Clinical and Genetic Heterogeneity of CARD14 Mutations in Psoriatic Skin Disease

Abstract

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.

Malt1 Protease Deficiency in Mice Disrupts Immune Homeostasis at Environmental Barriers and Drives Systemic T Cell–Mediated Autoimmunity

“…This, together with the hyper reactivity of Malt1PD mice to food and other Ags from the intestinal lumen, prompted us to investigate whether Malt1 signaling in epithelial cells could render intestinal tight junctions more permissive for Ags present in the intestinal lumen. However, although CBM complex activation plays a role in both endothelial and epithelial cells (17,19,52,73,74), we could not demonstrate a dominant role for Malt1 signaling in the nonhematopoietic compartment in driving the exacerbation of DSS-induced colitis. Instead, we confirmed the hematopoietic compartment as major driver of the Malt1PD mouse pathologic condition (26)(27)(28)(29) and propose that, rather than defective Malt1 signaling in epithelial cells, the disrupted intestinal immune homeostasis consequent to the global reduction of nTregs and iTregs in lymphoid organs and in the local gut environment is the main factor driving the loss of the intestinal barrier and the consequent induction of Abs against commensal Ags.…”

An update on generalized pustular psoriasis

“…Other gene mutations have been identified in different groups of patients with GPP (and related conditions) that lead to an enhanced inflammatory cascade and the recruitment of neutrophils and macrophages. These include mutations in CARD14 encoding caspase-activating recruitment domain member 14 and AP1S3 encoding adaptor protein complex 1 subunit sigma 3 ( Supplementary Table 1) [18,20,33,34,[38][39][40][41][42][43][44][45].…”

Germline CBM-opathies: From immunodeficiency to atopy

“…Autosomal dominant GOF CARD14 mutations are linked to psoriasis and the phenotypically related skin condition pityriasis rubra pilaris (PRP). [45][46][47]91 This link was first established in 2012 through genome-wide linkage analyses, which localized CARD14 to the psoriasis risk locus called psoriasis susceptibility locus 2. 92 Since then, more than 10 GOF CARD14 mutations have been linked to psoriatic skin disease, with even more variants found to be associated with this phenotype in linkage studies (Fig 3).…”

“…However, many variants have not undergone rigorous functional validation, and it is unclear whether certain variants have a causative or a predisposing role in disease. 8,91 The majority of these mutations and variants were heterozygous (some were compound heterozygous/homozygous), and most localized to the CARD and CC domains of CARD14. This distribution of genetic variation is similar to that of CARD11 in BENTA and in a similar fashion also disrupts CARD14 autoinhibition, causing constitutive assembly of CARD14-BCL10-MALT1 and NF-kB activation.…”