Psoriasis: genetic associations and immune system changes

Abstract

Psoriasis is a common inflammatory skin disease characterized by infiltration of inflammatory cells into the epidermis and altered keratinocyte differentiation. Psoriasis is currently thought of as a T-cell mediated 'Type-1' autoimmune disease. Gene expression changes in psoriasis lesions have been well documented, and strongly support an important role for tumor necrosis factor and interferon gamma signal pathways in its pathogenesis. The strongest genetic determinant of psoriasis identified to date lies within the class I region of the multiple histocompatibility locus antigen cluster, although its low penetrance implicates a requirement for other genetic risk factors. Multiple genome-wide linkage and an increasing number of association studies have been carried out, leading to multiple linkage peaks, and the identification of potential low risk variants. A number of these variants lie within genes encoding components of the immune system. However, the functional relationships between predisposing genetic variation is unclear, and presumably involves genetic susceptibility factors affecting both immune cell activation and keratinocyte differentiation. The interaction of environmental trigger factors with genetic effects is also not understood, but provide further evidence for the complex basis of this disease.

Keratinocyte differentiation induced by calcium, phorbol ester or interferon-γ elicits distinct changes in the retinoid signalling pathways

“…Although the authors did not explore the mechanism of inhibition, their results are very similar to ours. Furthermore, in a recent study we reported failure of exogenous RA to induce CRABPII in psoriatic skin lesions [25], where IFNγ is markedly increased due to the inflammatory process [35].…”

“…The proinflammatory agents, PMA and IFNγ, are also powerful inducers of keratinocyte differentiation in vitro, although their mechanisms of action are different [32][33][34]. PMA is an activator of the protein kinase C (PKC) -AP-1 signalling pathway and as such a potent inducer of skin tumours, whereas IFNγ elicits a gene response resulting in skin inflammation [35]. The aim of the study was, by using these stimuli and co-addition of various synthetic retinoids and inhibitors of AP-1 activity, to try and correlate the differentiation process to changes in the retinoid signalling pathways of human keratinocytes.…”

Psoriasis: crucial role of LXR-α RNomics

“…5,6 The nuclear receptor LXR-a has a welldocumented role in cholesterol homeostasis and inflammation. 7 Recently, the LXR-a gene has caught the imagination of dermatologists, 8,9 keeping in view the fact that LXR-a has crucial role in keratinocyte proliferation and differentiation.…”

Strong associations of psoriasis with antigen processing LMP and transport genes TAP differ by gender and phenotype

“…Strong evidence suggests a multilocus model of inheritance in association with environmental factors. 1 The etiology of the disease is still unclear. In several cases, however, low molecular weight chemicals (LMWC), such as drugs, were identified as etiologic agents, and variants of genes responsible for metabolizing LMWC are risk factors.…”