Targeting the elevated IFN - γ in vitiligo patients by human anti - IFN - γ monoclonal antibody hampers direct cytotoxicity in melanocyte

Abstract：

Vitiligo is an autoimmune disease that progressively destroys melanocytes in theskin, resulting in patchy disfiguringdepigmentation. The direct pathologicaleffect of IFN-γ,CXCL10 to the melanocytesin vitiligo has been reported, but there arecontradictory results to which cytokineexerts the critical cytotoxic effect onmelanocytes.We obtained the interstitial fluid analytefrom lesion and non-lesion skin of vitiligopatients and healthy control and sent forhigh sensitivity multiplex cytokine panel. Wefurther performed functional study toidentify the direct toxicity effect of the highlyexpressed cytokines.We found a significant elevation of IFN-γ,CXCL9, CXCL10, CXCL11 in the vitiligoskin. Ex vivo melanocyte studies supportthe directrole of IFN-γper se in melanocytecell loss, increased oxidative stress andmelanogenesis disruption. Interestingly, wefound that IFN-γregulated cell deaththrough oxidative stress-related ferroptosiscell death, which may initiate autoimmunityin vitiligo. In contrast to blocking selectedcell death pathway, our in vitro studysupports the rescue effect of human anti-IFN-γmonoclonal antibody 2A6Q to IFN-γinduced cell death, oxidative stress, andloss of function in melanocytes byinterrupting IFN-γsignaling, which may bea potential therapeutic option for vitiligo.