RESUMEN
Pyodermatitis pyostomatitis vegetans is a rare inflammatory condition, affecting the skin and/or mucous membrane. Some cases include both skin and mucous involvement, whereas others develop either skin or mucous lesions only. The typically affected areas are the scalp, face, trunk and extremities, including the flexural areas and umbilicus. Clinical features show erosive granulomatous plaques, keratotic plaques with overlying crusts and pustular lesions. Among mucous lesions, oral mucosa is most frequently involved, and gingival erythema, shallow erosions, cobblestone-like papules on the buccal mucosa or upper hard palate of the oral cavity are also observed. Some of the lesions assume a 'snail track' appearance. Although there are several similarities between pyodermatitis pyostomatitis vegetans and other diseases, that is pyoderma gangrenosum, pemphigus vegetans and pemphigoid vegetans, the histopathological features of pyodermatitis pyostomatitis vegetans are unique in that epidermal hyperplasia, focal acantholysis and dense inflammatory infiltrates with intraepidermal and subepidermal eosinophilic microabscesses are observed. Direct immunofluorescence findings are principally negative. Activated neutrophils are supposed to play an important role in the pathogenesis of pyodermatitis pyostomatitis vegetans. The expression of IL-36 and neutrophil extracellular traps (NETs) was observed in the lesional skin, and additionally, eosinophil extracellular traps (EETs) was detected in pyodermatitis pyostomatitis vegetans. A possible pathogenic role of NETs and EETs in the innate immunity and autoinflammatory aspects of pyodermatitis pyostomatitis vegetans was discussed.
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Trampas Extracelulares , Pénfigo , Piodermia , Estomatitis , Humanos , Piodermia/complicaciones , Piodermia/patología , Estomatitis/etiología , Estomatitis/patología , Neutrófilos/patología , Eritema , Compuestos OrgánicosRESUMEN
Pustulotic arthro-osteitis (PAO) is an infrequent condition, with its manifestation in children being even rare. Some reports propose an association between genetic variants and the onset of PAO. Currently, no definitive treatment protocol exists for paediatric patients with PAO. In this study, we present the paediatric case of PAO with an IL36RN variant who was successfully treated with tonsillectomy.
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Osteítis , Psoriasis , Tonsilectomía , Humanos , Niño , Osteítis/etiología , Tonsilectomía/efectos adversos , Psoriasis/complicaciones , InterleucinasRESUMEN
Generalized pustular psoriasis (GPP) is considered to be a distinct clinical entity from psoriasis vulgaris (PV), with different clinical and histological manifestations. The pathogenesis of GPP has not been thoroughly elucidated, especially in those patients lacking interleukin (IL)36RN. In present study, we performed RNA sequence analysis on skin lesions from 10 GPP patients (4 with and 6 without IL36RN mutation) and 10 PV patients without IL36RN mutation. Compared with PV, significantly overexpressed genes in GPP patients were enriched in IL-17 signalling pathway (MMP1, MMP3, DEFB4A and DEFB4B, etc.) and associated with neutrophil infiltration (MMP1, MMP3, ANXA and SERPINB, etc.). GPP with IL36RN mutations evidenced WNT11 upregulation and IL36RN downregulation in comparison to those GPP without IL36RN mutations. The expression of IL-17A/IL-36 in skin or serum and the origin of IL-17A in skin were also investigated. IL-17A expression in skin was significantly higher in GPP than PV patients, whereas, there were no differences in skin IL-36α/IL-36γ/IL-36RA or serum IL-17A/IL-36α/IL-36γ between GPP than PV. Besides, double immunofluorescence staining of MPO/IL-17A or CD3/IL-17A further confirmed that the majority of IL-17A in GPP skin was derived from neutrophils, but not T cells. These data emphasized the role of neutrophil-derived IL-17A in the pathogenesis of GPP with or without IL36RN mutations. Targeting neutrophil-derived IL-17A might be a promising treatment for GPP.
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Psoriasis , Enfermedades Cutáneas Vesiculoampollosas , Humanos , Interleucina-17/genética , Interleucinas/genética , Interleucinas/metabolismo , Metaloproteinasa 1 de la Matriz , Metaloproteinasa 3 de la Matriz , Neutrófilos/metabolismo , Psoriasis/tratamiento farmacológicoRESUMEN
Deficiency of the interleukin-36 receptor antagonist (DITRA) is a rare autoinflammatory disorder caused by mutations in the IL36RN gene. This mutation leads to a lack of functional interleukin-36 receptor antagonists (IL-36Ra), which results in an overactive immune system and chronic inflammation. Despite its rarity, numerous case series and individual reports in the literature emphasize the importance of recognizing and managing DITRA. Early identification of the cutaneous signs of DITRA is crucial for accurate diagnosis and timely administration of appropriate treatment. This review article provides a comprehensive overview of the current understanding of the cutaneous, non-cutaneous and histopathological manifestations of DITRA, with a focus on reported treatments. The disease typically presents in early childhood, although the age of onset can vary. Patients with DITRA exhibit recurrent episodes of skin inflammation, often with a pustular or pustular psoriasis-like appearance. Additionally, non-cutaneous manifestations are common, with recurrent fevers and elevated acute-phase reactants being the most prevalent. The exact prevalence of DITRA is unknown. Some cases of loss-of-function mutations in the IL36RN gene, considered a hallmark for diagnosis, have been identified in patients with familial generalized pustular psoriasis (GPP). Biological therapies with inhibition of IL-12/23 and IL-17 are promising treatment options; paediatric patients with DITRA have shown complete response with mild relapses. New and emerging biologic therapeutics targeting the IL-36 pathway are also of interest in the management of this rare autoinflammatory disorder.
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Interleucinas , Psoriasis , Humanos , Niño , Preescolar , Interleucinas/genética , Piel/patología , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Psoriasis/patología , Mutación , InflamaciónRESUMEN
PURPOSE: This study aims to elucidate the tear proteome and understand the underlying molecular mechanisms involved in the ocular complications following Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). METHODS: Mass spectrometry (MS) was performed to quantify the tear fluid proteins from chronic SJS/TEN patients (n = 22 eyes) and age- and gender-matched controls (n = 22 eyes). The candidate proteins were validated using ELISA (n = 80 eyes) in tear samples and immunohistochemistry (IHC; n = 12) in eyelid margin specimens. These proteins were compared for significant differences based on age, gender, disease duration, and ocular severity. RESULTS: A total of 1692 tear fluid proteins were identified, of which 470 were significantly differentially regulated in chronic SJS/TEN. The top 10 significantly upregulated proteins were neutrophil secretions including neutrophil elastase (p < .0001), defensin (p < .0001), and matrix metalloproteinase 8 (p < .0001). The presence of neutrophils was confirmed by the upregulation of IL-8 (p < .001) in tears, a key cytokine known for recruiting neutrophils. Additionally, positive expression of myeloperoxidase was observed in the keratinized eyelid margins of SJS/TEN to validate the presence of neutrophils. Among 41 unique proteins identified by MS, IL-36γ (p < .01) was expressed in three SJS/TEN patients and was confirmed in SJS/TEN tears and eyelid margins by ELISA and IHC, respectively. IL-36γ was specifically expressed in the superficial layers of eyelid margin keratinized conjunctiva. The majority of the significantly downregulated proteins were lacrimal gland secretions such as lacritin (p < .0001) and opiorphin (p < .002). Neutrophil elastase (p < .02) was significantly elevated in patients with severe eyelid margin keratinization. CONCLUSION: Our observations indicate a clear correlation between eyelid margin keratinization and the expression of IL-36γ, potentially mediated by neutrophils recruited via IL-8. Future experimental studies are needed to test the role of therapies targeting IL-8 and/or IL-36γ in reducing eyelid margin keratinization and its associated ocular complications in SJS/TEN.
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Interleucina-1 , Neutrófilos , Síndrome de Stevens-Johnson , Lágrimas , Humanos , Femenino , Masculino , Neutrófilos/metabolismo , Neutrófilos/inmunología , Interleucina-1/metabolismo , Síndrome de Stevens-Johnson/metabolismo , Síndrome de Stevens-Johnson/patología , Adulto , Lágrimas/metabolismo , Persona de Mediana Edad , Enfermedad Crónica , Inflamación/metabolismo , Anciano , Adulto JovenRESUMEN
BACKGROUND: Psoriasis is an inflammatory skin disease driven by upregulation of cytokines in the Th17 pathway, including interleukin-36 (IL-36). Previous studies have highlighted the utility of IL-36 immunostaining for psoriasis compared to spongiotic dermatitis and other psoriasiform dermatoses; however, no study has examined the role of IL-36 staining in distinguishing psoriasis from pityriasis rosea (PR) and pityriasis lichenoides (PL), known histologic mimickers of psoriasis. METHODS: We compared the immunostaining pattern of IL-36 for 21 PR cases, 22 PL cases, and 10 psoriasis cases. We graded the immunostaining as 0, negative; 1, focal weak; 2, diffuse weak; 3, focal, strong; or 4, diffuse strong. We further categorized stains as negative (0-2 score) or positive (3-4 score) and utilized Fisher's exact test to compare the immunostaining pattern of these entities. RESULTS: All psoriasis specimens were positive for IL-36, whereas all PR specimens were negative (p = 0.00000002). Twenty PL specimens were negative (p = 0.000001). Nine of 10 pityriasis lichenoides et varioliformis acuta cases were negative (p = 0.00012), and 11 of 12 cases of pityriasis lichenoides chronica were negative (p = 0.00003). CONCLUSIONS: Our findings highlight the potential role of IL-36 immunostaining in distinguishing psoriasis from other psoriasiform dermatoses, including PR and PL.
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Inmunohistoquímica , Interleucina-1 , Pitiriasis Liquenoide , Pitiriasis Rosada , Psoriasis , Humanos , Pitiriasis Liquenoide/diagnóstico , Pitiriasis Liquenoide/patología , Pitiriasis Liquenoide/metabolismo , Psoriasis/diagnóstico , Psoriasis/metabolismo , Psoriasis/patología , Pitiriasis Rosada/diagnóstico , Pitiriasis Rosada/patología , Pitiriasis Rosada/metabolismo , Diagnóstico Diferencial , Interleucina-1/metabolismo , Inmunohistoquímica/métodos , Masculino , Femenino , Adulto , Persona de Mediana EdadRESUMEN
This review explores the intricate relationship between generalized pustular psoriasis (GPP) and various systemic diseases, shedding light on the broader impacts of this severe skin condition beyond its primary dermatological manifestations. GPP is identified as not only a profound contributor to skin pathology but also a significant risk factor for systemic diseases affecting cardiovascular, hepatic, renal, pulmonary, and skeletal systems, as well as associated with an increased incidence of anemia, depression, anxiety, and arthritis. The research highlights the complex interplay of cytokines, particularly IL-17 and IL-36, which are central to the pathophysiology of GPP and implicated in the exacerbation of systemic conditions. Key findings indicate a higher incidence of cardiovascular events in GPP patients compared to those with other severe forms of psoriasis, notably with a stronger correlation between myocardial infarction history and GPP development. Liver disturbances, frequently reversible upon psoriasis remission, suggest a cytokine-mediated link to hepatic health. Renal dysfunction appears elevated in GPP sufferers, with IL-17 and IL-36 potentially driving renal fibrosis. Similarly, interstitial lung disease and osteoporosis in GPP patients underscore the systemic reach of inflammatory processes initiated in the skin. The associations with anemia, depression, anxiety, and arthritis further complicate the clinical management of GPP, requiring a multidisciplinary approach. The study concludes that managing GPP effectively requires a holistic approach that addresses both the cutaneous and systemic dimensions of the disease, advocating for continued research into the mechanisms that connect GPP with broader health implications to refine therapeutic strategies.
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Psoriasis , Humanos , Psoriasis/complicaciones , Psoriasis/patología , Citocinas/metabolismo , Enfermedades Cardiovasculares/etiologíaRESUMEN
PURPOSE: To study the effects of the anti-IL-23A antibody risankizumab on the IL-36γ/IL-23A/IL-17A signalling cascade we used a newly developed 3D skin model consisting of primary human keratinocytes, fibroblasts and γδ-T-cells. METHODS: In this in vitro study we developed new full-thickness 3D skin models containing normal human epidermal keratinocytes (NHEK), normal human dermal fibroblasts (NHDF) and IL-23A responsive and IL-17A producing γδ-T-cells. The effects of IL-36γ stimulation with and without risankizumab treatment on IL-23A and IL-17A expression were examined at the RNA and protein levels. RESULTS: In preliminary monolayer experiments stimulation of γδ-T-cells with IL-23A promoted the IL-17A expression that was inhibited after risankizumab treatment. Using 3D skin models containing γδ-T-cells, we found that stimulation with IL-36γ significantly increased not only IL-23A but also IL-17A expression. These effects were inhibited by concomitant treatment with risankizumab. CONCLUSIONS: Our results showed that blockade of IL-23A has inhibitory effects on the IL-36γ/IL-23A feedforward loop. Our newly developed 3D skin model containing IL-23A responsive and IL-17A producing γδ-T-cells enables molecular analysis of targeted therapies aimed at the IL-36γ/IL-23A/IL-17A signalling cascade in psoriasis.
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Anticuerpos Monoclonales , Interleucina-17 , Subunidad p19 de la Interleucina-23 , Queratinocitos , Piel , Humanos , Interleucina-17/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Anticuerpos Monoclonales/farmacología , Subunidad p19 de la Interleucina-23/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Piel/inmunología , Células Cultivadas , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Interleucina-1/metabolismo , Linfocitos Intraepiteliales/efectos de los fármacos , Linfocitos Intraepiteliales/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Psoriasis/tratamiento farmacológico , Psoriasis/inmunologíaRESUMEN
The IL-1 family of cytokines consists of IL-1α, IL-1ß, IL-18, IL-33, IL-36α, IL-36ß, and IL-36γ. These proteins form four signaling receptor complexes: the IL-1 receptor (IL-1R1 and IL-1RAcP), the IL-18 receptor (IL-18Rα and IL-18Rß), the IL-33 receptor (ST2 and IL-1RAcP), and the IL-36 receptor (IL-1Rrp2 and IL-1RAcP). The formation of receptor complexes is also regulated by various antagonistic molecules and decoy receptors. The IL-1 family cytokines are induced and secreted by both innate immune cells and tissue cells upon infection and tissue damage. Thus, they play a diverse role in mediating both innate and adaptive immune responses. During tumor development and cancer treatment, the expression of the IL-1 gene family is differentially regulated in tumor cells, tissue stromal cells, and immune cells in a stage specific and tissue specific manner. Like other cytokines, the IL-1 family proteins have pleiotropic functions that are dependent on diverse arrays of target cells. As a result, they play a complex role in tumorigenesis, cancer metastasis, immune suppression, and cancer immune surveillance. Here, we focus on reviewing experimental evidence demonstrating how members of the IL-1 family influence cancer development at the cellular and molecular level. The unique mechanisms of this group of cytokines make them attractive targets for new cancer therapy.
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Proteína Accesoria del Receptor de Interleucina-1 , Interleucina-33 , Humanos , Interleucina-33/genética , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transducción de Señal , Carcinogénesis/genéticaRESUMEN
Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.
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Inflamación/genética , Interleucinas/genética , Peroxidasa/genética , Psoriasis/genética , Enfermedades de la Piel/genética , Adulto , Animales , Citocinas/genética , Trampas Extracelulares/genética , Femenino , Humanos , Inflamación/patología , Interleucina-1/genética , Interleucinas/metabolismo , Masculino , Ratones , Mutación/genética , Neutrófilos/metabolismo , Psoriasis/patología , Enfermedades Raras/enzimología , Enfermedades Raras/genética , Enfermedades Raras/patología , Piel/enzimología , Piel/patología , Enfermedades de la Piel/patologíaRESUMEN
Interleukin-36α (IL-36α) is essential for various inflammatory conditions, such as psoriasis and rheumatoid arthritis, whereas its role in tumor immunity is unclear. In this study, it was demonstrated that IL-36α could activate the NF-κB and MAPK signaling pathways in macrophages, leading to the expression of IL-1ß, IL-6, TNF-α, CXCL1, CXCL2, CXCL3, CXCL5 and iNOS. Importantly, IL-36α has significant antitumor effects, altering the tumor microenvironment and promoting the infiltration of MHC IIhigh macrophages and CD8+ T cells while decreasing the levels of monocyte myeloid-derived suppressor cells, CD4+ T cells and regulatory T cells. This ultimately results in the inhibition of tumor growth and migration. Furthermore, IL-36α synergized with the PD-L1 antibody increased the immune cells infiltration and enhanced the anti-tumor effect of the PD-L1 antibody on melanoma. Collectively, this study reveals a new role for IL-36α in promoting anti-tumor immune responses in macrophages and suggests its potential for cancer immunotherapy.
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Antígeno B7-H1 , Melanoma , Humanos , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos , Interleucinas/metabolismo , Macrófagos , Melanoma/metabolismo , Microambiente TumoralRESUMEN
The IL-36 cytokines are a recently described subset of the IL-1 family of cytokines, and have been shown to play a role in the pathogenesis of respiratory diseases such as asthma and COPD. Given the common aetiological links between COPD and lung cancer development, as well as the involvement of other IL-1 family members in lung tumorigenesis, the aim of this work was to investigate the role of IL-36 cytokines in the pathogenesis of lung cancer. In this study we demonstrate that expression of IL-36 cytokines and receptor mRNA and protein are significantly increased in lung cancer tissue compared to adjacent non-tumour tissue. In vitro assays showed that stimulation of two lung cancer cell lines, SKMES-1 human squamous cell and LLC murine lung cancer, with IL-36R agonists resulted in increased cellular migration and proliferation. All IL-36 cytokines induced the expression of pro-inflammatory chemokines in both lung cancer cell lines with synergistic effects identified upon co-stimulation of cells with IL-17, IL-22 and TNFα. Furthermore, we report that IL-36 cytokines induce protein expression of the immune checkpoint inhibitor protein PD-L1 on lung cancer cells. Taken together, this data indicates that targeting IL-36R signalling may be a useful targeted therapy for lung cancer patients with IL-36R+ cancer cells.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Ratones , Animales , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Citocinas/metabolismo , Pulmón/metabolismo , Interleucina-1/metabolismo , CarcinogénesisRESUMEN
BACKGROUND: Interleukin-36s (IL-36s) are a category of inflammatory cytokines and an increasing number of studies over the past decade have found that different kinds of IL-36s play different roles in cancers. This systematic review and meta-analysis aimed to evaluate the prognostic value of IL-36s in different cancer types. METHOD: Two reviewers independently searched in PubMed, Cochrane Library and EMBASE up to December 13, 2022. We extracted the hazard ratio (HR) and the confidence intervals (CIs) of the related prognostic outcomes and analyzed the pooled HR. RESULTS: We included 12 studies including 1925 patients. In all, six studies including IL-36α, five including IL-36γ and one including IL-36ß. A high expression of IL-36α was associated with better overall survival (OS) (HR = 0.48, 95 %CI: 0.37-0.62, P < 0.001) of cancer patients. The expression of IL-36γ was not related with cancers. Further, subgroup analysis showed that the expression of IL-36γ had no correlation with the OS of colorectal cancer (CRC) and nonsmall cell lung cancer (NSCLC) patients. Interestingly, a high expression of IL-36γ played contrasting prognostic roles in hepatocellular carcinoma (HCC) (HR = 0.43, 95 %CI: 0.27-0.69, P < 0.001) patients and gastric cancer (GC) (HR = 1.58, 95 %CI: 1.33-1.87, P < 0.001) patients. The only IL-36ß related study showed the expression of IL-36ß was not correlated with the prognosis of CRC patients (P > 0.05). CONCLUSION: IL-36α, IL-36ß and IL-36γ possibly play different roles in different cancers. High expression of IL-36α may be associated with good prognostic value in cancer patients, especially in CRC patients. The association between cancers prognosis and expression of IL-36ß or IL-36γ needs further evaluation. These conclusions need more clinical prognostic data for confirmation.
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Carcinoma Hepatocelular , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Hepáticas , Neoplasias Pulmonares , Humanos , Interleucina-1/metabolismo , Pronóstico , Interleucinas/metabolismoRESUMEN
Generalized pustular psoriasis (GPP) is a rare subset of psoriasis involving episodes of sterile pustules accompanied by inflammation and, often, systemic involvement. The inflammatory nature of GPP has potential for severe multisystem complications including high-output cardiac failure, infections, digestive system issues, and disfiguring or lethal acute flare episodes. The disease tends to have higher prevalence in females and Asians. The IL-1/IL-36 inflammatory pathway is a critical facet of GPP's pathology. Genetic mutations that are associated with GPP include modifications of Interleukin 36 Receptor Antagonist (IL36RN), Caspase Recruitment Domain Family Member 14 (CARD14), Adaptor Related Protein Complex 1 Subunit Sigma 3 (AP1S3), Myeloperoxidase (MPO) and Serpin Peptidase Inhibitor Clade A Member 3 (SERPINA3) genes. Treatment guidelines for GPP are not well-entrenched. Currently, only one GPP-specific treatment, the interleukin-36 receptor antagonist (IL-36Ra) spesolimab, has been approved for use in the United States. Additional anti-IL-36 pathway therapies are currently being developed. Other treatment options include other biologic therapies such as IL-17 inhibitors, IL-23 inhibitors and TNFα inhibitors. Non-biologic therapeutic options include retinoids, cyclosporine and methotrexate. Treatment options differ throughout the world; most countries utilize retinoids, cyclosporine and methotrexate as first-line non-biologic options. China and United Kingdom have no GPP-specific biologic therapies approved for use, while several biologic therapies are approved for use in Japan. This review aims to serve as an update on the current global management of GPP while also including relevant aspects of disease pathogenesis, diagnosis, clinical presentation, histopathology, aetiology and epidemiology.
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Psoriasis , Enfermedades Cutáneas Vesiculoampollosas , Femenino , Humanos , Interleucinas/genética , Metotrexato/uso terapéutico , Psoriasis/tratamiento farmacológico , Psoriasis/diagnóstico , Ciclosporina/uso terapéutico , Enfermedad Aguda , Enfermedad Crónica , Retinoides , Guanilato Ciclasa , Proteínas de la Membrana , Proteínas Adaptadoras de Señalización CARD/genéticaRESUMEN
Generalised pustular psoriasis (GPP) is a rare and severe neutrophilic skin disorder, manifesting with acute episodes of pustulation and systemic upset. The discovery of recessive IL36RN mutations associated with GPP has transformed our understanding of disease drivers, paving the way for the development of targeted anti-IL36 therapeutics. In the light of these remarkable successes, this viewpoint reviews the significance of IL36RN mutations in GPP, their functional impact and their correlation with clinical phenotypes. It then covers the discovery of further genetic determinants (recessive MPO mutations) and risk factors (AP1S3 and CARD14 low-frequency variants) for the disease. It discusses the growing evidence for genetic complexity in GPP and concludes by outlining collaborative strategies that may be adopted to overcome the challenges ahead.
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Psoriasis , Enfermedades Cutáneas Vesiculoampollosas , Humanos , Interleucinas/genética , Psoriasis/genética , Piel , Mutación , Guanilato Ciclasa/genética , Proteínas de la Membrana/genética , Proteínas Adaptadoras de Señalización CARD/genéticaRESUMEN
Psoriasis is a chronic, immune-mediated skin disease that affects over 3% of adults in the United States. Psoriasis can present in several clinical forms. Of these, generalized pustular psoriasis is an acute, severe form, associated with increased morbidity and mortality. Unlike the more common plaque psoriasis, which is thought to feature dysregulation of the adaptive immune system, generalized pustular psoriasis reflects heightened autoinflammatory responses. Recent advances in genetic and immunological studies highlight a key role of the IL-36 immune axis in the pathogenesis of generalized pustular psoriasis. In this article, we review the psoriatic subtypes and discuss diagnostic criteria of generalized pustular psoriasis, discuss several newly identified genetic variants associated with pustular disease in the skin, and discuss how these mutations shed light on pustular disease mechanisms. Furthermore, we gather insights from recent transcriptomic studies that similarly implicate a pathogenic role of the IL-36 immune axis in generalized pustular psoriasis.
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Psoriasis , Adulto , Humanos , Piel , Enfermedad Crónica , Enfermedad Aguda , MutaciónRESUMEN
Generalized Pustular psoriasis (GPP), a rare and potentially life-threatening auto-inflammatory disease, is associated with IL36RN mutations. Here, we analyse the prevalence of IL36RN mutations in our multi-ethnic GPP cohort and assess differences in the clinical profile of patients with (IL36RN-positive) and without (IL36RN-negative) mutations. IL36RN mutations were present in 17.7% of 137 GPP patients (29.7% of Chinese cases, 17.3% of Malay cases, but 0% of Indian patients). 92% of these individuals carried the c.115 + 6 T > C mutation. Male: female ratio was 1:2.3. Females predominate in both groups with no significant difference between IL36RN-positive and IL36RN-negative individuals. The overall mean age (±SD) at disease onset for GPP was 37.6 ± 17.2 years, but disease onset was significantly earlier in IL36RN-positive vs IL36RN-negative cases (mean age:30.6 ± 18.92 vs. 39.2 ± 16.49 years, p = 0.027). IL36RN-positive patients were less likely to have associated plaque psoriasis (52.4% vs. 83.5%, p-value = 0.002). There was no difference in the common clinical and laboratory manifestations or triggers of GPP between IL36RN-positive and -negative patients, except for geographic tongue which was significantly more common in IL36RN-positive patients (41.7% vs. 11.9%, p-value = 0.002). Annual flare rate was significantly higher in IL36RN-positive compared to IL36RN-negative (mean ± SD of 1.92 ± 1.32 vs. 1.46 ± 0.90, p = 0.041) cases. However, no significant difference in the rate of hospitalization and length of hospital stay was observed between the two groups. These observations demonstrate that IL36RN disease alleles occur with varying frequencies among Asian populations and are associated with a severe, early-onset clinical phenotype.
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Interleucinas , Psoriasis , Femenino , Humanos , Masculino , Enfermedad Aguda , Pueblo Asiatico , Enfermedad Crónica , Interleucinas/genética , Malasia , Mutación , Psoriasis/epidemiología , Psoriasis/etnología , Psoriasis/genética , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana EdadRESUMEN
BACKGROUND: Effisayil 1 was a randomized, placebo-controlled study of spesolimab, which is an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare. OBJECTIVE: To assess the effects of spesolimab over the 12-week study. METHODS: The primary endpoint of the study was Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 at week 1. Patients (N = 53) were randomized (2:1) to receive a single intravenous dose of 900 mg spesolimab or placebo on day 1. Patients could receive open-label spesolimab for persistent flare symptoms on day 8. RESULTS: Most patients receiving spesolimab achieved a GPPGA pustulation subscore of 0 (60.0%) and GPPGA total score of 0 or 1 (60.0%) by week 12. In patients randomized to placebo who received open-label spesolimab on day 8, the proportion with GPPGA pustulation subscore of 0 increased from 5.6% at day 8 to 83.3% at week 2. No factors predictive of spesolimab response were identified in patient demographics or clinical characteristics. LIMITATIONS: The effect of initial randomization was not determined conventionally beyond week 1 due to patients receiving open-label spesolimab. CONCLUSION: Rapid control of generalized pustular psoriasis flare symptoms with spesolimab was sustained over 12 weeks, further supporting its potential use as a therapeutic option for patients.
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Psoriasis , Humanos , Resultado del Tratamiento , Psoriasis/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Método Doble CiegoRESUMEN
BACKGROUND: Sepsis is defined as a life-threatening syndrome caused by an unbalanced host response to infection. The role of interleukin (IL)-36 cytokines binding to the IL-36 receptor (IL-36R) in host response during sepsis remains unknown. METHODS: Serum IL-36 level was measured in 47 septic patients sampled on the day of intensive care unit (ICU) and emergency department admission, 21 non-septic ICU patient controls, and 21 healthy volunteers. In addition, the effects of IL-36R deletion on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis was determined. RESULTS: On the day of ICU and emergency department admission, the patients with sepsis showed a significant increase in serum IL-36 levels compared with ICU patient controls and healthy volunteers, and the serum IL-36 levels were related to the severity of sepsis. Non-survivors of septic patients displayed significantly lower serum IL-36 levels compared with survivors. A high serum IL-36 level in ICU and emergency department admission was associated with 28-day mortality, and IL-36 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, IL-36R deletion increased lethality in CLP-induced polymicrobial sepsis. Septic mice with IL-36R deletion had higher bacterial load and demonstrated more severe multiple organ injury (including lung, liver, and kidney) as indicated by clinical chemistry and histopathology. Mechanistically, IL-36R ligands released upon lung damage activated IL-36R+lung fibroblasts thereby inducing expression of the antimicrobial protein lipocalin 2. Moreover, they induced the apoptosis of lung epithelial cells. CONCLUSIONS: Septic patients had elevated serum IL-36 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-36R deletion in increasing lethality.
Asunto(s)
Lesión Pulmonar , Sepsis , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Células Epiteliales , Fibroblastos , InterleucinasRESUMEN
BACKGROUND: Chronic actinic dermatitis (CAD) is an immune-mediated photodermatosis characterized by a high eosinophil count and total immunoglobulin E (IgE) in the peripheral blood of patients. At present, however, the reasons for their elevation remain unclear. OBJECTIVE: The current study aimed to detect changes in inflammatory cytokines in CAD and explore their role in this disease. METHODS: Enzyme-linked immunosorbent assay and Luminex assay were conducted to measure inflammatory factor levels. Immunohistochemical analysis and quantitative real-time polymerase chain reaction were performed to evaluate the expression levels of interleukin-36γ (IL-36γ), IL-8, chemokine (C-C motif) ligand 17 (CCL17), and CCL18. CCK8 kits were used to assess cell proliferation. Immunofluorescence was used to detect nuclear factor κB (NF-κB) p65 nuclear translocation. Western blot analysis was performed to detect the protein expression level of phosphorylated NF-κB (p-NF-κB) p65. Hematoxylin and eosin and Masson trichrome staining were applied to observe histological changes in a chronic photo-damaged mouse model. RESULTS: Eosinophils, total IgE, IL-36γ, IL-8, tumor necrosis factor α, CCL17, and CCL18 were elevated in CAD. Of note, IL-36γ promoted the proliferation of eosinophilic cells (EOL-1) and the production of IgE in peripheral blood mononuclear cells. IL-36γ also promoted the production of IL-8 and CCL18 in immortalized human keratinocytes (HaCaT cells), while ultraviolet radiation (UVR)-induced IL-36γ via activation of the NF-κB signaling pathway. CONCLUSIONS: IL-36γ was involved in the pathogenesis of CAD and UVR contributed to the production of IL-36γ, which may provide a novel therapeutic target for CAD.