Regional Differences in the Permeability Barrier of the Skin-Implications in Acantholytic Skin Diseases.

The chemical milieu, microbiota composition, and immune activity show prominent differences in distinct healthy skin areas. The objective of the current study was to compare the major permeability barrier components (stratum corneum and tight junction (TJ)), investigate the distribution of (corneo)desmosomes and TJs, and measure barrier function in healthy sebaceous gland-rich (SGR), apocrine gland-rich (AGR), and gland-poor (GP) skin regions. Molecules involved in cornified envelope (CE) formation, desquamation, and (corneo)desmosome and TJ organization were investigated at the mRNA and protein levels using qRT-PCR and immunohistochemistry. The distribution of junction structures was visualized using confocal microscopy. Transepidermal water loss (TEWL) functional measurements were also performed. CE intracellular structural components were similarly expressed in gland-rich (SGR and AGR) and GP areas. In contrast, significantly lower extracellular protein levels of (corneo)desmosomes (DSG1 and CDSN) and TJs (OCLN and CLDN1) were detected in SGR/AGR areas compared to GP areas. In parallel, kallikrein proteases were significantly higher in gland-rich regions. Moreover, gland-rich areas were characterized by prominently disorganized junction structures ((corneo)desmosomes and TJs) and significantly higher TEWL levels compared to GP skin, which exhibited a regular distribution of junction structures. According to our findings, the permeability barrier of our skin is not uniform. Gland-rich areas are characterized by weaker permeability barrier features compared with GP regions. These findings have important clinical relevance and may explain the preferred localization of acantholytic skin diseases on gland-rich skin regions (e.g., Pemphigus foliaceus, Darier's disease, and Hailey-Hailey disease).

Rosacea Is Characterized by a Profoundly Diminished Skin Barrier.

Rosacea is a common chronic inflammation of sebaceous gland-rich facial skin characterized by severe skin dryness, elevated pH, transepidermal water loss, and decreased hydration levels. Until now, there has been no thorough molecular analysis of permeability barrier alterations in the skin of patients with rosacea. Thus, we aimed to investigate the barrier alterations in papulopustular rosacea samples compared with healthy sebaceous gland-rich skin, using RNA sequencing analysis (n = 8). Pathway analyses by Cytoscape ClueGO revealed 15 significantly enriched pathways related to skin barrier formation. RT-PCR and immunohistochemistry were used to validate the pathway analyses. The results showed significant alterations in barrier components in papulopustular rosacea samples compared with sebaceous gland-rich skin, including the cornified envelope and intercellular lipid lamellae formation, desmosome and tight junction organizations, barrier alarmins, and antimicrobial peptides. Moreover, the barrier damage in papulopustular rosacea was unexpectedly similar to atopic dermatitis; this similarity was confirmed by immunofluorescent staining. In summary, besides the well-known dysregulation of immunological, vascular, and neurological functions, we demonstrated prominent permeability barrier alterations in papulopustular rosacea at the molecular level, which highlight the importance of barrier repair therapies for rosacea.

Immunotopographical Differences of Human Skin.

The immunological barrier of the healthy skin is considered to be unified on the whole body surface-however, recent indirect findings have challenged this dogma since microbial and chemical milieu (e.g., sebum, sweat, and pH) exhibit remarkable differences on topographically distinct skin areas. Therefore, in the present study, we performed whole transcriptomic and subsequent pathway analyses to assess differences between sebaceous gland rich (SGR) and sebaceous gland poor (SGP) regions. Here, we provide the first evidence that different skin regions exhibit a characteristic innate and adaptive immune and barrier milieu as we could detect significantly increased chemokine (CCL2, 3, 19, 20, 23, 24) and antimicrobial peptide (S100A7, A8, A9, lipocalin, ß-defensin-2) expression, altered barrier (keratin 17, 79) functions, and a non-inflammatory Th17/IL-17 dominance in SGR skin compared to SGP. Regarding pro-inflammatory molecules (IL-1α, IL-6, IL-8, IL-33, TNF-α), similarly low levels were detected in both regions. Our data may explain the characteristic topographical localization of some immune-mediated and autoimmune skin disorders and we also propose that the term "healthy skin control sample," widely used in experimental Dermatology, should only be accepted if researchers carefully specify the exact region of the healthy skin (along with the site of the diseased sample).

Myeloid but not plasmacytoid blood DCs possess Th1 polarizing and Th1/Th17 recruiting capacity in psoriasis.

Psoriasis is a common inflammatory skin disease and dendritic cells (DCs) play crucial role in the development of skin inflammation. Although the characteristics of skin DCs in psoriasis are well defined, less is known about their peripheral blood precursors. Our aim was to characterize the phenotypic features as well as the cytokine and chemokine production of CD1c+ myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in the blood samples of psoriatic patients. Blood DCs were isolated by using a magnetic separation kit, and their intracytoplasmic cytokine production and CD83/CD86 maturation/activation marker expression were investigated by 8-colour flow cytometry. In CD1c+ mDCs the intracellular productions of Th1, Th2, Th17, Th22 and Treg polarizing cytokines were examined simultaneously, whereas in pDCs the amounts of IFNα as well as IL-12, IL-23 and IL-6 were investigated. The chemokine production of both DC populations was investigated by flow-cytometry and ELISA. According to our results psoriatic CD1c+ mDCs were in a premature state since their CD83/CD86 maturation/activation marker expression, IL-12 cytokine, CXCL9 and CCL20 chemokine production was significantly higher compared to control cells. On the other hand, blood pDCs neither produced any of the investigated cytokines and chemokines nor expressed CD83/CD86 maturation/activation markers. Our results indicate that in psoriasis not only skin but also blood mDCs perform Th1 polarizing and Th1/Th17 recruiting capacity, while pDCs function only in the skin milieu.