It is clear that this immunopathologic mechanisms differ appreciably from those responsible for the lesions of classical pemphigus. overcome the natural resistance and activate the Phenylephrine HCl cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to highlight that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients. Keywords: Pemphigus vulgaris, Pemphigus foliaceus, autoantigen, autoantibody, apoptolysis, prednisone Introduction Autoimmune pemphigus is usually a life-threatening mucocutaneous blistering disease associated with IgG antibodies targeting several types of keratinocyte antigens and eliciting epidermal clefting (acantholysis) via intracellular signaling activating apoptotic enzymes (apoptolysis) [1]. Systemic administration of glucocorticosteroid hormones is essential to establish control of disease during the acute stage [2]. Although glucocorticosteroid treatment is usually life-saving, it may cause severe side effects, including death [3,4]. Therefore, pemphigus patients need drugs that can replace glucocorticosteroids. The development of nonsteroidal treatment has been hampered by a lack of clear understanding of the mechanisms leading to keratinocyte detachment and death in pemphigus. This overview of recent advances in the knowledge of pemphigus autoimmunity difficulties the existing dogmas, helps handle aged controversies, and identifies new perspectives for treatment. It encompasses knowledge on pemphigus vulgaris (PV) and pemphigus foliaceus (PF), but specifically excludes reports on paraneoplastic pemphigus, or PNP, originally explained by Anhalt et al. [5], because this disease is not related to PV and PF. The notion that PNP represents a variant of classical pemphigus stems from the facts that patients with PV or PF sometime have concomitant neoplasms [6-8] and that Phenylephrine HCl some patients with PNP develop anti-desmoglein (Dsg) 1 and/or 3 antibodiesthe hallmark of classical pemphigus [9]. In fact, PNP represents only one manifestation of the heterogeneous autoimmune syndrometermed paraneoplastic autoimmune multiorgan syndrome (PAMS)targeting both tegumental epithelium and internal organs [10]. In marked contrast to classical pemphigus, PAMS has an overall mortality more than 90% despite therapy, with progressive respiratory failure with clinical features of bronchiolitis obliterans being the most frequent cause of death [11]. Sloughing of bronchial epithelial cells contributes to the occlusion of the small airways that provides a potential mechanism for the respiratory failure [10]. Patients with PAMS develop mucocutaneous lesions that resemble pemphigoid, erythema multiforme, lichen planus, and graft vs. host disease, as well as the pemphigus-like variant that was termed PNP in the index patient with PAMS. Oral mucosal lesions of painful, progressive stomatitis are the hallmark of the disease and usually are the initial manifestation of PAMS [12]. The proposed pathogenesis of PAMS continues to evolve. It is obvious that this immunopathologic mechanisms differ appreciably from Phenylephrine HCl those responsible for the lesions of classical pemphigus. The spectrum of PAMS includes patients with disease predominantly or exclusively mediated by the cellmediated autoimmunity effectors and those Phenylephrine HCl with both autoantibodies and cellular cytotoxicity [13]. Pemphigus autoantigens Following the discovery of IgG autoantibodies in patients with PV [14] and Phenylephrine HCl PF [15], numerous attempts have been made to identify targeted antigens. HD3 The patient’s serum and isolated IgG portion were utilized in the immunoprecipitation and immunoblotting experiments using the epidermal or keratinocyte culture proteins as well as saliva and urine as substrates. Even though low-sensitivity approaches, such as fluorography with metabolically labeled keratinocyte proteins preabsorbed with human serum [16], demonstrated single protein bands, a more sensitive but less specific immunoblotting technique revealed more than a dozen of targeted keratinocyte proteins [17]. An enhanced sensitivity immunoprecipitation assay exhibited that different PV or PF patients produce antibodies realizing both common and unique antigens [18]. Representative images of protein bands recognized by PV and PF sera are shown in Physique 1. The full list of pemphigus antigens reported to date contains over 40 protein bands with apparent molecular weights (MWs) of 12, 18, 25, 30, 33, 35, 38, 40, 45, 47, 50, 52, 55, 57, 59, 60, 62, 66, 67, 68, 70, 75, 78, 80, 85, 95, 100, 102, 105, 110, 112, 120, 130, 140, 160, 170,180, 185/190, 210, and 260 kD [16,18-37]. Indeed, some of these bands may include the same polypeptides migrated with slightly different MWs, and vice versa, some may include two or.
