Pemphigus vulgaris (PV and pemphigus foliaceous (PF) are life-threatening autoimmune blistering diseases. In PV, antibodies against desmoglein 3 (Dsg3) cause loss of cell adhesion in the deep layers of stratified squamous epithelia, whereas in PF, anti-desmoglein 1 (Dsg1) antibodies cause loss of cell adhesion in superficial epidermis but not in mucous membrane. It has been speculated that pemphigus antibodies cause loss of cell adhesion directly by their effect on desmogleins or more indirectly through release of plasminogen activator (PA). The goal of this project is to understand the pathophysiology of pemphigus including why blisters form, where they form, and what factors might modulate blister formation induced by autoantibodies. Pemphigus antibody pathogenicity will be studied in an established neonatal mouse passive transfer model. The first specific aim is to determine if urokinase (u-PA) or tissue-PA (t-PA) is necessary for, or modulates, pathogenicity of PV and PF antibodies. Pemphigus IgG will be injected in neonatal mice that are genetically deficient in u-PA, t-PA, or both, or that over-express PA inhibitor 1 in skin. The second specific aim is designed to test the hypothesis that the tissue-distribution and the level of the blister within the tissue is dependent on the distributions and overlapping expression of Dsg3 and Dsg1. PF antibodies will be injected in neonatal DSG3 knockout mice. In these same mice it can be determined if the anti-Dsg1 antibodies found in most PV sera are pathogenic. PF and PV antibodies will also be injected in neonatal transgenic mice expressing Dsg3 throughout the epidermis. The third specific aim is designed to determine whether Dsg1 can substitute for Dsg3 in stabilizing adhesion in the deep epidermis by rescuing the PV-like phenotype of DSG3 knockout mice with a transgene expressing Dsg1 under the control of a K14 promoter. Finally, it will be determined if glucocorticoids can stabilize adhesion and rescue the PV phenotype in these knockout mice.
| Amagai, Masayuki; Stanley, John R (2012) Desmoglein as a target in skin disease and beyond. J Invest Dermatol 132:776-84 |
