Maintenance of immune hyporesponsiveness to melanosomal proteins by DHICA-mediated antioxidation: Possible implications for autoimmune vitiligo.
Melanocyte destruction in the skin of vitiligo patients has been considered to be a consequence of an autoimmune response against melanosomal proteins. However, little is known about the molecular mechanisms by which the immune system recognizes these sequestered intracellular self-proteins, which are confined in specialized organelles termed melanosomes, and is provoked into an autoimmune response to melanocytes. Here, we utilize a sucrose density-gradient ultracentrifugation protocol to enrich melanosomal components from dopachrome tautomerase (Dct)-mutant or wild-type melanocytes exposed to a pulse of hydrogen peroxide at a noncytotoxic concentration to evaluate their immunogenicity in mice challenged with the corresponding melanosomal proteins. The results demonstrate that enhanced humoral and cellular immune responses to a challenge with late-stage melanosomal proteins, especially with those derived from Dct-mutant melanocytes, are found in the immunized mice. To elucidate whether a reduced 5,6-dihydroxyindole-2-carboxylic acid (DHICA) content in melanin might cause a loss in antioxidative protection to the proteins, we incubated these melanosomal proteins in vitro with synthetic 5,6-dihydroindole (DHI)-melanin or DHI/DHICA (1:1)-melanin and then used them to immunize mice. T cell proliferation and IgG antibody responsiveness to the challenges were significantly induced by melanosomal proteins treated with DHI-melanin, but not by those treated with DHI/DHICA (1:1)-melanin. Moreover, we observed that melanosomal proteins derived from Dct-mutant melanocytes are subject to oxidative modifications that alter their antigenic configurations to attain an enhanced immunogenicity compared with those derived from wild-type melanocytes. From these results, we conclude that DHICA-mediated antioxidation plays a critical role in the maintenance of immune hyporesponsiveness to melanosomal proteins.
Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Xiao-Ming
XM
Liu
Qiong
Q
Zhou
Shi-Zheng
SZ
Xu
Kazumasa
K
Wakamatsu
Tie-Chi
TC
Lei
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000975:Antioxidants / Q000378:metabolism; D015551:Autoimmunity; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007108:Immune Tolerance; D007117:Immunization, Secondary; D007211:Indoles / Q000737:chemistry / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008543:Melanins / Q000276:immunology / Q000378:metabolism; D008544:Melanocytes / Q000276:immunology / Q000378:metabolism; D020460:Melanosomes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics / Q000276:immunology; D010084:Oxidation-Reduction; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D014820:Vitiligo / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D000975:Antioxidants; D007211:Indoles; D008543:Melanins; C030692:5,6-dihydroxy-2-indolylcarboxylic acid; D006861:Hydrogen Peroxide; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase