From IL-17 to IFN-γ in inflammatory skin disorders: Is transdifferentiation a potential treatment target?

The targeted inhibition of effector cytokines such as interleukin 17 (IL-17) in psoriasis and IL-13 in atopic dermatitis offers impressive efficacy with a favorable side effect profile. In contrast, the downregulation of interferon gamma (IFN-γ) in T helper (Th) 1-dominant skin disorders may lead to more adverse events, given the crucial role of IFN-γ in antiviral and antitumoral immunity. Modulating Th17 and Th2 cell differentiation is performed by blocking IL-23 and IL-4, respectively, whereas anti-IL-12 antibodies are only moderately effective in downregulating Th1 lymphocyte differentiation. Therefore, a targeted approach of IFN-γ-driven disorders remains challenging. Recent literature suggests that certain pathogenic Th17 cell subsets with Th1 characteristics, such as CD4+CD161+CCR6+CXCR3+IL-17+IFN-y+ (Th17.1) and CD4+CD161+CCR6+CXCR3+IL-17-IFN-y+ (exTh17), are important contributors in Th1-mediated autoimmunity. Differentiation to a Th17.1 or exTh17 profile results in the upregulation of IFN-y. Remarkably, these pathogenic Th17 cell subsets are resistant to glucocorticoid therapy and the dampening effect of regulatory T cells (Treg). The identification of Th17.1/exTh17 cells in auto-immune disorders may explain the frequent treatment failure of conventional immunosuppressants. In this review, we summarize the current evidence regarding the cellular plasticity of Th17 cells in inflammatory skin disorders. A deeper understanding of this phenomenon may lead to better insights into the pathogenesis of various skin diseases and the discovery of a potential new treatment target.

The delicate relation between melanocytes and skin immunity: A game of hide and seek.

Melanocytes exhibit a complex and intriguing relationship with the skin immune response, leading to several clinical conditions. In some disorders, inappropriate melanocyte destruction (e.g., vitiligo, halo naevi) is problematic, while in others, immune tolerance should be broken (melanoma). Important parts of the dysregulated pathways have been unraveled in pigment disorders, ranging from upregulated interferon (IFN)-γ signaling to memory T cells, regulatory T cells, and immune checkpoints. Although a network of many factors is involved, targeting key players such as IFN-γ or checkpoint inhibitors (e.g., programmed death-ligand 1 (PD-L1)] can shift the balance and lead to impressive outcomes. In this review, we focus on the immunological mechanisms of the most common inflammatory disorders where the interaction of the immune system with melanocytes plays a crucial role. This can provide new insights into the current state of melanocyte research.