Epiplakin Is a Paraneoplastic Pemphigus Autoantigen and Related to Bronchiolitis Obliterans in Japanese Patients

Abstract

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 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 PNP patients 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 major PNP autoantigens and is related to PNP-related bronchiolitis obliterans.Journal of Investigative Dermatology accepted article preview online, 19 October 2015. doi:10.1038/jid.2015.408.

Pemphigus

“…A multivariant ELISA and a biochip assay are also available to detect anti-envoplakin autoantibodies 118,127 . Anti-epiplakin autoantibodies might be associated with bronchiolitis obliterans in Japanese patients with paraneoplastic pemphigus 128 .…”

Paraneoplastic pemphigus associated with Castleman disease: progression from mucous to mucocutaneous lesions with epitope-spreading phenomena

“…D ear E ditor , Paraneoplastic pemphigus (PNP) is a frequently fatal autoimmune blistering disease of the skin and mucous membranes . PNP is commonly associated with malignant neoplasms or haematological disorders such as Castleman disease (CD).…”

Untitled

“…Bronchiolitis Obliterans (BO) is the most common complication and progressive respiratory failure caused by BO is the most important cause of death. Evidence to date indicates that in paraneoplastic pemphigus, autoantibodies directed against plakin proteins may be responsible for acantholytic changes in the respiratory epithelium, among which, epiplakin and desmoglein3 might be the major autoantigens [14][15][16]. Moreover, there is an increased occurrence of Castleman's disease in patients with pulmonary complications [17].…”

“…This 170-kd protein has recently been identified as alpha-2-macroglobulin-like-1 (A2ML1), a broad range protease inhibitor expressed in stratified epithelia and other tissue damaged in PNP [25,26]. In 2016 a Japanese study indicated that epiplakin is one of the major PNP autoantigens and is related to PNP-related bronchiolitis obliterans [16]. A large cohort of 104 patients with PNP found statistically significant correlations between positive desmoglein 3 reactivity and genital lesions, and between positive desmoglein 3 reactivity and bronchiolitis obliterans [14].…”