Structural and immunological barriers of the skin as potential therapeutic targets

Skin is the structure that covers our body and protects it from not only the entry of pathogens or allergens but also from the leakage of water, solutes or nutrients. These outside-in and inside-out skin barrier functions are dependent on the epidermis, a stratified epithelial cellular sheet. While mucus covers the epidermis in fish and amphibian tadpoles, terminally differentiated cornified cellular sheets called stratum corneum (SC) constitute the outermost epidermal barrier in amphibian adults, reptiles, birds and mammals. Beneath the mucus or SC, apical paracellular spaces of epidermal cells are sealed with tight junctions (TJs) that limit paracellular leakage of water and electrolytes to maintain fluid homeostasis. We applied time-of-flight secondary-ion-mass-spectrometry (TOF-SIMS) imaging technology to analyze the SC in skin sections, and found that the SC consisting of three layers of distinct functional properties. Under the barriers of the SC and TJ, antigen-presenting dendritic cells called Langerhans cells (LCs) distribute within the epidermis. LCs elongate their dendrites to penetrate through epidermal TJs upon activation and uptake antigens from extra-TJ environment. During antigen uptake, new TJs are formed between keratinocytes and LC dendrites to maintain the integrity of epidermal TJ barriers. To understand the epidermal barrier system and its deficiency observed in human skin diseases, we need to re-evaluate human epidermal barrier as a composite barrier consisting of SC and TJs and to investigate the molecular mechanism and immunological consequences of the extra-TJ antigen uptake activity of LCs.