Psoriasis and other Th17-mediated skin diseases

Abstract

T helper (Th) 17 cells have crucial functions in host defense, and dysregulated Th17 responses mediate a variety of autoimmune and inflammatory conditions. Th17 cells coexpress interleukin (IL)-22, and its receptor is expressed on epidermal keratinocytes. IL-17 and IL-22 cooperatively enhance some immunological responses. A close relationship between IL-17 and the cutaneous milieu has been suggested by a number of observations. IL-17 induces the production of certain cytokines, chemokines and antimicrobial peptides by keratinocytes, and its cooperation with IL-22 has been documented. Recent findings have suggested that Th17 cells profoundly participate in the pathogenesis of certain skin disorders, in particular, psoriasis. The concept of the subsets of T cells responsible for psoriasis has been modified in the order of Th1, T cytotoxic 1, and again Thl, and Thl7 cells. IL-22 is the strongest cytokine in the keratinocyte-proliferative ability. Since IL-22 is produced by Th17 cells, they are crucial for the proliferation of keratinocytes. Furthermore, IL-22 with the help of IL-17 can induce the critical events of psoriasis, including signal transducer and activator of transcription 3 (STAT3) activation, cytokine/chemokine (IL-8 etc.) production, and antimicrobial peptide elaboration. For maintaining Th17 cells, IL-23 is required and is released from tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthetase (iNOS)-producing dendritic cells (TIP-DCs). TIP-DCs are activated via an autocrine mechanism by virtue of TNF-alpha. The above cytokine network in the pathogenesis of psoriasis has been proven by the therapeutic effectiveness of cytokine-blocking biologics. Antibodies against TNF-alpha or its soluble receptor have already been widely used in the treatment of psoriasis. The involvement of Th17 cells has also been shown in allergen-specific immune responses. The percentage of Th17 cells is increased in the peripheral blood of patients with atopic dermatitis (AD) and associated with the severity of AD. Drug eruption is another disease where Th17 cells are involved in the pathogenesis. The percentage of circulating Th17 cells are increased in drug-induced hypersensitivity syndrome, etc. Th17 cells and IL-22 are increased in patients with acute generalized exanthematous pustulosis. Since IL-17 and IL-22 cooperatively stimulate keratinocytes to produce IL-8, keratinocyte-derived IL-8 contributes to the accumulation ofneutrophils in the lesional epidermis of this drug eruption.