Epidermolysis bullosa (EB) is a group of autosomal dominant and recessive blistering skin diseases in which pathogenic mutations have been reported in 13 different genes encoding structural proteins involved in keratinocyte integrity, as well as cell-matrix or cell-cell adhesion. We now report an inherited skin fragility disorder with a homozygous nonsense mutation in the dystonin gene (DST) that encodes the coiled-coil domain of the epithelial isoform of bullous pemphigoid antigen 1, BPAG1-e (also known as BP230). The mutation, p.Gln1124X, leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduced labeling for plectin, the beta4 integrin subunit, and for type XVII collagen. The 38-year-old affected individual has lifelong generalized trauma-induced spontaneous blisters and erosions, particularly around the ankles. In addition, he experiences episodic numbness in his limbs, which started at the age of 37 years. These neurological symptoms may also be due to DST gene mutation, although he has a concomitant diagnosis of CADASIL (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy), a cerebral small-vessel arteriopathy, which thus complicates the genotype-phenotype interpretation. With regard to skin blistering, the clinicopathological findings expand the molecular basis of EB by identifying BPAG1-e pathology in a new form of autosomal recessive EB simplex.

Psoriasis has been considered an autoimmune, T cellmediated disorder in which adaptive immune responses predominate over those of non-antigen-specific innate immunity. To test this hypothesis, we profiled the transcriptome of psoriatic tissue and compared the data with that from cultured human keratinocytes exposed to the proinflammatory cytokine interleukin (IL)-1␣ and the Th1 cytokine interferon-␥. When compared with patient-matched, nonlesional skin biopsies, psoriatic samples exhibited regulation of 90 transcripts including several members of the epidermal differentiation complex, molecules with antimicrobial activity, and hyperproliferation-associated keratins. Stimulation of keratinocytes with interferon-␥ resulted in regulation of 252 transcripts, with particularly strong expression of the CXCR3-binding ligands CXCL9, -10, and -11 and class II major histocompatibility complex genes, primarily those of the HLA-DR and -DP families. In contrast, the transcriptome resulting from exposure of keratinocytes to IL-1␣ elicited differences in just 19 transcripts, particularly genes within the epidermal differentiation complex and antimicrobial molecules, including PI3 and DEFB4. Major differences between the two keratinocyte transcriptomes were exhibited with only five induced IL-1␣ transcripts also regulated in the interferon-␥ set. Unexpectedly, there was a high correlation between psoriatic lesional tissue and the IL-1␣ transcriptome. These findings suggest that the inflammatory milieu in the epidermal microenvironment in psoriasis is more likely dependent on evolutionarily ancient cytokines such as IL-1, rather than those of the adaptive immune response. (Am J

Psoriasis is an inflammatory skin disease of unknown origin, but with a clear genetic component. The strongest genetic association has been found with the major histocompatibility complex (MHC) region, and specifically between susceptibility to familial early onset psoriasis and human leukocyte antigen (HLA)-Cw6. The basis of this association of the HLA-C locus with disease pathogenesis is, however, not clear, and it is possible that other genes, or a combination of genes, in the HLA region are of functional importance. The MHC S gene is expressed specifically in keratinocyte differentiation and, being located 160 kb telomeric of HLA-C, is a plausible candidate gene. We analysed the allelic distribution of two polymorphisms in the MHC S gene (at +619 and +1243) in a case-control association study. We could confirm a significant association between psoriasis and HLA-Cw6 [odds ratio (OR) = 7.75]. No association was found between disease (or any subtypes) and the MHC S gene polymorphism at position +619, despite its close proximity to HLA-C and the strong linkage disequilibrium between the loci. However, a significant trend with the rarer allele at MHC S (+1243) and psoriasis was detected in the overall data set (OR = 2. 66; P = 2 [times] 10(-)9). This effect was most pronounced in the type 1a (early onset) psoriatics (OR = 3.43). Furthermore, homozygosity for the associated allele at MHC S (+1243) increased the risk of disease over that for carriage of HLA-Cw6 alone (OR = 9. 38), suggesting that allele 2 of MHC S (+1243) provides an additional risk in psoriasis susceptibility. The strong association found here, coupled with the biological involvement of the MHC S gene product corneodesmosin in skin physiology, implicates this locus (or a haplotype across HLA-C and MHC S ) in the impaired desquamation characteristic of psoriasis.