Abstract Research on the genetic abnormalities and pathogenetic processes of ichthyoses has progressed remarkably, and many causative genes and molecules have been identified in ichthyoses and ...ichthyosis syndromes. Most of the genes/molecules causative of ichthyosis are associated with the barrier function of the stratum corneum, and defects in the skin barrier play important roles in the pathogenesis of various ichthyosis phenotypes. It has been elucidated that, of the ichthyosis-causative genes, ABCA12 , ALOXE3, ALOX12B , CYP4F22, CERS3, ABHD5 , PNPLA1 and ELOVL4 work in the formation of the corneocyte lipid envelope (CLE), a structure that is essential to sound skin barrier function. The CLE mostly consists of ultra-long-chain (ULC) ceramides derived from ULC-acylceramide (EOS; a combination of esterified ω-hydroxy fatty acids and sphingosines). In this review, I shed light on the synthesis, metabolism and transport of epidermal ceramides, especially on ULC-acylceramide and the processes of CLE formation. In addition, I summarize the pathogeneses of various ichthyoses and ichthyosis syndromes from the aspects of abnormal synthesis of ULC-acylceramide and malformation of the CLE. Investigations on the pathomechanisms of ichthyoses have provided novel knowledge on the synthesis and metabolism of ceramides in the epidermis. Conversely, research on the dynamics of epidermal ceramides has contributed to the elucidation of the pathogenesis of ichthyoses. Advances in our understanding of the biology of epidermal lipids and the disease pathogeneses of ichthyoses and ichthyosis syndromes promise to provide clues for the development of effective therapies for ichthyosis patients in the near future.
•Autoinflammation is predominantly involved in pustular psoriasis pathogenesis.•Pustular psoriasis is an autoinflammatory keratinization disease (AiKD).•IL36RN, CARD14, AP1S3, MPO and SERPINA3 are ...associated with pustular psoriasis.•The IL-36 axis plays an important role in the pathogenesis of pustular psoriasis.•Several cytokine pathways, including IL-36 signaling, are novel treatment targets.
Pustular psoriasis is a chronic inflammatory skin disease characterized by erythematous plaques with sterile pustules. It includes the distinct clinical entities generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau (ACH) and palmoplantar pustular psoriasis (PPPP). Recently clarified pathomechanisms of pustular psoriasis indicate that hyperactivation of the skin innate immunity, including of the IL-1/IL-36 axis, plays an important role in the pathogenesis of pustular psoriasis. Autoinflammatory keratinization disease (AiKD) is the umbrella clinical entity for inflammatory keratinization disorders with genetic autoinflammatory pathomechanisms, and pustular psoriasis is a representative AiKD. To date, mutations/variants in five genes—IL36RN, CARD14, AP1S3, MPO and SERPINA3—have been reported to be genetic causative or predisposing factors for pustular psoriasis. The pathogenic mechanisms induced by the mutations/variants in these genes are all closely related to the excessive activation of skin innate immunity and autoinflammation. A number of biologics (e.g., tumor necrosis factor inhibitors, IL-17/IL-17 receptor inhibitors and IL-23 inhibitors) and granulocyte and monocyte adsorption apheresis are used to treat pustular psoriasis. Recently, based on novel information on the pathomechanisms of pustular psoriasis, which are mainly associated with autoinflammation, inhibitors of several pathogenic pathways, including of the IL-1, IL-36, IL-8 and granulocyte colony-stimulating factor signaling pathways, have been studied as emerging treatments.
ATP-binding cassette (ABC) transporters form a large superfamily of transporters that bind and hydrolyze ATP to transport various molecules across limiting membranes or into vesicles. The ABCA ...subfamily members are thought to transport lipid materials. ABCA12 is a keratinocyte transmembrane lipid transporter protein associated with the transport of lipids via lamellar granules. ABCA12 is considered to transport lipids including ceramides to form extracellular lipid layers in the stratum corneum of the epidermis, which is essential for skin barrier function. ABCA12 mutations are known to underlie the three major types of autosomal recessive congenital ichthyoses: harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma. ABCA12 mutations result in defective lipid transport via lamellar granules in the keratinocytes, leading to ichthyosis phenotypes from malformation of the stratum corneum lipid barrier. Studies on ABCA12-deficient bioengineered models have revealed that lipid transport by ABCA12 is required for keratinocyte differentiation and epidermal morphogenesis. Defective lipid transport due to loss of ABCA12 function leads to the accumulation of intracellular lipids, including glucosylceramides and gangliosides, in the epidermal keratinocytes. The accumulation of gangliosides seems to result in the apoptosis of Abca12−/− keratinocytes. It was reported that AKT activation occurs in Abca12−/− granular-layer keratinocytes, which suggests that AKT activation serves to prevent the cell death of Abca12−/− keratinocytes. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.
•ABCA12 is a keratinocyte lipid transporter.•ABCA12 mutations cause autosomal recessive congenital ichthyosis.•ABCA12 dysfunction results in epidermal barrier defects.•ABCA12 deficiency leads to disturbed keratinocyte differentiation.
Mutations in ABCA12 have been described in autosomal recessive congenital ichthyoses (ARCI) including harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis ...(LI). HI shows the most severe phenotype. CIE and LI are clinically characterized by fine, whitish scales on a background of erythematous skin, and large, thick, dark scales over the entire body without serious background erythroderma, respectively. To date, a total of 56 ABCA12 mutations have been reported in 66 ARCI families including 48 HI, 10 LI, and 8 CIE families of African, European, Pakistani/Indian, and Japanese origin (online database: http://www.derm-hokudai.jp/ABCA12/). A total of 62.5% of reported ABCA12 mutations are expected to lead to truncated proteins. Most mutations in HI are truncation mutations and homozygous or compound heterozygous truncation mutations always results in HI phenotype. In CIE families, at least one mutation on each allele is typically a missense mutation. Combinations of missense mutations in the first ATP-binding cassette of ABCA12 underlie the LI phenotype. ABCA12 is a keratinocyte lipid transporter associated with lipid transport in lamellar granules, and loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in an ichthyotic phenotype. Recent work using mouse models confirmed ABCA12 roles in skin barrier formation. Hum Mutat 31:1-7 2010.
Whole-exome and whole-genome sequencing have become widespread in approximately the last 15 years, and the predisposing factors and pathomechanisms of inflammatory keratinization diseases, which have ...been unknown for a long time, have gradually been revealed. Hence, various inflammatory keratinization diseases are recognized to cause innate immunity hyperactivation. Therefore, we have been advocating for the clinical entity, "autoinflammatory keratinization diseases (AiKDs)" since 2017. AiKDs are inflammatory keratinization diseases caused by autoinflammatory-related pathomechanisms in the skin. The aberrant activation of innate immunity and the resultant autoinflammation in the epidermis and the superficial dermis in AiKDs cause hyperkeratosis in the epidermis. Our initially proposed concept of AiKDs included generalized pustular psoriasis and related conditions, pityriasis rubra pilaris type V, and familial keratosis lichenoides chronica. Since then, the number of diseases known to be AiKDs has increased as previously unknown disease-causing factors and pathogenetic mechanisms of inflammatory keratinization diseases have been clarified one by one. To date, porokeratosis, hidradenitis suppurative, keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome, and AiKDs associated with epidermal growth factor receptor (EGFR) deficiency or with hepatitis and autism have been recognized as AiKDs. The concept of AiKDs is considered extremely useful in our precise understanding of the pathogeneses behind inflammatory keratinization diseases and our appropriate treatment method selection. The number of AiKDs is expected to grow with the clarification of the pathomechanisms of further inflammatory keratinization diseases.
As predisposing factors and pathogenic mechanisms of inflammatory keratinization disorders of the skin have become increasingly elucidated in recent years, a number of inflammatory keratinization ...disorders are now known to have the excessive activation of innate immunity as their pathogenesis. Autoinflammation-associated pathogeneses have been clarified in patients with generalized pustular psoriasis (GPP), pityriasis rubra pilaris (PRP) type V, and familial keratosis lichenoides chronica (KLC). Thus, based on these findings, in 2017, we proposed the clinical entity "autoinflammatory keratinization disease (AiKD)," which comprehensively includes inflammatory keratinization disorders with pathogenic mechanisms related to autoinflammation (the excessive activation of innate immunity). In 2017, GPP and associated diseases, PRP type V, and familial KLC came to be considered as AiKDs. In addition to these diseases, hidradenitis suppurative, porokeratosis, keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome, and AiKDs with hepatitis and autism have been newly recognized as AiKDs. The concept of AiKD may contribute to the selection of novel treatment methods. For example, recognizing hidradenitis suppurativa precisely as an AiKD has resulted in the application of adalimumab, an anti-tumor necrosis factor alpha antibody, as a treatment. The concept of AiKD is thought to be useful toward our accurate understanding of the pathogeneses of inflammatory keratinization disorders and our choice of appropriate treatment methods. As the pathogenic mechanisms of inflammatory keratinization disorders are further elucidated, it is presumed that the number of keratinization diseases whose pathogeneses are associated with autoinflammation will increase and that the number of diseases recognized as AiKDs will grow more and more.
Inherited ichthyoses are a group of genetic disorders characterized by generalized dry skin, scaling and hyperkeratosis, and often associated with erythroderma. These manifestations are due to ...mutations in genes mostly involved in skin barrier formation. Inherited ichthyoses consist of non‐syndromic ichthyoses and ichthyosis syndromes. Non‐syndromic ichthyoses are characterized by the phenotypic expression of the disorder being seen only in the skin. Non‐syndromic ichthyoses include ichthyosis vulgaris, recessive X‐linked ichthyosis, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis and other forms. This review focuses on updates for each type of non‐syndromic ichthyosis, highlighting molecular mechanisms and phenotype/genotype correlations. Included in autosomal recessive congenital ichthyosis are three of the major phenotypes (harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma) and three of the minor subtypes (self‐healing collodion baby, acral self‐healing collodion baby and bathing suit ichthyosis). Keratinopathic ichthyosis is proposed as an umbrella term for ichthyoses caused by mutations in keratin genes. Next‐generation sequencing technologies have become powerful tools for the diagnosis of inherited ichthyoses and the discovery of their genetic causes. This article reviews the current understanding of molecular pathomechanisms for non‐syndromic ichthyoses and explores future perspectives.
Generalized pustular psoriasis (GPP) is a chronic, systemic inflammatory disease accompanied by high fever and general malaise. Diffuse erythema and swelling of the extremities occur, with multiple ...sterile pustules all over the body in GPP patients. GPP often relapses over the lifetime and can be life-threatening. Recent discoveries of the underlying molecular genetic basis of many cases of this disorder have provided major advances to clinicians and researchers towards an understanding of the pathomechanism of GPP. However, the therapeutic management of GPP still faces many challenges and much uncertainty, and an evidence-based review summarizing the available clinical data on the management of this heterogeneous disease is needed. The present review addresses challenges regarding the precise clinical diagnosis and evaluation of clinical symptoms in GPP. In addition, we update and briefly summarize the current understanding of molecular pathomechanisms behind GPP as an autoinflammatory keratinization disease. Recent publications have clarified the genetic backgrounds of patients with GPP and ethnic differences in predisposing factors. Although there are ethnic differences in the prevalences of these pathogenic alleles, from recent reports, at most 60.5% (IL36RN), 5.9% (CARD14), and 10.8% (AP1S3) of GPP patients have the mutations/variations of these genes. All the reported biologics studied seemed effective and relatively well tolerated. Although it is difficult to evaluate therapeutic efficacy from studies on just a few cases, recent findings suggest that biologics can be a useful, powerful tool for controlling skin and systemic inflammation in GPP and for improving the quality of life of GPP patients.
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