Insights into psoriasis and other inflammatory diseases from large-scale gene expression studies

Abstract

Approximately 2% of the Caucasian population is affected by psoriasis (PS); a chronic inflammatory skin disease triggered by both genetic and environmental risk factors. In addition to a major contribution from the HLA class I region, PS susceptibility loci have been mapped to a number of regions including 1q21, 3q21, 4qter, 14q31-q32, 17q24-q25, 19p13.3 and 20p. Some of these overlap with loci implicated in other autoimmune/inflammatory diseases. Global gene expression studies are beginning to provide insights into the etiology of these and other complex diseases. We used Affymetrix oligonucleotide arrays comprising approximately 12 000 known genes to initiate a more comprehensive analysis of the transcriptional changes that occur in involved and uninvolved skin of 15 psoriatic patients versus six normal controls. Expression levels of the transcripts detected on the arrays were first used to determine the relationship of samples to each other using hierarchical clustering. This analysis clearly differentiated involved psoriatic skin from uninvolved and normal skin. Clusters of differentially expressed genes with similar expression patterns in the same samples were then identified. Six out of 32 clusters contained a total of 177 transcripts that were differentially expressed in involved psoriatic skin versus normal skin. These differences were independent of the gender, age, skin site and HLA class I status of the patient. Ten of the 177 genes were also differentially expressed in uninvolved skin, and several mapped to regions previously shown to harbor psoriasis susceptibility loci.

The Effects of IL-20 Subfamily Cytokines on Reconstituted Human Epidermis Suggest Potential Roles in Cutaneous Innate Defense and Pathogenic Adaptive Immunity in Psoriasis

“…These data suggest that IL-22 might be one of the primary soluble factors that link the adaptive immune response with KCs and innate immunity in the pathophysiology of psoriasis. Expression studies of psoriatic vs normal or uninvolved skin have identified altered expression of Ͼ1300 genes in psoriatic lesions (38,48,49). We demonstrated here that the genes regulated by IL-20 subfamily cytokines were highly correlated with genes modified in psoriatic skin, further supporting their potential roles in the pathogenesis of psoriasis.…”

“…Proteins of this family, whose genes are found in the epidermal differentiation complex, are calcium-binding proteins that are associated with inflammation, some of which have been shown to have chemotactic and direct antimicrobial activities (51)(52)(53). Other genes induced by the IL-20 subfamily cytokines and also in psoriatic skin include chemokines, angiogenic factors, tissue kallikreins, and ␤-defensins (38,48,49,71). Chemokines and angiogenic factors might further enhance proinflammatory responses through a positive feedback loop by recruiting additional leukocytes and promoting angiogenesis in the skin.…”

Characterization of the loricrin (LOR) gene as a positional candidate for the PSORS4 psoriasis susceptibility locus

“…(Nair et al 1997;Matthews et al 1996;Capon et al 1999;Enlund et al 1999;Lee et al 2000;Veal et al 2001). PSORS4 was originally identified in an Italian population (Capon et al 1999) and later independent replication of this linkage was obtained in 2001 (Bowcock et al 2001). Using linkage disequilibrium mapping we refined the PSORS4 susceptibility locus to a specific genomic interval of about 100 Kb where a single well-defined gene, loricrin (LOR), is located.…”

Up-regulation of corticotropin releasing hormone is associated with the downregulation of corticotropin releasing hormone binding protein and up-regulation of IL- 33 and IL-8 expression in psoriasis

“…In human, it is one of the prevalent T cell arbitrated inflammatory diseases. A highly elevated expression of cytokines has been reported in psoriasis which include but are not limited to IL-1, IL-6 and IL-12 [20]. CRH is an important stress induced hormone that has been reported to trigger immune response indirectly [21].…”