BACKGROUND:The Fas/Fas Ligand (Fas/FasL) system mediates key physiological and pathological pathways. Therapies targeting this system are currently unavailable due to the complexity of the Fas/FasL pathway and the side effects associated with reduced apoptosis of cancer cells and the lack of regulation of the immune system. PC111 is a human monoclonal antibody that uniquely targets the soluble (s) but not the membrane-bound (m) FasL, the latter being responsible for immunosurveillance and cancer; the selective mode of action of PC111 precludes its interference with the latter mechanisms. We showed previously that selective blocking soluble FasL (sFasL) could be an effective non-immunosuppressive treatment in mouse models of Pemphigus (PV) and Stevens-Johnson/toxic epidermal necrolysis (SJS/TEN). AIM:To identify additional diseases where sFasL is elevated and potentially involved in their pathogenesis. FINDINGS:sFasL is up regulated in drug reaction with eosinophilia and systemic symptoms. Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren syndrome also have elevated levels of sFasL that are involved in some of the mechanisms underlying the diseases. Finally, sFasL is elevated in the bronchoalveolar lavage (BAL) and plasma of Acute Respiratory Distress Syndrome, while blocking sFasL reverses apoptosis in lung epithelial cells, thus reducing mortality. CONCLUSION:By selectively blocking sFasL, one could potentially modify the course of several diseases.

BACKGROUND:Pemphigus vulgaris (PV) is a chronic autoimmune blistering disease with high morbidity and mortality, treated mainly with long-term immunosuppressants. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is an acute, life-threatening drug reaction with severe skin and mucosal involvement. No approved therapies currently exist for SJS/TEN. AIM:To demonstrate that the soluble form of Fas ligand (sFasL) is a relevant therapeutic target in both PV and SJS/TEN, and to provide evidence that PC111, a fully human monoclonal antibody against sFasL, is effective in both conditions. EVIDENCE REVIEW:In PV, autoantibodies (PVIgG) target desmogleins, leading to blistering via signaling cascades. sFasL, released upon PVIgG binding, contributes to this process by promoting desmoglein degradation and acantholysis. In SJS/TEN, elevated sFasL induces keratinocyte apoptosis, contributing to epidermal detachment. FINDINGS:PC111 blocks acantholysis and blister formation in PV through a local, rapid mechanism, downstream of the immune system, thus differentiating from the currently used immunosuppressive treatments. In SJS/TEN, PC111 prevents keratinocyte apoptosis induced by patient serum and improves ocular symptoms in a mouse model. Its fast action suggests potential for early intervention to halt disease progression. CONCLUSIONS:PC111 may act as a disease-modifying agent, promoting long-term remission in PV and preventing progression in early-stage SJS/TEN.

Psoriasis is a chronic inflammatory skin disease characterized by dysregulation of the interleukin 17 (IL-17) signaling axis. Given that psoriasis development depends on keratinocyte stem cells and early progenitors’ sensitivity to differentiation, we analyzed IL-17 ligands and the expression and function of in a novel subset of keratinocyte subpopulations: keratinocyte stem cells (KSC) and early and late Transit Amplifying (ETA or LTA, respectively) cells. We found that all subpopulations expressed all IL-17 variants, predominantly in ETA and LTA. Conversely, IL-17 receptor expression resulted in more heterogeneity, with IL-17RA, -C, and -E being the most differentially regulated. Stimulus with IL-17A, IL-17-F, IL-17-A/F, and IL-17C promotes the upregulation of CXCL1, CXCL8, and DEFB4 mRNAs expression in both KSC and ETA. Moreover, IL-17A and IL-17A/F mainly decrease KSC proliferation and promote cell cycle block. Globally, IL-17A and IL-17A/F modulated the expression of proliferation, differentiation, and psoriasis-associated markers. Furthermore, KSC- and ETA-derived 3D reconstructions displayed increased epidermal thickness and upregulated KRT16 expression after treatment with IL-17A or IL-17A/F. Therefore, our data demonstrated that IL-17 family members perform distinctive functions in a specific keratinocyte subpopulation and define IL-17 signaling as a critical modulator of KSC behavior, proving its role in epidermal homeostasis dysregulation of psoriasis.

Background Atopic dermatitis (AD) is a chronic inflammatory skin condition, considered to be the most common cutaneous-related disease in children; early management in infancy with treatments of acceptable efficacy and safety has been recognized as important for outcomes.Methods An international panel of six European dermatologists and pediatric specialists was formed to discuss and develop a practical algorithm for the management of AD in pediatric patients in a European setting. The discussion combined a comprehensive review of published literature with clinical experience.Results Current guidelines recommend topical corticosteroids (TCS) as a first-line anti-inflammatory treatment for short-term AD flares, with specific recommendations for pediatric populations and sensitive areas of skin; however, due to the lack of long-term utility and associated side effects with TCS, there is a need for alternative treatments.Conclusion In this article, we propose an algorithm for a TCS-sparing treatment strategy, focusing on topical calcineurin inhibitors for the management of mild-to-moderate AD in infants and children, including AD of sensitive skin areas. This algorithm is intended as a supplementary tool to the current international and national evidence-based treatment guidelines, and to aid physicians who see and treat children with AD in their clinical practice.

The involvement of the neurotrophin network in pathological skin conditions, such as psoriasis or squamous cancer, by their common neurotrophin receptor CD271 has become recently evident. Depending on the specific ligand and co-receptor interacting with it, CD271 mediates various cellular responses in keratinocytes. In vitro analysis shows that it is implicated in the transition from human interfollicular keratinocyte stem cells to transient amplifying cells. However, no in vivo models are available to dissect the complexity of these mechanisms, including the effect on the inflammatory response. Here, we develop and characterize two novel mouse models, the CD271cKO and the CD271ciKO, where CD271 is conditionally absent in keratinocytes during development or after topical induction, respectively. By histology, functional assay, transcriptomics and molecular analysis, we identified substantial skin changes correlated to CD271 deletion, including epidermal hyperproliferation, “activated” keratinocyte signature, and a delayed in the differentiation process, mostly linked to PI3K/Akt and mitogenic pathways-dependent processes. KO keratinocyte displays upregulation of Ki67, PCNA, KRT5, KRT6, and ERK phosphorylation, as well as major expression of IL1α, Cxcl15, and TGFβ. KO skin resemble dysplastic skin conditions, including the recruitment of immune cells, particularly T cells, macrophages, and neutrophils, and release of inflammatory cytokines involved in TNF, JAK/Stat, IL17, and PI3k/Akt signaling pathways. Overall, our data defines CD271 as a crucial regulator of skin homeostasis. Therefore, our models represent an exceptionally useful tool for the characterization of skin pathophysiology linked to CD271 and possibly for developing appropriate therapies.

In the interfollicular epidermis, keratinocyte stem cells (KSC) generate a short-lived population of transit amplifying (TA) cells that undergo terminal differentiation after several cell divisions. Recently, we isolated and characterized a highly proliferative keratinocyte cell population, named “early” TA (ETA) cell, representing the first KSC progenitor with exclusive features. This work aims to evaluate epidermis, with a focus on KSC and ETA cells, during transition from infancy to childhood. Reconstructed human epidermis (RHE) generated from infant keratinocytes is more damaged by UV irradiation, as compared to RHE from young children. Moreover, the expression of several differentiation and barrier genes increases with age, while the expression of genes related to stemness is reduced from infancy to childhood. The proliferation rate of KSC and ETA cells is higher in cells derived from infants’ skin samples than of those derived from young children, as well as the capacity of forming colonies is more pronounced in KSC derived from infants than from young children’s skin samples. Finally, infants-KSC show the greatest regenerative capacity in skin equivalents, while young children ETA cells express higher levels of differentiation markers, as compared to infants-ETA. KSC and ETA cells undergo substantial changes during transition from infancy to childhood. The study presents a novel insight into pediatric skin, and sheds light on the correlation between age and structural maturation of the skin.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a severe spectrum of rare mucocutaneous reactions, primarily drug-induced and characterized by significant morbidity and mortality. These conditions manifest through extensive skin detachment, distinguishing them from other generalized skin eruptions. The rarity and severity of SJS/TEN underscore the importance of accurate diagnostic criteria and effective treatments, which are currently lacking consensus. This review proposes new diagnostic criteria to improve specificity and global applicability. Recent advancements in understanding the immunopathogenesis of SJS/TEN are explored, emphasizing the role of drug-specific T cell responses and HLA polymorphisms in disease onset. The review also addresses current therapeutic approaches, including controversies surrounding the use of immunosuppressive agents and the emerging role of TNF-α inhibitors. Novel therapeutic strategies targeting specific pathogenic mechanisms, such as necroptosis and specific immune cell pathways, are discussed. Furthermore, the development of new drugs based on these insights, including targeted monoclonal antibodies and inhibitors, are examined. The review concludes by advocating for more robust and coordinated efforts across multidisciplinary medical fields to develop effective treatments and diagnostic tools for SJS/TEN, with the aim of improving patient outcomes and understanding of the disease and its mechanisms.

CD271 overexpression strongly enhances Aβ(25-35) killing effect.

Evaluation of the role of CD271 in drug resistance

CD271 silencing reduces Aβ(25-35) killing effect.

Recently, the involvement of the ionic channel TPC2 in cancer has gained increasing attention, since it regulates numerous cellular functions, such as proliferation, autophagy and angiogenesis, by releasing Ca2+ in response to the second messenger NAADP. TPC2 is also implicated in all the major steps of tumor metastasis, namely adhesion, migration, and invasion. The aim of the project was to study the role of TPC2 in melanoma with different aggressiveness and microenvironments. TPC2 expression is mostly localized in tumor areas in human primary melanoma and metastatic melanoma. Moreover, the number of TPC2 positive cells in melanoma increases proportionally to the Breslow Index. Similarly, using the Cancer Genome Atlas, TPC2 mRNA is differentially expressed within primary melanomas, with an increase that correlates with a higher Breslow Index. In vitro, TPC2 inhibition by Naringenin (Nar) decreases the growth of melanoma spheroids in a dose and time dependent manner. The decrease was confirmed by TPC2 silencing. Moreover, TPC2 inhibition induces the epithelial mesenchymal transition marker switch and decreases the collagen invasion in 3D melanoma models. Nar also acts as chemosensitizing agent, inhibiting spheroid growth, when used in combination with the existing chemotherapeutic dacarbazine. Finally, Nar treatment increases melanosomal marker expression but affect the processing or trafficking of PMEL17, decreasing melanosome secretion and consequently the migratory capacity of cancer-associated fibroblasts. These results indicate that TPC2 plays an active role in melanoma and may be an attractive target for drug development.