Cytokines as genetic modifiers in K5 super(-/-) mice and in human epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) is a skin disorder caused by fully-penetrant mutations in the keratin genes KRT5 and KRT14, leading to extensive cytolysis and cell fragility of basal keratinocytes. EBS is subject to environmental conditions and displays high intra- and interfamilial variability, suggesting modifying loci. Here, we demonstrate that upregulation of certain cytokines accompanies mutations in keratin 5 (K5) but not in keratin 14 (K14). We find for the first time that cytokines macrophage chemotactic protein (MCP)-1/[chemokine (C-C motif) ligand 2] (CCL2), macrophage inflammatory protein (MIP)-3 beta /CCL19 and MIP-3 alpha /CCL20, all regulated by nuclear factor kappa B (NF Kappa B) and involved in the recruitment, maturation, and migration of Langerhans cells (LCs) in the epidermis, are upregulated in the skin of K5 super(-/-), but not of K14 super(-/-) mice. In neonatal K5 super(-/-) epidermis, the number of LCs was increased two-fold. At the same time, tumor necrosis factor alpha (TNF alpha ) remained unaltered, demonstrating the specificity of that process. Most remarkably, enhanced LC recruitment within the epidermis was found in five EBS patients carrying mutations in the KRT5 gene but not in EBS patients with KRT14 gene mutations. In agreement with the NF Kappa B-dependent regulation of these cytokines, we found a decrease in p120-catenin in the basal epidermis of K5 super(-/-) mice. These data provide the first explanation for distinct, keratin-type-specific genotype-phenotype correlations in EBS and represent a rationale to investigate gene loci affecting skin pathology in EBS. Hum Mutat 0, 1-10, 2009.