(Taken from the application): Autoimmune reactions to components of skin and its appendages produce a spectrum of skin diseases. Vitiligo, characterized by partial or complete loss of skin pigmentation and alopecia areata, a chronic inflammatory hair disorder are two such diseases. Interestingly, while certain autoimmune skin disorders such as bullous diseases result from reactions limited to specific components of skin, vitiligo and alopecia often manifest in association with other autoimmune diseases. This suggests that immune tolerance to self-antigens on pigment producing melanocytes and cells in the hair follicles is broken relatively easily. The molecular identity of these antigens and the role of humoral vs. cellular immune responses in the pathogenesis of these diseases remain unknown. Biochemical and immunocytochemical techniques employed to identify antigens recognized by autoantibodies in the sera of patients have failed to yield definitive knowledge of target antigens in these disorders. Similarly, methodological limitations in analyzing and characterizing T lymphocytes in vitro have precluded extensive studies on the role of T cells in the pathogenesis of vitiligo and alopecia. Recent developments in the field of human tumor immunology provide an opportunity to overcome these limitations on molecular identification of targets for immune responses in autoimmune skin disorders. First, it has been demonstrated that screening cDNA expression libraries with serum antibodies from cancer patients can be used to identify antigen targets for humoral responses. Second, this screening method, termed SEREX, also allows identification of antigens recognized by cytotoxic CD8 T cells in patients with cancer. Together with recent studies that showed the presence of HLA class II-restricted CD4 T cells to tumor antigen recognized by CD8 cells, these observations from SEREX analysis reinforce the concept of simultaneous presentation of self-antigens to humoral and cellular immune systems. This raises the possibility that SEREX analysis with sera from patients with autoimmune skin disorders could allow identification of tissue-specific antigens recognized by antibodies and T cells. Molecular identification of the array of antigens targeted for immune response in these diseases will help delineate mechanisms of their pathogenesis. We propose to generate cDNA expression libraries from pooled cultures of neonatal melanocytes obtained from different racial backgrounds and pooled hair follicles microdissected from normal scalp biopsies. These expression libraries will provide a source of unlimited supply of tissue-specific gene products to begin dissecting immune responses by SEREX analysis. It is expected that such analysis will allow identification of targets for both antibody and T cell responses in vitiligo and alopecia areata.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZAR1-AAA-A (M1))
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Moshell, Alan N
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Wake Forest University Health Sciences
Schools of Medicine
United States
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