Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations. Plaque psoriasis, which is the most common manifestation of psoriasis, is located on one end of the spectrum, dominated by adaptive immune responses, whereas the rarer pustular psoriasis lies on the opposite end, dominated by innate and autoinflammatory immune responses. In recent years, genetic studies have identified six genetic variants that predispose to pustular psoriasis, and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis. In this review, we discuss the presentation and clinical subtypes of pustular psoriasis, contribution of genetic predisposing variants, critical role of the IL-36 family of cytokines in disease pathophysiology, and treatment perspectives for pustular psoriasis. We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.

“Autoinflammatory psoriasis”—genetics and biology of pustular psoriasis

Psoriasis is a chronic inflammatory skin condition affecting diverse racial/ethnic groups throughout the world. Large population-based studies suggest that psoriasis occurs most often in individuals of European ancestry, followed by black and Hispanic individuals, although the true prevalence of psoriasis in non-white individuals is likely underestimated. Despite similarities in psoriasis between ethnic groups, there are notable differences in the presentation, quality-of-life impact, and treatment of psoriasis with important implications for the management of non-white individuals. Overall, heterogeneity in psoriasis susceptibility alleles, in combination with cultural and socioeconomic factors, may explain these differences. In this article, we review the epidemiology, clinical presentation, genetic polymorphisms, quality-of-life impact, and treatment nuances of psoriasis in patients with skin of color.

Psoriasis in Skin of Color: Insights into the Epidemiology, Clinical Presentation, Genetics, Quality-of-Life Impact, and Treatment of Psoriasis in Non-White Racial/Ethnic Groups

The CARD: BCL10: MALT1 (CBM) complex is an essential signaling node for maintaining both innate and adaptive immune responses. CBM complex components have gained considerable interest due to the dramatic effects of associated mutations in causing severe lymphomas, immunodeficiencies, carcinomas and inflammatory disease. While MALT1 and BCL10 are ubiquitous proteins, the CARD-containing proteins differ in their tissue expression. CARD14 is primarily expressed in keratinocytes. The CARD14-BCL10-MALT1 complex is activated by upstream pathogen-associated molecular pattern-recognition in vitro, highlighting a potentially crucial role in innate immune defense at the epidermal barrier. Recent findings have demonstrated how CARD14 orchestrates activation of the NF-κB and MAPK signaling pathways via recruitment of BCL10 and MALT1, leading to the upregulation of pro-inflammatory genes encoding IL-36γ, IL-8, Ccl20 and anti-microbial peptides. Following the identification of CARD14 gain-of function mutations as responsible for the psoriasis susceptibility locus PSORS2, the past years have witnessed a large volume of case reports and association studies describing CARD14 variants as causal or predisposing to a wide range of inflammatory skin disorders. Recent publications of mouse models also helped to better understand the physiological contribution of CARD14 to psoriasis pathogenesis. In this review, we summarize the clinical, genetic and functional aspects of human and murine CARD14 mutations and their contribution to psoriatic disease pathogenesis.

/pdf/clinical-and-genetic-heterogeneity-of-card14-mutations-in-44ujoeb0at.pdf

Clinical and Genetic Heterogeneity of CARD14 Mutations in Psoriatic Skin Disease.

CARMA proteins represent a family of scaffold molecules which play several crucial biological functions, including regulation of immune response and inflammation, tissue homeostasis, and modulation of G-Protein Coupled Receptor (GPCR) signaling. Among the CARMA proteins, CARD14/CARMA2 and its alternatively spliced isoforms are specifically expressed in epithelial cells and keratinocytes. Recent evidences have shown that CARD14/CARMA2 mediates induction of inflammatory response in keratinocytes, and that mutations in CARD14/CARMA2 gene segregate with familial transmission of chronic inflammatory disorders of the human skin. Similarly to CARD11/CARMA1 and CARD10/CARMA3, CARD14/CARMA2 signaling occurs trough formation of a trimeric complex which includes BCL10 and MALT1 proteins. However, it is becoming increasingly evident that in addition to the CBM complex components, a number of accessory molecules are able to finely modulate the signals conveyed on and amplified by CARD14/CARMA2. The study of these molecules is important both to understand the molecular mechanisms that underlie the role of CARMA2 in keratinocytes and because they represent potential therapeutic targets for the development of therapeutic strategies aiming at the treatment of inflammatory diseases of the human skin. In this review, we provide an overview on the molecular mechanisms mediating CARD14/CARMA2 signaling and its implication in our understanding of the pathogenesis of human inflammatory skin disorders.

/pdf/card14-carma2-signaling-and-its-role-in-inflammatory-skin-2msn8kk8gu.pdf

CARD14/CARMA2 Signaling and its Role in Inflammatory Skin Disorders.

Autoinflammatory diseases (AID) are a genetically heterogeneous group of diseases caused by mutations of genes encoding proteins which play a pivotal role in the regulation of the inflammatory response. In the pathogenesis of AID, the role of the genetic background is triggered by environmental factors through the modulation of the innate immune system. Monogenic AID are characterized by Mendelian inheritance and are caused by highly penetrant genetic variants in single genes. During the last years, remarkable progress has been made in the identification of disease-associated genes by using new technologies, such as next generation sequencing (NGS), which has allowed the genetic characterization in undiagnosed patients and in sporadic cases by means of targeted resequencing of a gene panel and whole exome sequencing. In this review, we delineate the genetics of the monogenic AIDs, report the role of the most common gene mutations and describe the evidences of the most sound genotype/phenotype correlations in AID.

/pdf/monogenic-autoinflammatory-diseases-with-mendelian-495m3ziaud.pdf

Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations.

SummaryBackground
Rare highly penetrant gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) can lead to psoriasis, a chronic inflammatory disease of the skin and other organs.

Objectives
To investigate the contribution of rare CARD14 variants to psoriasis in the Tunisian population and to expand knowledge of CARD14 variants in the European population.

Methods
CARD14 coding exons were resequenced in patients with psoriasis and controls from Tunisia and Europe, including 16 European cases with generalized pustular psoriasis (GPP). Novel variants were evaluated for their effect on nuclear factor (NF)-κB signalling.

Results
Rare variants in CARD14 were significantly enriched in Tunisian cases compared with controls. Three were collectively found in 5% of Tunisian cases, and all affected the N-terminal region of the protein harbouring its caspase recruitment domain or coiled-coil domain. These variants were c.349G>A (p.Gly117Ser), c.205C>T (p.Arg69Trp) and c.589G>A (p.Glu197Lys). c.589G>A (p.Glu197Lys) led to upregulation of NF-κB activity in a similar manner to that of previously described psoriasis-associated mutations. p.Arg69Trp led to sevenfold downregulation of NF-κB activity. One Tunisian case harboured a c.1356+5G>A splice alteration that is predicted to lead to loss of exon 9, which encodes part of the coiled-coil domain. No cases of GPP harboured an interleukin-36RN mutation, but one of 16 cases of GPP with a family history of psoriasis vulgaris harboured a c.1805C>T (p.Ser602Leu) mutation in CARD14.

Conclusions
These observations provide further insights into the genetic basis of psoriasis in the Tunisian population and provide functional information on novel CARD14 variants seen in cases from Tunisia and other populations.

/pdf/card14-alterations-in-tunisian-patients-with-psoriasis-and-4ichszi3y3.pdf

CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.

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CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.