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Proteomic Scan for Tyrosinase Peptide Antigenic Pattern in Vitiligo and Melanoma: Role of Sequence Similarity and HLA-DR1 Affinity¹

Alberta Lucchese^*, Jörg Willers, Abraham Mittelman, Darja Kanduc^2, and Reinhard Dummer

^* Department of Odontostomatology and Surgery, University of Bari, Bari, Italy; Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; Department of Medicine, Division of Oncology/Hematology, New York Medical College, Valhalla, NY 10595; and Department of Biochemistry and Molecular Biology, University of Bari, Bari, Italy

Immune responses contribute to the pathogenesis of vitiligo and target melanoma sometimes associated with vitiligo-like depigmentation in some melanoma patients. We analyzed the sera from patients with vitiligo and cutaneous melanoma for reactivity toward tyrosinase peptide sequences 1) endowed with low level of similarity to human proteome, and 2) potentially able to bind HLA-DR1 Ags. We report that the tyrosinase autoantigen was immunorecognized with the same molecular pattern by sera from vitiligo and melanoma patients. Five autoantigen peptides composed the immunodominant anti-tyrosinase response: aa_95–104FMGFNCGNCK; aa_175–182 LFVWMHYY; aa_176–190FVWMHYYVSMDALLG; aa_222–236IQKLTGDENFTIPYW, and aa_233–247 IPYWDWRDAEKCDIC. All of the five antigenic peptides were characterized by being (or containing) a sequence with low similarity level to the self proteome. Sera from healthy subjects were responsive to aa_95–104FMGFNCGNCK, aa_222–236IQKLTGDENFTIPYW, and aa_233–247 IPYWDWRDAEKCDIC, but did not react with the aa_175–182LFVWMHYY and aa_176–190FVWMHYYVSMDALLG peptide sequences containing the copper-binding His¹⁸⁰ and the oculocutaneous albinism I-A variant position F176. Our results indicate a clear-cut link between peptide immunogenicity and low similarity level of the corresponding amino acid sequence, and are an example of a comparative analysis that might allow to comprehensively distinguish the epitopic peptide sequences within a disease from those associated to natural autoantibodies. In particular, these data, for the first time, delineate the linear B epitope pattern on tyrosinase autoantigen and provide definitive evidence of humoral immune responses against tyrosinase.