Genetics of Psoriasis: Evidence for Epistatic Interaction between Skin Barrier Abnormalities and Immune Deviation

Abstract

Psoriasis was until recently regarded as a T-cell-driven disease with presumed (auto)immune mechanisms as its primary cause. This view was supported by clinical data and genetic studies that identified risk factors functioning in adaptive and innate immunity, such as HLA-C*06, ERAP1, the IL-23 pathway, and NF-k B signaling. Candidate gene approaches and genome-wide association studies, however, have identified copy number polymorphisms of the b-defensin cluster and deletion of late cornified envelope (LCE) 3B and 3C genes (LCE3C_LCE3B-del) as psoriasis risk factors.As these genes are expressed in epithelial cells and not by the immune system, these findings may cause a change of paradigm for psoriasis, not unlike the reported filaggrin association that has profoundly changed the views on atopic dermatitis. In addition to genetic polymorphisms of the immune system, genetic variations affecting the skin barrier are likely to contribute to psoriasis. Recent studies have shown epistatic interactions involving HLA-C*06, ERAP1, and LCE3C_LCE3B-del, which makes psoriasis a unique model to investigate genetic and biological interactions of associated genes in a complex disease. We present a model for disease initiation and perpetuation, which integrates the available genetic, immunobiological, and clinical data.

A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia

“…Secondarily, the epidermis itself produces a range of cytokines and chemokines that help maintain the disease (3)(4)(5)(6)(7)(8)(9)(10)(11). While copy number polymorphisms in the β-defensins and deletions of the LCE3C/B locus have been associated with psoriasis (12), a primary role for epidermal defects in the pathogenesis of psoriasis is controversial. In particular, it is unknown whether epidermal repair pathways play important roles in the disease and whether such pathways interact with infiltrating immune cells.…”

Analysis of protein–protein interaction between late cornified envelope proteins and corneodesmosin

“…HLA-C*06 in PSORS1 and deletion of the late cornified envelope (LCE) 3B and 3C genes (LCE3C-LCE3B-del) in PSORS4 are known genetic risk factors for this disease (2). The LCE gene family consists of 18 members divided into six groups LCE1-LCE6 (3), which are located on chromosome 1q21 in a region called the epidermal differentiation complex (4).…”

Are Newly Discovered Drivers of Immune-Mediated Skin Disorders Expressed in Normal Skin Regenerating from Standardized Surface Injury?

“…The skin barrier function results from the physical properties of the outer layer of the epidermis, the stratum corneum, which exists out of terminally differentiated keratinocytes [1,2]. Recently, research showed that the epidermal compartment, in more particular the skin barrier function, is involved in the pathogenesis of immune-mediated skin disorders such as atopic dermatitis [3] and psoriasis [4]. In addition, some skin diseases such as lichen planus, vitiligo and psoriasis arise at sites of a disrupted skin barrier, which is known as the Koebner phenomenon [5].…”