Bullous pemphigoid (BP) is the most common autoimmune blistering diseases (AIBD), mainly targeting type XVII collagen (CLO17). Intravenous immunoglobulin (IVIg) is used to treat numerous autoimmune diseases, including BP. The major mechanism of action for IVIgin AIBD is thought to be an immunomodulatory effect. However, little is known about the precise mechanisms of IVIg in BP. We investigated the effects of IVIg for the treatment of BP, using cell culture system. IgG from BP patients (BP-IgG) targeting NC16A domain of COL17 induces the depletion of COL17 in cultured keratinocytes. The COL17 levels detected by Western blotting in keratinocyte were found to be decreased by 50% after BP-IgG stimulation, resulting in decreased adhesion strength. In contrast, BP-IgG with IVIg was found to result in 70-90% increases in COL17 compared to BP-IgG without IVIg. The titer of BP-IgG detected by COL17 NC16A ELISA was measured with IVIg to investigate the mechanism of action of IVIg in the COL17-depletion. As a result, IVIg pretreatment reduced the titer by 30%. These results suggest that IVIg impairs the binding of BP-IgG to COL17, in which IVIg may function as an anti-idiotypic antibody. To confirm it, we depleted anti-idiotypic antibodies from IVIG. IVIg contained approximately 0.02% of anti-idiotypic antibodies against BP-IgG. The titer of BP-IgG was measured in the presence of IVIg with or without idiotype. The titer was decreased in setting of BP-IgG with IVIg containing idiotype, but not BP-IgG without idiotype. Furthermore, similar result was found in cell adhesion assay and cryosecion assay. These findings suggest that IVIg contains anti-idiotypic antibodies against BP-IgG. These antibodies may show clinical effects on BP by preventing COL17-depletion and dermal-epidermal separation induced by BP-IgG.

High-dose immunoglobulin contains anti-idiotypic antibodies against BP-IgG