Clarification of pathophysiological mechanisms of autoimmune skin disease, pemphigus

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Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by IgG autoantibodies directed against desmogleins (Dsg), cadherin-type cell-cell adhesion molecules found in desmosomes. The goal of this study is to clarify the immunological mechanisms of autoimmune diseases by taking two unique approaches ; analyzing pemphigus model mice and investigating the contact points of skin infection and autoimmunity.We have achieved the following progresses ; 1)isolated 8 clones for pathogenic and non-pathogenic AK-series anti-Dsg3 mAbs from PV model mice and showed the epitope is a critical factor determining the pathogenicity, 2)developed B cell transgenic mice from cDNA for the variable regions of AK7 mAb and analyzed the fate of the autoreactive B cells, 3)developed several Dsg3-reactive T cell clones from Dsg3-/- mice and analyzed their roles in the production of pathogenic anti-Dsg3 Abs, 4)clarified the molecular mechanisms that exfoliative toxins (ETA,ETB, and ETD) produced by S.aureus, which causes SSSS and bullous impetigo, are Dsg1-specific serine proteases, 5)demonstrated that some patients with SSSS developed low titers of anti-Dsg1 IgG autoantibodies.We further achieved the following unexpected progresses ; 6)found a potentially new peripheral B cell tolerance mechanism by showing the elimination of Dsg3-specific B cells from peripheral lymphoid organs by injection of pathogenic AK23 mAb, 7)demonstrated the autoimmune reaction against a novel desmoglein isoform, Dsg4, in subsets of pemphigus patients, providing a new framework for better understanding the onset of autoimmune diseases including autoimmune alopecia.We have established a unique physiological system for organ-specific autoimmune diseases by using PV model mice, Dsg3-specific B cell transgenic mice, and, in the near future, Dsg3-specific T cell transgenic mice. We aimed to establish a novel standard experimental system to uncover the mysteries of autoimmunity and tolerance to peripheral antigens.