Psoriasis and psoriatic arthritis are chronic inflammatory diseases of unknown etiology, affecting 2-3% of the world population. Initially, psoriasis was thought to be a hyper-proliferation disorder of keratinocytes only, but as time passed, the role of immune system became more evident and now both diseases are considered autoimmune disorders. In last few years, the discovery of interleukin (IL)-23/Th17 axis in pathophysiology of psoriatic diseases shifts the cytokine paradigm from Th1 to Th17 cytokines, focused mainly on IL-17 and IL-22. Therapeutic experiences strongly support the use of cytokine antagonists as an important modality in the treatment of psoriatic arthritis and plaque psoriasis. Studies examining these therapeutic agents which target different steps of the psoriatic inflammatory cascade have also shown significant efficacy. The relatively new IL-23/Th17 axis in psoriatic diseases got more importance with the success of ustekinumab, a new monoclonal antibody against IL-12 and IL-23. In IL-17 and IL-22 knock-out and transgenic mouse models, it has been found that recombinant IL-23 fails to produce epidermal hyperplasia which resembles psoriasis. Also, some success in animal models of psoriasis was found with anti IL-17A and anti IL-22. More studies are needed to validate the efficacy and safety of these cytokine antagonists in psoriatic diseases. Using a historical perspective and a chess game as an analogy, the main objective of this review is to summarize the central role of some of these cytokines in psoriasis pathophysiology and to develop a strategic approach to new therapeutic weapons within the armamentarium of psoriasis treatment.

Leishmania braziliensis is the causative agent of human cutaneous leishmaniasis in parts of the New World. In the murine model of infection, L. braziliensis does not produce severe or lasting cutaneous lesions in either BALB/c or C3H mice. However, when the parasites are injected into BALB/c mice with salivary gland lysate of the sand fly vector for the parasite, infection is significantly enhanced, as measured by lesion size, parasite burden, and the outcome of infection. Histologic examination of these cutaneous lesions showed that initially, nodular and diffuse dermal infiltrates of neutrophils, eosinophils, and histiocytes occurred in all mice. Over time, the saliva-free lesions progressed to small organized granulomas of epithelioid macrophages that contained few parasites, with eventual resolution of inflammation and mild dermal fibrosis. The saliva-associated lesions progressed to extensive, poorly organized accumulations of heavily parasitized epithelioid macrophages, with persistent neutrophils and eosinophils, and minimal fibroplasia. These results indicate that sand fly salivary gland lysate markedly modifies the inflammatory response to infection with L. braziliensis.

Atopic dermatitis (AD) is the most common inflammatory skin condition. Skin barrier dysfunction is of major importance in AD because it facilitates allergen sensitization and systemic allergic responses. Long regarded as a pro-apoptotic protease, emerging studies indicate granzyme B (GzmB) to have extracellular roles involving the proteolytic cleavage of extracellular matrix, cell adhesion proteins, and basement membrane proteins. Minimally expressed in normal skin, GzmB is elevated in AD and is positively correlated with disease severity and pruritus. We hypothesized that GzmB contributes to AD through extracellular protein cleavage. A causative role for GzmB was assessed in an oxazolone-induced murine model of dermatitis, comparing GzmB À/À mice with wild-type mice, showing significant reductions in inflammation, epidermal thickness, and lesion formation in GzmB À/À mice. Topical administration of a small-molecule GzmB inhibitor reduced disease severity compared with vehicle-treated controls. Mechanistically, GzmB impaired epithelial barrier function through Ecadherin and FLG cleavage. GzmB proteolytic activity contributes to impaired epidermal barrier function and represents a valid therapeutic target for AD.

T cells, particularly CD4+ T cells, have been associated with many aspects of skin disease. Current evidence suggests, however, that the role of CD4+ T lymphocytes in the development of cutaneous inflammation surpasses that of pro-inflammatory activation of effector T cells that direct the immune response. T cell subtypes with regulatory capacity, such as CD4+CD25+ high Tregs, have been identified. Recent observations suggest that in some skin diseases the function of these cells is modified. Therefore, the development and function of Treg cells in Dermatology are currently attractive topics because of their importance in controlling the immune system response against tumors and infectious diseases, as well as in inhibiting auto-immunity and allergy development. Therefore, defective regulatory mechanisms may allow a breach in peripheral immune tolerance followed by chronic inflammation and disease. Functional abnormalities and contributions of different subtypes of regulatory T cells in the development of dermatological illnesses are detailed in this review. Possible targets for therapy and modifications of regulatory T cells caused by immunomodulators used in Dermatology are highlighted. Keywords: Dermatology; Skin diseases; T-Lymphocytes; T-Lymphocytes, suppressor-inducer; Therapeutics Resumo: Células T, em particular as células T CD4+, têm sido associadas a muitos aspectos das doenças de pele. A evidência atual sugere, porém, que o papel dos linfócitos T CD4+ no desenvolvimento de inflamação cutânea excede o de ativador pró-inflamatório das células T de ação que dirigem a resposta imune. Subtipos de células T com capacidade reguladora, tais como

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