly induced the death of pathological MCs - highlighting the protein’s tumor suppressor activity and therapeutic potential in this model. Conclusion. Our study i- opens up new hypotheses with regard to the spontaneous regression of CM in pediatric patients and ii- highlights, a new mechanism contributing to the pathogenesis of ASM and suggests new therapeutic targets in this pathology

Lipofilling: A New Therapeutic Option for the Treatment of Lupus Panniculitis-Induced Atrophy

Lupus panniculitis is a rare manifestation of cutaneous lupus erythematosus, which may lead to major aesthetic sequelae with a severe impact on patients’ quality of life. We report 2 cases supporting the short- and long-term efficacy and safety of lipofilling in the treatment of lupus panniculitis-induced atrophy. These observations pave the way for prospective, larger-scale studies in patients with scarring lupus panniculitis, provided that the autoimmune pathogenic process is in complete, stable remission

Mast cells in spondyloarthritis, more than simple inflammatory bystanders?

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Recent advances in the understanding and therapeutic management of mastocytosis

International audienceMastocytosis is a rare disease due to the abnormal accumulation of mast cells in various tissues. Its clinical presentation is heterogeneous depending on mast cell infiltration and mediators release. In some cases, it is associated with hematological malignancies. Prognosis varies from very good with a life expectancy similar to the general population in indolent forms of the disease to a survival time of just a few months in mast cell leukemia. Although in most cases a somatic KIT D816V mutation is found in tumor mast cells, the physiopathology of the disease is not yet fully understood. Additional germline and somatic mutations may explain this heterogeneity. Treatments aim at blocking effect of mast cell mediators, reducing mast cell activation and tumor burden. New drugs mainly directed against the tyrosine kinase activity of KIT have dramatically changed the quality of life and prognosis of mast cell diseases. Present and future therapeutic strategies are discussed in this review

Criteria for the Regression of Pediatric Mastocytosis: A Long-Term Follow-Up

International audienceMastocytosis is a neoplastic condition characterized by the accumulation of mast cells (MCs) in 1 or more organ. Adults tend to have persistent, systemic mastocytosis, whereas MC infiltration in children is usually limited to the skin and typically regresses after several years. Both adults and children could display mast cell activation symptoms (MCASs) due to MC mediator release. In more than 85% of both adult and pediatric cases, KIT mutations are present, with the KIT D816V mutation being present in most affected adults but in only half the affected children

Epithelial barrier dysfunction in desmoglein-1 deficiency

International audienceMutations in the desmoplakin (DSP) and desmoglein-1 (DSG1) genes have been implicated in patients with the inherited inflammatory skin disease known as severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome (MIM#603165, see Tables E1 and E2 in this article's Online Repository at www.jacionline.org).1, 2 The DSP and DSG1 genes encode desmosome components that are critical for the structure of intercellular junctions and maintenance of epithelial barrier integrity. DSP and DSG1 are also key regulators of signaling pathways involved in differentiation, epidermal homeostasis, and carcinogenesis. DSG1 promotes keratinocyte differentiation by inhibiting epidermal growth factor receptor/extracellular signal-regulated kinase signaling through ERBB2-interacting protein (ERBIN), a scaffolding and signaling protein.3 Through characterization of a new syndrome featuring severe allergic dermatitis and DSG1 deficiency, we highlighted the pivotal role of the functional DSG1/ERBIN interaction as an inhibitor of skin inflammation through the nuclear factor κB (NF-κB) signaling pathway

Neuropilin-1 cooperates with PD-1 in CD8+ T cells predicting outcomes in melanoma patients treated with anti-PD1

International audienceTargeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies