Psoriasis genetics: breaking the barrier

Abstract

Psoriasis is a common incurable inflammatory skin disease affecting 2-3% of the European population. Psoriatic skin contains large numbers of immune cells which produce many cytokines, chemokines and inflammatory molecules. The epidermis divides much faster than normal and has a defective outer layer or barrier which under normal circumstances protects from infection and dehydration. Psoriatic skin is characterized by a distinct set of inflammation and epidermal proliferation and differentiation markers, and it has not been clear if the genetic basis of psoriasis is due to defects of the immune system or the skin. One genetic determinant lies within the major histocompatibility complex class 1 region. Genome-wide association studies have revealed genetic susceptibility factors that play a role in the formation of immune cells found in psoriasis lesions. Others affect epidermal proliferation and the formation of the skin's barrier. Hence, genetic components of both the immune system and the epidermis predispose to disease. Psoriasis: a common inflammatory skin disease with a genetic componentPsoriasis affects 2-3% of the European population, is rarer in individuals of Asian descent (0.1% or less), and exceedingly rare in Africa [1]. Initial outbreaks typically affect individuals in their twenties, but can occur at any age [2]. Psoriasis patients have a natural history of outbreaks (flares) followed by temporary remissions. Environmental factors can trigger or exacerbate flares. These factors include HIV infection [3], use of drugs such as lithium, betablockers, or anti-malarials, and the withdrawal of corticosteroids [4]. As many as 10-30% of psoriasis patients develop an inflammatory arthritis termed psoriatic arthritis which is progressive and leads to destruction of the joints if it is not treated aggressively [5]. Although psoriasis often appears sporadically, with patients having no family history of disease, it is a complex disease which includes a familial component. Having a family member with the disease will increase ones risk of being affected. Siblings of an individual with psoriasis are at a 4-6 fold increased risk of developing psoriasis compared to the general population [1].Psoriasis and psoriatic arthritis are serious, poorly understood, diseases. There are no cures and they require sophisticated medical care and treatments. Moreover, having psoriasis increases the risk of heart disease and stroke [6,7]. Recent developments in genetic analysis have been instrumental in highlighting important biological pathways in disease susceptibility. In the case of psoriasis genetic studies such as these are providing a far better understanding of the fundamental biological pathways leading to disease. It is expected that this in turn will lead to the development of better and specific forms of treatment. Here we review recent genetic * Corresponding author: Bowcock, A.M. (bowcock@genetics.wustl.edu).Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for public...

The Blood-Testis Barrier and Its Implications for Male Contraception

“…Introduction. Studies in multiple epithelia and/or blood-tissue barriers in various organs (e.g., kidney, small intestine, brain, eyes), including the BTB in adult mammalian testes, have demonstrated the role of cytokines, such as TNF␣, interferon-␥, TGF-␤2/-␤3, IL-1␣, and IL-12, in regulating TJ permeability barrier function under normal and pathological conditions (e.g., inflammation, tumorigenesis) (Walsh et al, 2000;Xia et al, 2005a;Lui and Cheng, 2007;Li et al, 2008Li et al, , 2009aCapaldo and Nusrat, 2009;Turner, 2009;Marchiando et al, 2010a;Roberson and Bowcock, 2010;John et al, 2011). It is noted that endocytic vesicle-mediated protein trafficking events (e.g., endocytosis, transcytosis, recycling, or intracellular protein degradation mediated by endosome-and/or ubiquitin-dependent pathways) that determine the levels of integral membrane proteins at the TJ barrier play a critical role in modulating the adhesive status of cell adhesion protein complexes (e.g., cadherins, occludins, JAMs, claudins) at the barrier, and protein endocytosis can be mediated by either clathrinor caveolae-dependent pathways or macropinocytosis (Tuma and Hubbard, 2003;Maxfield and McGraw, 2004;Mehta and Malik, 2006;Clague and Urbé, 2010;Golachowska et al, 2010;Hsu and Prekeris, 2010).…”

PAPD5-mediated 3′ adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease

“…Combined, the above indicates that disruptions in the degradation pathway of miR-21 are a hallmark of cancer across a wide range of tissues. We then asked whether disruption of the miR-21 degradation pathway is relevant in noncancerous proliferative diseases such as psoriasis, a skin disease characterized by increased proliferation of basal cells in the epidermis (42). Small RNA-sequencing data consisting of 67 patient samples of psoriatic and normal skin previously revealed (25) that at the molecular level psoriasis, like cancer, is characterized by elevated expression levels of miR-21 (Kruskal-Wallis P = 8.8e-11; Fig.…”

A20-binding inhibitor of NF-κB (ABIN1) controls Toll-like receptor-mediated CCAAT/enhancer-binding protein β activation and protects from inflammatory disease

“…SLE can affect almost any organ, including skin, brain, joints, and kidney; psoriasis initially is limited to the skin but in as many as 10-30% of cases progresses toward arthritis (2,3). Still, SLE and psoriasis seem to involve similar pathogenetic mechanisms, whereby tissue-derived nucleic acids, liberated upon cell death, form complexes with autoreactive antibodies (SLE) or antimicrobial peptides (psoriasis and SLE) that trigger specific TLRs (i.e., TLR9 and TLR7), thereby providing a possible link between tissue injury and perpetuation of inflammation (2)(3)(4)(5). Although such observations support the idea that TLRs and their signaling pathways are involved in the promotion of inflammatory disease, the etiology of both SLE and psoriasis is largely unclear.…”