Cytokines Imbalance and their Role in Vitiligo Pathogenesis
Cytokine imbalance has been shown in vitiligo skin [150]. Elevated serum levels of soluble IL-2 receptor, which correlated with disease activity in vitiligo patients, have been reported, as have increased synthesis of IL-6, a cytokine induces ICAM-1 expression on melanocytes which could facilitate leukocyte–melanocyte interaction, as well as elevated levels of IL-8, neutrophils, T lymphocytes, and basophils recruiter [151, 152]. Recently this has been added to by the revelation of elevation of T helper (Th) 1 (IL-2, interferon (IFN)-γ, TNF-β), Th2 (IL-4, IL-5, IL-10, IL-13) and Th17 (IL-17, IL-23)-innate cytokines in the serum of all 44 vitiligo patients examined, with a higher ratio of Th1/Th2 cytokines [153]. Expression of the pro-inflammatory cytokine TNF-α is significantly elevated in lesional and peri-lesional vitiligo patient skin, whereas a variety of melanogenic mediators such as endothelin-1, stem cell factor, basic fibroblastic growth factor and granulocyte monocyte-colony stimulating factor are expressed at lower levels in vitiliginous lesions [154]. Recently it has been shown that melanocyte adhesion is disrupted in vitiligo skin through increased levels of MMP-9, produced by keratinocytes in response to IFN-γ and TNF-α, and disturbing E-cadherin on the pigment cells [155]. Both human patients and a mouse model of vitiligo, show high levels of IFN-γ, the cytokine required for the cutaneous recruitment of melanocyte-specific autoreactive CD8+ T lymphocytes, and of IFN-γ-induced cytokine CXCL10, and its receptor CXCR3, found on autoreactive CD8+ T cells [71]. Knocking out CXCR3 or blocking CXCL10 action prevents and reverses depigmentation in vitiligo [76].