Is Endoplasmic Reticulum Stresslinked to the Pathogenesis of Pemphigus Vulgaris?

Abstract

Pemphigus vulgaris (PV) is anorgan-specific autoimmune blistering disease, affecting the skin and the mucous membranes. Despite the breakthroughs in therapy for advanced disease in the recent years, the management of PV remains challenging with poor prognosis and limited therapeutic options.Cloning of cDNAs encoding pemphigus antigens has provided ample evidence that IgG autoantibodies recognize the desmogleins (DSGs) that are found in the adhering junctions, the desmosomes. Binding of such IgGs in the DSGs results in the weakeningof intercellular adhesion of keratinocytes in the upper part of the epidermis and eventually to acantholysis. Desmosomes have instrumental roleas a protective barrier in maintaining the integrity and function of the epidermis and the mucous epithelia.Mechanistically, the production of IgG autoantibodies against DSG1 and DSG3 is linked to disease pathogenesis. Recently,endoplasmic reticulum (ER) stress,a highly conserved cellular stress response,has been proposed to play a role in the development and progression of PV. ER stress triggers the activation ofseveral intracellular signaling pathwaysthat collectively constitute the unfolded protein response (UPR) thatinitially aims to restore homeostaticbalance while subsequently becomes proapoptotic. The discovery that ER stress occurs during PV development implies that deregulated UPR may contribute to the pathogenesis of the disease. Future studies should be directed toward understanding how modulation of the ER can provide new therapeutic possibilities for the treatment of  PV patients.Key Words:Pemphigus Vulgaris (PV), desmogleins (DSGs), Endoplasmic Reticulum (ER) stress ER-stress, Unfolded protein response (UPR), C/EBP-homologous protein (CHOP), autoimmune disease