Abstract The BJD prides itself on the quality and breadth of its content. Our current publications span the Journal’s key domains of translational research, clinical trials, epidemiology, global ...health, evidence-based dermatology, and outcomes and qualitative research, with the editorial aim of publishing the best clinically relevant science, advances in dermatology and items of clinical or practical value and interest to dermatologists and other colleagues working in related disciplines.
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The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, http://www.guidetopharmacology.org) provides expert-curated molecular interactions between successful and potential drugs and their targets in the human ...genome. Developed by the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS), this resource, and its earlier incarnation as IUPHAR-DB, is described in our 2014 publication. This update incorporates changes over the intervening seven database releases. The unique model of content capture is based on established and new target class subcommittees collaborating with in-house curators. Most information comes from journal articles, but we now also index kinase cross-screening panels. Targets are specified by UniProtKB IDs. Small molecules are defined by PubChem Compound Identifiers (CIDs); ligand capture also includes peptides and clinical antibodies. We have extended the capture of ligands and targets linked via published quantitative binding data (e.g. Ki, IC50 or Kd). The resulting pharmacological relationship network now defines a data-supported druggable genome encompassing 7% of human proteins. The database also provides an expanded substrate for the biennially published compendium, the Concise Guide to PHARMACOLOGY. This article covers content increase, entity analysis, revised curation strategies, new website features and expanded download options.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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8.
Autoinflammatory keratinization diseases Akiyama, Masashi; Takeichi, Takuya; McGrath, John A. ...
Journal of allergy and clinical immunology,
December 2017, 2017-12-00, 20171201, Volume:
140, Issue:
6
Journal Article
Peer reviewed
Open access
...AIKDs have primary genetic causative factors associated with the hyperactivation of innate immunity (autoinflammation), mainly in the epidermis and upper dermis.IL-36Ra works as an antagonist to ...the IL-1 family members IL-36 α, β, and γ (Fig 1)....deficiency of IL-36Ra caused by IL36RN loss-of-function mutations is thought to result in acceleration of IL-36-driven skin inflammation.Inflammatory hyperkeratotic skin lesions are not common in patients with conventional autoinflammatory diseases....although AIKDs are thought to have autoinflammatory pathogenic mechanisms, unique pathomechanisms with inflammation that involves epidermal keratinocytes and results in hyperkeratosis are assumed in patients with AIKDs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
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10.
Metabolic perturbations in fibrosis disease Ung, Chuin Ying; Onoufriadis, Alexandros; Parsons, Maddy ...
International journal of biochemistry & cell biology,
October 2021, 2021-10-00, 20211001, Volume:
139
Journal Article
Peer reviewed
Open access
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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