Psoriasis is a chronic inflammatory skin disease, the immunologic model of which has been profoundly revised following recent advances in the understanding of its pathophysiology. In the current model, a crosstalk between keratinocytes, neutrophils, mast cells, T cells, and dendritic cells is thought to create inflammatory and pro-proliferative circuits mediated by chemokines and cytokines. Various triggers, including recently identified autoantigens, Toll-like receptor agonists, chemerin, and thymic stromal lymphopoietin may activate the pathogenic cascade resulting in enhanced production of pro-inflammatory and proliferation-inducing mediators such as interleukin (IL)-17, tumor necrosis factor (TNF)-α, IL-23, IL-22, interferon (IFN)-α, and IFN-γ by immune cells. Among these key cytokines lie therapeutic targets for currently approved antipsoriatic therapies. This review aims to provide a comprehensive overview on the immune-mediated mechanisms characterizing the current pathogenic model of psoriasis.

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the progressive loss of axonal myelin in several areas of the central nervous system (CNS) that is responsible for clinical symptoms such as muscle spasms, optic neuritis, and paralysis. The progress made in more than one decade of research in animal models of MS for clarifying the pathophysiology of MS disease validated the concept that MS is an autoimmune inflammatory disorder caused by the recruitment in the CNS of self-reactive lymphocytes, mainly CD4⁺ T cells. Indeed, high levels of T helper (Th) cells and related cytokines and chemokines have been found in CNS lesions and in cerebrospinal fluid (CSF) of MS patients, thus contributing to the breakdown of the blood–brain barrier (BBB), the activation of resident astrocytes and microglia, and finally the outcome of neuroinflammation. To date, several types of Th cells have been discovered and designated according to the secreted lineage-defining cytokines. Interestingly, Th1, Th17, Th1-like Th17, Th9, and Th22 have been associated with MS. In this review, we discuss the role and interplay of different Th cell subpopulations and their lineage-defining cytokines in modulating the inflammatory responses in MS and the approved as well as the novel therapeutic approaches targeting T lymphocytes in the treatment of the disease.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that strongly activates dendritic cells (DC) and can initiate allergic inflammation. The factors inducing the production of human TSLP are not known. In this study, we show that proinflammatory (TNF-α or IL-1α) and Th2 (IL-4 or IL-13) cytokines synergized to induce the production of TSLP in human skin explants. TSLP production in situ was restricted to epidermal keratinocytes of the suprabasal layer. TSLP production could not be inhibited by factors regulating Th2 inflammation, such as IL-10, TGF-β, or IFN-γ. Cytokine-treated skin culture supernatants induced the maturation of blood CD11c⁺ DC in a TSLP-dependent manner. Our data provide the first evidence of TSLP induction and subsequent DC activation in human skin. Blocking TSLP-inducing cytokines could represent a novel strategy for the treatment of allergic diseases.

T helper (Th) 17 cells are a subtype of CD4 T lymphocytes characterized by the expression of retinoic acid-receptor (RAR)-related orphan receptor (ROR)γt transcription factor, encoded by gene Rorc. These cells are implicated in the pathology of autoimmune inflammatory disorders as well as in the clearance of extracellular infections. The main function of Th17 cells is the production of cytokine called interleukin (IL)-17A. This review highlights recent advances in mechanisms regulating transcription of IL-17A. In particular, we described the lineage defining transcription factor RORγt and other factors that regulate transcription of Il17a or Rorc by interacting with RORγt or by binding their specific DNA regions, which may positively or negatively influence their expression. Moreover, we reported the eventual involvement of those factors in Th17-related diseases, such as multiple sclerosis, rheumatoid arthritis, psoriasis, and Crohn's disease, characterized by an exaggerated Th17 response. Finally, we discussed the potential new therapeutic approaches for Th17-related diseases targeting these transcription factors. The wide knowledge of transcriptional regulators of Th17 cells is crucial for the better understanding of the pathogenic role of these cells and for development of therapeutic strategies aimed at fighting Th17-related diseases.

Fas and Fas Ligand (FasL) are two molecules involved in regulation of cell death. Their interaction leads to apoptosis of thymocytes that fail to rearrange correctly their T cell receptor genes (TCR) and of those that recognize self-antigens, a process called negative selection; moreover, Fas-FasL interaction leads to activation-induced cell death, a form of apoptosis induced by repeated TCR stimulation, responsible for the peripheral deletion of activated T cells. Both control mechanisms are particularly relevant in the context of autoimmune diseases, such as multiple sclerosis (MS), where T cells exert an immune response against self-antigens. This concept is well demonstrated by the development of autoimmune diseases in mice and humans with defects in Fas or FasL. In recent years, several new aspects of T cell functions in MS have been elucidated, such as the pathogenic role of T helper (Th) 17 cells, and the protective role of T regulatory (Treg) cells. Thus, in this review we summarize the role of the Fas-FasL pathway, with particular focus on its involvement in MS, then we discuss recent advances concerning the role of Fas-FasL in regulating Th17 and Treg cells’ functions, in the context of MS.