On the Role of the Epidermal Differentiation Complex in Ichthyosis Vulgaris, Atopic Dermatitis and Psoriasis

S. Hoffjan; S. Stemmler

Disclosures

The British Journal of Dermatology. 2007;157(3):441-449. 

In This Article

Role of the Epidermal Differentiation Complex in the Pathogenesis of Psoriasis

Psoriasis is another chronic inflammatory skin disease, characterized by thick, silvery-scale patches.[52] First symptoms usually occur within the third decade of life, and the prevalence of psoriasis is between 1 and 3% worldwide.[53] The skin disease psoriasis can be accompanied by psoriatic arthritis in 10-30% of cases.[53] Similarly to AD, a multifactorial pathogenesis is evident for psoriasis.[53] Yet, the mechanisms of skin inflammation in these two common skin diseases are quite different.[35] In contrast to the Th2-dominated immune response in AD, the immune response in psoriasis is predominated by Th1 cytokine production (e.g. IL-12 and interferon-γ) and associated with local neutrophil infiltration.[35]

Several genome screens for psoriasis have been completed to date that revealed that the HLA region on chromosome 6p21 harbours the main determinant for psoriasis susceptibility (this locus has been named PSORS1).[53] Additionally, several other susceptibility loci for this disease have been described. Among others, suggestive evidence for linkage to chromosome 1q21 (PSORS4) was found in the Italian population[54] which overlapped with the linkage signal for AD in the British population[37] (see above) and the Italian population.[55] Yet, the susceptibility variant responsible for this linkage signal has not yet been identified. Fine mapping of the PSORS4 locus in Italian families pointed to the genomic region containing the loricrin gene (LOR),[55] and loricrin expression was found to be low in affected individuals.[56] Yet, resequencing of the entire LOR gene in Italian psoriasis patients and analysis of association with the disease did not support a role of variation in this gene for psoriasis pathogenesis.[56] Similarly, some S100 proteins were found to be overexpressed in psoriatic skin[57] but association of genetic variation in S100 genes with disease susceptibility has not been reported. A coding polymorphism in the S100A2 gene was identified (Asn62Ser) but did not show association with the disease in a small American case-control cohort.[58] Similarly, the S100A7 gene was examined for variation and excluded as a candidate gene for psoriasis.[59] Recently, polymorphisms in two peptidoglycan recognition protein genes within the EDC, PGLYRP3 and PGLYRP4, were evaluated for an association with psoriasis in two independent patient cohorts.[60] While in the family-based analysis several polymorphisms and haplotypes were significantly associated with psoriasis, the case-control cohort did not show any association with disease.[60] These somewhat conflicting results still await replication in additional populations. In a very recent report, the two FLG loss-of-function mutations (R501X and 2282del4) were evaluated in German patients with psoriasis or psoriatic arthritis, and no association with disease was found despite a markedly altered filaggrin expression in psoriatic skin.[61]

In conclusion, there is initial evidence from linkage as well as expression studies that genetic variation within the EDC might also contribute to psoriasis susceptibility. Yet, the susceptibility variation(s) in this region have not been elucidated to date. Lack of association of FLG mutations with psoriasis in a first report suggests that the genetic background underlying the epidermal barrier defect in psoriasis might be different from that found in AD,[61] but additional studies of FLG mutations in psoriasis are warranted in order to confirm this result. Further, analysis of variation in other EDC genes might shed light on the role of heritable skin barrier defects in psoriasis.

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