•Autoinflammatory keratinization diseases have autoinflammatory pathomechanisms.•The clinical entity “autoinflammatory keratinization diseases” includes IL36Ra-related pustulosis.•CARD14-mediated ...pustular psoriasis falls within the concept of autoinflammatory keratinization diseases.•Pityriasis rubra pilaris type V and keratosis lichenoides chronica are included in autoinflammatory keratinization diseases.•Improved understanding of disease pathophysiology may lead to innovative targeted therapies.
Classifying inflammatory skin diseases is challenging, especially for the expanding group of disorders triggered by genetic factors resulting in hyperactivated innate immunity that result in overlapping patterns of dermal and epidermal inflammation with hyperkeratosis. For such conditions, the umbrella term “autoinflammatory keratinization diseases” (AIKD) has been proposed. AIKD encompasses diseases with mixed pathomechanisms of autoinflammation and autoimmunity, and includes IL-36 receptor antagonist (IL-36Ra)-related pustulosis, CARD14-mediated pustular psoriasis, pityriasis rubra pilaris (PRP) type V, and familial keratosis lichenoides chronica (KLC). Mechanistically, the entities include generalized pustular psoriasis (GPP) without psoriasis vulgaris, impetigo herpetiformis and acrodermatitis continua, which are IL-36Ra-related pustuloses caused by loss-of-function mutations in IL36RN; GPP with psoriasis vulgaris and palmoplantar pustular psoriasis which are CARD14-mediated pustular psoriasiform dermatoses with gain-of-function variants of CARD14; PRP type V which is caused by gain-of-function mutations in CARD14; and, familial KLC in which mutations in NLRP1, an inflammasome sensor protein predominantly expressed in skin, have been identified. It is likely that further inflammatory keratinization disorders will also fall within the concept of AIKD, as elucidation of novel pathogenic mechanisms of inflammatory keratinization diseases emerges. A better understanding of the pathophysiology of AIKD is likely to lead to innovative, targeted therapies that benefit patients.
Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the ...inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.
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•Germline, gain-of-function NLRP1 mutations cause MSPC and FKLC syndromes.•Mutant NLRP1 proteins have lower threshold for inflammasome activation.•The Pyrin (PYD) and LRR domains of NLRP1 inhibit its self-oligomerization.•NLRP1 mutants cause skin hyperplasia via paracrine inflammatory signaling.
Gain-of-function mutations in the inflammasome sensor NLRP1 increase susceptibility to skin cancer and unmask unique regulatory autoinhibition in the inflammasome.
Metabolic perturbations in fibrosis disease Ung, Chuin Ying; Onoufriadis, Alexandros; Parsons, Maddy ...
The international journal of biochemistry & cell biology,
October 2021, 2021-10-00, 20211001, Letnik:
139
Journal Article
Recenzirano
Odprti dostop
Metabolic changes occur in all forms of disease but their impact on fibrosis is a relatively recent area of interest. This review provides an overview of the major metabolic pathways, glycolysis, ...amino acid metabolism and lipid metabolism, and highlights how they influence fibrosis at a cellular and tissue level, drawing on key discoveries in dermal, renal, pulmonary and hepatic fibrosis. The emerging influence of adipose tissue-derived cytokines is discussed and brings a link between fibrosis and systemic metabolism. To close, the concept of targeting metabolism for fibrotic therapy is reviewed, drawing on lessons from the more established field of cancer metabolism, with an emphasis on important considerations for clinical translation.
Background Several new targeted genes and clinical subtypes have been identified since publication in 2008 of the report of the last international consensus meeting on diagnosis and classification of ...epidermolysis bullosa (EB). As a correlate, new clinical manifestations have been seen in several subtypes previously described. Objective We sought to arrive at an updated consensus on the classification of EB subtypes, based on newer data, both clinical and molecular. Results In this latest consensus report, we introduce a new approach to classification (“onion skinning”) that takes into account sequentially the major EB type present (based on identification of the level of skin cleavage), phenotypic characteristics (distribution and severity of disease activity; specific extracutaneous features; other), mode of inheritance, targeted protein and its relative expression in skin, gene involved and type(s) of mutation present, and–when possible–specific mutation(s) and their location(s). Limitations This classification scheme critically takes into account all published data through June 2013. Further modifications are likely in the future, as more is learned about this group of diseases. Conclusion The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and molecular features of each EB subtype, and has sufficient flexibility incorporated in its structure to permit further modifications in the future.
Background Since publication in 2000 of the Second International Consensus Report on Diagnosis and Classification of Epidermolysis Bullosa, many advances have been made to our understanding of this ...group of diseases, both clinically and molecularly. At the same time, new epidermolysis bullosa (EB) subtypes have been described and similarities with some other diseases have been identified. Objective We sought to arrive at a new consensus of the classification of EB subtypes. Results We now present a revised classification system that takes into account the new advances, as well as encompassing other inherited diseases that should also be included within the EB spectrum, based on the presence of blistering and mechanical fragility. Current recommendations are made on the use of specific diagnostic tests, with updates on the findings known to occur within each of the major EB subtypes. Electronic links are also provided to informational and laboratory resources of particular benefit to clinicians and their patients. Limitations As more becomes known about this disease, future modifications may be needed. The classification system has been designed with sufficient flexibility for these modifications. Conclusion This revised classification system should assist clinicians in accurately diagnosing and subclassifying patients with EB.
Epidermolysis bullosa (EB) comprises a collection of clinically diverse inherited blistering diseases that affect the skin and, in some subtypes, mucous membranes and other organs. Currently ...classified into four main subtypes (EB simplex, junctional EB, dystrophic EB, and Kindler syndrome, mainly based on the level of skin cleavage), the spectrum of EB extends to more than 30 clinical subtypes with pathogenic mutations in at least 18 distinct genes. This review focuses on three recent additions to variants of EB: all are autosomal recessive, and result from mutations in either DST-e (coding for epidermal dystonin, also known as the 230 kDa bullous pemphigoid antigen, BP230), EXPH5 (coding for exophilin-5, also known as Slac2-b), or ITGA3 (coding for the integrin alpha-3 subunit). Each of these new forms of EB is reviewed with respect to the initial gene discovery, clinical features, the current mutation database, and skin pathology. Awareness of these recently described forms of EB is helpful in the clinical evaluation of patients with EB and in defining genotype-phenotype correlation for inherited blistering skin diseases.
Objective:Schizophrenia and bipolar disorder are associated with multidimensional disability. This study examined differential predictors of functional deficits in the two disorders.
...Method:Community-dwelling individuals with schizophrenia (N=161) or bipolar disorder (N=130) were assessed with neuropsychological tests, symptom measures, and performance-based social and adaptive (i.e., everyday living skills) functional competence measures as well as three domains of real-world functioning: community and household activities; work skills; and interpersonal relationships. The authors used confirmatory path analysis to find the best-fitting models to examine the direct and indirect (as mediated by competence) prediction of the three domains of real-world functioning.
Results:In all models for both groups, neurocognition's relationship with outcomes was largely mediated by competence. Symptoms were negatively associated with outcomes but unassociated with competence, with the exception of depression, which was a direct and mediated (through social competence) predictor in bipolar disorder. In both groups, neurocognition was related to activities directly and through a mediated relationship with adaptive competence. Work skills were directly and indirectly (through mediation with social competence) predicted by neurocognition in schizophrenia and entirely mediated by adaptive and social competence in bipolar disorder. Neurocognition was associated with interpersonal relationships directly in the schizophrenia group and mediated by social competence in both groups.
Conclusions:Although there was greater disability in schizophrenia, neurocognition predicted worse functioning in all outcome domains in both disorders. These results support the shared role of neurocognition in bipolar disorder and schizophrenia in producing disability, with predictive differences between disorders in domain-specific effects of symptoms and social and adaptive competence.
Epidermolysis bullosa (EB) is a group of inherited skin and mucosal fragility disorders resulting from mutations in genes encoding basement membrane zone (BMZ) components or proteins that maintain ...the integrity of BMZ and adjacent keratinocytes. More than 30 years have passed since the first causative gene for EB was identified, and over 40 genes are now known to be responsible for the protean collection of mechanobullous diseases included under the umbrella term of EB. Through the elucidation of disease mechanisms using human skin samples, animal models, and cultured cells, we have now reached the stage of developing more effective therapeutics for EB. This review will initially focus on what is known about blister wound healing in EB, since recent and emerging basic science data are very relevant to clinical translation and therapeutic strategies for patients. We then place these studies in the context of the latest information on gene therapy, read-through therapy, and cell therapy that provide optimism for improved clinical management of people living with EB.
Abstract Background Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and ...optimal ways to reduce it have not been fully determined. Objectives To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients. Methods Using bulk RNA sequencing, we evaluated affected and unaffected skin biopsy samples from six patients with DDEB (all with the very itchy pruriginosa subtype) and four healthy individuals. Single-cell transcriptomes of affected (n = 2) and unaffected (n = 1) DDEB skin and healthy skin (n = 2) were obtained. Dupilumab treatment was provided for three patients. Results The skin bulk transcriptome showed significant enrichment of T helper (Th)1/2 and Th17 pathways in affected DDEB skin compared with nonlesional DDEB skin and healthy skin. Single-cell transcriptomics showed an association of glycolytically active GATA3+ Th2 cells in affected DDEB skin. Treatment with dupilumab in three people with DDEB led to significantly reduced visual analogue scale (VAS) itch scores after 12 weeks (mean VAS 3.83) compared with pretreatment (mean VAS 7.83). Bulk RNAseq and quantitative polymerase chain reaction showed that healthy skin and dupilumab-treated epidermolysis bullosa (EB) pruriginosa skin have similar transcriptomic profiles and reduced Th1/Th2 and Th17 pathway enrichment. Conclusions Single-cell RNAseq helps define an enhanced DDEB-associated Th2 profile and rationalizes drug repurposing of anti-Th2 drugs in treating DDEB pruritus.
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare monogenic blistering disorder caused by the lack of functional type VII collagen, leading to skin fragility and subsequent trauma-induced ...separation of the epidermis from the underlying dermis. A total of 46% of patients with RDEB harbor at least one premature termination codon (PTC) mutation in COL7A1, and previous studies have shown that aminoglycosides are able to overcome RDEB PTC mutations by inducing “read-through” and incorporation of an amino acid at the PTC site. However, aminoglycoside toxicity will likely prevent widespread clinical application. Here the FDA-approved drug amlexanox was tested for its ability to read-through PTC mutations in cells derived from patients with RDEB. Eight of 12 different PTC alleles responded to treatment and produced full length protein, in some cases more than 50% relative to normal controls. Read-through type VII collagen was readily detectable in cell culture media and also localized to the dermal-epidermal junction in organotypic skin culture. Amlexanox increased COL7A1 transcript and the phosphorylation of UPF-1, an RNA helicase associated with nonsense-mediated mRNA decay, suggesting that amlexanox inhibits nonsense-mediated mRNA decay in cells from patients with RDEB that respond to read-through treatment. This preclinical study demonstrates the potential of repurposing amlexanox for the treatment of patients with RDEB harboring PTC mutation in COL7A1.
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