Pemphigus is an organ specific autoimmune disease. Over the last two decades, the molecular basis and pathophysiology of the disease has been defined as follows. IgG class autoantibodies target molecules of the cadherin supergene family. In pemphigus foliaceus, (PF), the autoantigen is Desmoglein 1 (Dsg1). In pemphigus vulgaris (PV), autoantibodies recognize Desmoglein 3 (Dsg3)1 in patients with just oral disease, and both Dsg3 and Dsg1 in those with mucocutaneous invovlement2. The autoantibodies have been proven by us to play a primary pathogenic role in the blister formation by a passive transfer model in neonatal mice 3. The importance of Dsg3 as an adhesion molecule was confirmed when genetically engineered mice with a targeted disruption of Dsg3 gene developed mucocutaneous lesions typical of pemphigus vulgaris4. The strong linkage of disease susceptibility to HLA DR4 and DR6 genes has also been established5,6,7. However, current models do not allow us to examine the initiation of autoimmunity against these antigens, the natural course of the disease or potential immunologic interventions. The goal of our study is to develop an active autoimmune model of PV by breaking immune tolerance in susceptible strains of mice using three different strategies: 1. To break immune tolerance in transgenic mice expressing the human HLA DR4 gene (HLA-DRB1*0402) by immunization with recombinant human Dsg3. 2. To break immune tolerance in mice by injection with naive antigen presenting cells (APC), derived from murine fetuses of the same genetic background, and pulsed with recombinant human Dsg3. 3. To break immune tolerance in mice by immunizing with murine fibroblasts, stably transfected with full length of murine major histocompatibility complex (MHC) class II molecule and the extracellular portion of murine Dsg3. Pemphigus is a """"""""clean"""""""" model of autoimmunity, and is an ideal candidate disease that could allow us to study fundamental mechanisms of autoimmunity, potential immune manipulation and immunologic therapies. This cannot occur in the absence of an active disease model, which we propose to develop by these studies.
| Anhalt, Grant J (2004) Paraneoplastic pemphigus. J Investig Dermatol Symp Proc 9:29-33 |
| Thorne, Jennifer E; Anhalt, Grant J; Jabs, Douglas A (2004) Mucous membrane pemphigoid and pseudopemphigoid. Ophthalmology 111:45-52 |
| Nikolskaia, O V; Nousari, C H; Anhalt, G J (2003) Paraneoplastic pemphigus in association with Castleman's disease. Br J Dermatol 149:1143-51 |
| Mimouni, Daniel; Anhalt, Grant J; Cummins, Deborah L et al. (2003) Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil. Arch Dermatol 139:739-42 |
