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Basophils are a rare type of granulocyte in peripheral blood. Owing to their accessibility in circulation and similarities to mast cells, basophils were considered a tool to gain insight into the function of mast cells. However, recent studies have uncovered that basophils have unique biology, specifically in activation, recruitment, and potential biomarkers. Accordingly, some previously unrecognized functions, particularly in neuroimmunology, have been found, suggesting a role of basophils in inflammatory and pruritic disorders. In this review, we aim to present an overview of basophil biology to show how basophils contribute to certain pruritic skin diseases.

The mast cell-nerve unit classically has represented a fundamental neuroimmune axis in the development of itch because of the traditional prominence of histamine as a pruritogen. However, it is appreciated increasingly that most chronic itch disorders are likely nonhistaminergic in nature, provoking the hypothesis that other novel effector itch mechanisms derived from mast cells are important. In this review, we present an overview of classical mast cell biology and put these concepts into the context of recent advances in our understanding of the regulation and function of the mast cell-nerve unit in itch biology.

Epicutaneous sensitization has been an important route for protein allergen sensitization in atopic disease. Although the skin is irradiated by sunlight daily, the influence of visible light on epicutaneous sensitization has not been explored. In this study, by using a well-established murine protein-patch model, we show that low-energy visible light (LEVL) irradiation could differentially modulate the predominant Th2 immune response induced by epicutaneous sensitization with protein antigen. When the induced Th2 response was strong, as usually observed in BALB/c mice, LEVL irradiation suppressed the response. In contrast, LEVL irradiation enhanced the weaker Th2 response in C57BL/6 mice. Increased IL-18 and decreased TGF-beta expression in draining lymph nodes after LEVL irradiation was observed in BALB/c mice, but not in C57BL/6 mice. LEVL irradiation also enhanced IL-18 expression in skin and reduced the downregulation of CD24 expression on epidermal Langerhans cells in draining lymph nodes of BALB/c mice. Collectively, these results provide evidence for immunomodulatory effects of LEVL irradiation and will help us develop a useful strategy for prevention of allergen sensitization.

Programmed death-1 (PD-1) is involved in T-cell tolerance to self-antigens. For some cancers, it has been suggested that the expression of a ligand of PD-1, namely PD-L1, could contribute to tumor escape from immune destruction. Nevertheless, the relationship between PD-1 expression on tumor-infiltrating T lymphocytes (TILs), disease stage, and TIL responsiveness is still poorly documented. In this study, we show that freshly isolated CD4(+) and CD8(+) TILs express substantial levels of PD-1 in primary melanomas. The expression of PD-1 was further increased at later stages in distant cutaneous metastases, especially on CD8(+) TILs. The expression of PD-1 ligands was frequent only in metastases, on both tumor cells and tumor-derived myeloid cells. TILs isolated from these cutaneous tumors are poorly reactive ex vivo, with blunted calcium response and IFN-γ production after TCR stimulation. Surprisingly, in distinct parts of a primary melanoma, either invasive or regressing, we show that TILs similarly express PD-1 and remain dysfunctional. The expressions of PD-1 and PD-L1 in metastatic melanoma lesions could be considered as witnesses of an unsuccessful anti-tumoral immune response, but the direct involvement of PD-1 in the severity of the disease, and the importance of TILs in tumor regression, remain to be established.

Spleen tyrosine kinase (Syk), a nonreceptor tyrosine kinase, was initially identified as a crucial regulator in proximal immunoreceptor signaling. Additional studies have revealed its pleiotropic roles, and drugs targeting Syk are under development for inflammatory diseases. Syk expression in the skin has been detected, but its functions in the skin are still unknown. Here, we found that Syk phosphorylation and expression in primary human keratinocytes decreased gradually along with terminal differentiation. Human skin specimens showed similar in vivo patterns. Syk inhibitors or knockdown of Syk increased the expression of differentiation markers under in vitro differentiation models. Furthermore, EGFR activation prominently induced Syk phosphorylation, which could be inhibited by the EGFR inhibitor gefitinib or knockdown of EGFR. The Src inhibitor also partially attenuated EGF-induced phosphorylation of Syk. However, Syk inhibition suppressed EGF-induced phosphorylation of EGFR. Immunoprecipitation and confocal microscopy further revealed the increased molecular interaction between EGFR and Syk after EGF stimulation. This study unravels the role of Syk in EGFR-mediated signaling and reveals regulatory roles of Syk in keratinocyte differentiation, suggesting the clinical potential of topical or systemic Syk inhibitors in the treatment of skin diseases with aberrant differentiation.