Animal models

Abstract

Our understanding of bullous skin disorders has increased enormously since the beginning of the century, when a patient with generalized blisters was firmly diagnosed as having pemphigus vulgaris only upon his demise. Those fortunate patients who survived obviously did not have true pemphigus vulgaris. They very likely had “pemphigus of the aged” or “bullous dermatitis herpetiformis.” The key observations that defined these diseases more precisely were the careful histopathological studies of Lever 1 and the immunofluorescent studies of Beutner and Jordon. 2,3 The auto-antibodies in pemphigus vulgaris and bullous pemphigoid that can be detected both bound into and around lesions and circulating in the serum have not only proven to be crucial for the accurate diagnosis of these conditions, but also appear to be of primary importance in the pathogenesis of the diseases as well. There is now substantial evidence that pemphigus auto-antibodies bind specifically to a cell surface antigen on squamous epithelia, and can directly induce cell-to-cell detachment and acantholysis of those cells through mechanisms currently being investigated. The cornerstone of our current knowledge of the mechanisms of tissue injury in pemphigus was the observation in 1964 by Beutner and Jordon that the majority of pemphigus patients have IgG class antibodies in the serum that bind in the intercellular spaces of stratified squamous epithelia. 2,3 Subsequently, much has been learned of the importance of these auto-antibodies in the disease process but much still remains poorly understood. There is a large body of evidence that these epithelial autoantibodies are pathogenic in the disease and not merely an epiphenomenon. This is based on clinical observations, in vitro, and in vivo data. The clinical observations are as follows: ( 1) in many, but certainly not all patients with pemphigus, the titers of these antibodies, as measured by indirect immunofluorescence (IF), correlate with disease activity; ( 2) plasmapheresis has been reported to induce short-term remissions in pemphigus patients and may be an effective adjunct to therapy in acute cases 4–7; and ( 3) pemphigus has occurred in neonates born to mothers with active pemphigus, and the disease has resolved in the newborns after parturition. 8, 9 Presumably, transplacental transfer of maternal IgG induces the disease, which resolves as their levels diminish in the neonates. In vitro studies also support the pathogenic role of pemphigus antibodies in the induction of acantholysis. Bellone and Leone, 10 Schiltz and Michel, 11 and Morioka et al. 12 have demonstrated that pemphigus serum, or IgG fractions from pemphigus serum, induce acantholysis in human skin expiants. Farb, et al. 13 and Diaz and Marcelo 14 have shown that pemphigus serum added to murine primary epidermal cell cultures will cause epidermal cell detachment. This effect is highly reproducible and specific, for it does not occur when cultures are treated with normal human IgG or with IgG fractions from bullous pemphigoid, lupus erythematosus, or anti-AB sera, as demonstrated by Woo, et al. in our laboratories. 16 Finally, there is also convincing in vivo evidence of their pathogenicity. Despite previous reports that parenteral passive transfer or local injections of pemphigus auto-antibodies into animals failed to induce disease consistently, 16–20 our laboratory has demonstrated that, given in sufficient doses, IgG fractions purified from pemphigus serum induce a disease in neonatal mice that reproduces the clinical, histological, and immunological features of the human disease. 21