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All plakin family proteins are known to be autoantigens in paraneoplastic pemphigus (PNP). In this study, we first examined whether PNP sera also react with epiplakin, another plakin protein, by various immunological methods using 48 Japanese PNP sera. Immunofluorescence confirmed that cultured keratinocytes expressed epiplakin. Epiplakin was detected by 72.9% of PNP sera by immunoprecipitation-immunoblotting with KU-8 cell extract, but not by immunoblotting of either normal human epidermal extract or KU-8 cell extract. Epiplakin was essentially not detected by 95 disease and normal control sera. Statistical analyses of various clinical and immunological findings revealed a significant correlation of the presence of anti-epiplakin antibodies with both bronchiolitis obliterans and mortality. No epiplakin-negative PNP case developed bronchiolitis obliterans. However, although 29.4% of European patients with PNP had bronchiolitis obliterans, significant correlation with anti-epiplakin autoantibodies was not observed. In further studies for lung, immunofluorescence showed the presence of epiplakin in normal human lung, particularly respiratory bronchiole, immunoprecipitation-immunoblotting showed that PNP sera reacted with epiplakin in cultured lung cells, and mice injected with polyclonal antibody specific to epiplakin histopathologically showed abnormal changes in small airway epithelia. These results indicated that epiplakin is one of the major PNP autoantigens and is related to PNP-related bronchiolitis obliterans., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)