Platinum-induced autoantibodies target nucleoplasmic antigens related to active transcription.
Research on autoimmune diseases has revealed that autoimmunity can be induced by heavy metals such as mercury and gold. Following the introduction of platinum-containing catalytic converters in automobiles, the emission of platinum compounds constitutes an abundant environmental pollutant, however, potential immunological hazards resulting from platinum-containing emissions were not yet examined. In our previous studies on molecular mechanisms of heavy metal-induced autoimmunity, we showed a platinum-dependent subcellular redistribution of the autoantigen fibrillarin from the nucleolus to the nucleoplasm. Since H-2s mice constitute a valuable model to study the role of heavy metals in the development of systemic autoimmunity, we treated susceptible B10.S mice with hexachloroplatinate (Na2PtCl6, Pt4+) to examine whether platinum induces the production of autoantibodies. The present study shows for the first time that chronic administration of Pt4+ generated an autoimmune response in mice which targets distinct nucleoplasmic antigens. Dual-labeling revealed substantial colocalization of these nucleoplasmic autoantigens with (i) nascent RNA, (ii) the active, phosphorylated form of RNA polymerase II, and partial overlap with (iii) acetylated histone 4 protein, and (iv) 20S proteasomes in dendritic cells isolated from platinum-treated mice. The results suggest that platinum elicits antibodies against antigens associated with active sites of transcription which may be subject to proteasomal processing during heavy metal-induced autoimmunity.
Chen
Min
M
Junior Research Group of Molecular Cell Biology, Institut für Umweltmedizinische Forschung, Heinrich-Heine-University, Düsseldorf, Germany. chenmin@uni-duesseldorf.de
Hemmerich
Peter
P
von Mikecz
Anna
A
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood* / Q000276:immunology*; D034961:Antigens, Nuclear / Q000276:immunology; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000235:genetics; D002460:Cell Line; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000276:immunology / Q000633:toxicity*; D003546:Cysteine Endopeptidases / Q000648:ultrastructure; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D005260:Female; D006657:Histones / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018613:Microscopy, Confocal; D009097:Multienzyme Complexes / Q000648:ultrastructure; D046988:Proteasome Endopeptidase Complex; D012313:RNA / Q000276:immunology; D012319:RNA Polymerase II / Q000276:immunology; D013154:Spleen / Q000276:immunology; D014158:Transcription, Genetic / Q000235:genetics
D000974:Antibodies, Antinuclear; D034961:Antigens, Nuclear; D006657:Histones; D009097:Multienzyme Complexes; D012313:RNA; D012319:RNA Polymerase II; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin; C038762:disodium hexachloroplatinate