Role of Melanocyte Defect in Smyth Line Vitiligo

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DESCRIPTION (provided by applicant): Vitiligo is a common acquired hypopigmentary disorder characterized by a loss of epidermal melanocytes. Although the pathogenesis of vitiligo is still poorly understood, evidence suggests that in many cases vitiligo is an autoimmune disorder and melanocyte loss is the result of an immunological response. The mutant Smyth line chicken is an accepted animal model for autoimmune vitiligo. Chickens from this line develop a spontaneous, vitiligo-like, postnatal loss of melanin producing pigment cells (melanocytes) in feather and choroidal tissue between 6 and 14 weeks of age. Like many autoimmune diseases, SL vitiligo is a multifactorial disorder, involving an inherent melanocyte defect, an immune system component, and an environmental component. Studies examining the basic defect manifested within the SL melanocyte describe the presence of a competent pigment system at hatch. Prior to visible signs of vitiligo, the earliest abnormality detected within SL melanocytes are irregularly shaped melanosomes containing pigmented membrane extensions, hyperactive melanization, and selective autophagocytosis of melanosomes. These aberrant processes precede the degeneration of SL melanocytes in vivo and in vitro but are not sufficient to cause the expression of vitiligo without a functioning immune system. Mechanisms underlying the dysfunction, progressive degeneration, and eventually, immune recognition and destruction of SL melanocytes are poorly understood. It is the goal of this proposal to study the mechanism by which the local and internal environment of the vitiliginous SL melanocyte contributes to and/or results in the degeneration of melanocytes and the development of autoimmune vitiligo. Specifically, we propose to investigate the role of oxidative stress, antioxidant capacity, inflammatory mediators and immunofunctional activities of melanocytes in the degeneration/survival of melanocytes in vivo and in vitro. These studies will be carried out using feather tissue and melanocyte cultures from SL chickens that are highly susceptible to the development of vitiligo, parental BL chickens that are susceptible to the development of vitiligo but rarely express vitiligo, and LBL chickens that are vitiligo resistant. The knowledge that will be gained from these studies regarding the underlying mechanism of the SL melanocyte's inherent susceptibility for degeneration and autoimmune destruction. may open up new venues for treatment and prevention of this disorder.