Classification, clinical manifestations, and immunopathological mechanismsof the epithelial variant of paraneoplastic autoimmune multiorgan syndrome- A reappraisal of paraneoplastic pemphigus

Background: Recent studies suggest that paraneoplastic pemphigus (PNP) is a heterogeneous autoimmune syndrome involving several internal. organs and t hat the pathophysiological mechanisms mediating cutaneous, mucosal, and int ernal lesions are not limited to autoantibodies targeting adhesion molecule s. Objective: To classify the diverse mucocutaneous and respiratory presentati ons of PNP and characterize the effecters of humoral and cellular autoimmun ity mediating epithelial tissue damage. Methods: We examined 3 patients manifesting the lichen planus pemphigoidesl ike subtype of PNP. A combination of standard immunohistochemical technique s, enzyme-linked immunosorbent assay with desmoglein (DSG) baculoproteins, and an immunoprecipitation assay were used to characterize effecters of hum oral and cellular autoimmunity in patients with PNP and in neonatal wild-ty pe and DSG3-knockout mice with PNP phenotype induced by passive transfer of patients' IgGs. Results: In addition to the known "PNP antigenic complex," epithelial targe ts recognized by PNP antibodies included 240-, 150-, 130-, 95-, 80-, 70-, 6 6-, and 40/42-kd proteins but excluded DSG1 and DSG3. In addition to skin a nd the epithelium lining upper digestive and respiratory tract mucosa, depo sits of autoantibodies were found in kidney, urinary bladder, and smooth as well as striated muscle. Autoreactive cellular cytotoxicity was mediated b y CD8(+) cytotoxic T lymphocytes, CD56(+) natural killer cells, and CD68(+) monocytes/macrophages. Inducible nitric ox ide synthase was visualized bot h in activated effecters of cellular cytotoxicity and their targets. Kerati n 14-positive basal epithelial cells sloughed from the large airways and ob structed small airways. Conclusions: The paraneoplastic disease of epithelial adhesion known as PNP in fact represents only 1 manifestation of a heterogeneous autoimmune synd rome in which patients, in addition to small airway occlusion and depositio n of autoantibodies in different organs, may display a spectrum of at least 5 different clinical and immunopathological mucocutaneous variants (ie, pe mphiguslike, pemphigoidlike, erythema multiforme-like, graft-vs-host diseas e-like, and lichen planus-like). We suggest that the more encompassing term "paraneoplastic autoimmune multiorgan syndrome," or PAMS, be applied. The pathophysiological mechanisms of PAMS involve both humoral and cellular aut oimmunity responses. Epithelial cell membrane antigens other than DSG1 or D SG3 are targeted by effecters of PAMS autoimmunity. Apoptosis of damaged ba sal cells mediates epithelial clefting, and respiratory failure results pos sibly from obstruction of small airways with sloughed epithelial cells.