Psoriasis is an inflammatory disease of the skin that is mediated by T cells, dendritic cells (DCs), and a broad range of cytokines and chemokines. However, much of the clinical disease phenotype is caused by hyperplasia of epidermal keratinocytes, altered differentiation of these cells in a 'regenerative' pathway and increased growth of dermal blood vessels (causing thick, red, scaly plaques on the skin surface).Psoriasis has been proposed to be a T-cell-mediated autoimmune disease, because clonal populations of T cells have been identified in skin lesions and the overall characteristics of these T cells indicate that they are T helper 1 cells and type 1 cytotoxic T-cell effectors. However, as reactivity to a self-antigen has not been shown, others have suggested that immune activation in the skin is triggered through innate immune pathways stimulated by Toll-like receptors, heat-shock-protein receptors or glycolipid-antigen receptors.The molecules that are involved in pathogenic inflammation in the skin have been defined by large-scale gene-expression studies, and many interactive pathways of inflammation have been suggested to occur. Two ideas that stem from this work are that, first, lymphoid tissue (self-perpetuating infiltrates of T cells and DCs) is organized in the skin by local expression of chemokines and that, second, a 'type 1' pathway of inflammatory gene products (involving interleukin-23, interferon-γ and signal transducer and activator of transcription 1) is central to pathogenic inflammation in psoriasis.There is a strong interrelationship between regenerative growth of the epidermis (as programmed for wound healing) and activation of cellular immunity through innate and adaptive immune pathways. Genes that confer susceptibility to psoriasis could alter keratinocyte differentiation responses, cellular immune responses or common molecular pathways that control the balance of epithelial-cell hyperplasia and immune activation in the skin.Approximately half of all patients with psoriasis have a susceptibility variant from the MHC class I region. However, some patients can develop psoriasis without any contribution from the MHC locus. In most cases, several genetic variants are required for disease to develop. Genetic studies of families have localized 20 such loci.So far, only a handful of psoriasis-susceptibility genes have been identified in a single population. Their role in disease pathogenesis and the effect of environmental triggers on these genes is not clear.One susceptibility variant for psoriasis that maps to human chromosome 17q25 has been shown to result in the loss of an enhancer binding site for the RUNX (runt-related transcription factor) family of transcription factors. Changes in RUNX-binding sites have also been seen at different loci in individuals with either systemic lupus erythematosus or rheumatoid arthritis, indicating that some changes in psoriasis are within pathways that are altered in other autoimmune diseases.Several variants for psoriasis and other autoimmune or inflammatory diseases reduce the threshold for T-cell activation or affect immunological synapse formation or dissolution.
