IgG4, complement, and the mechanisms of blister formation in pemphigus and bullous pemphigoid.

Autoimmune bullous diseases are at the forefront of the research field on autoimmune diseases. Pemphigus and pemphigoid were historical entities in the world of descriptive dermatology for a long time. Recently, however, dermatologists and skin biologists have elegantly explained the novel pathomechanism of pemphigus and pemphigoid diseases. IgG4 is the major subclass of autoantibodies in autoimmune bullous diseases and is known to have little activity to activate complement. It is quite acceptable for pemphigus, because acantholysis in pemphigus has been demonstrated to be complement-independent. On the other hand, subepidermal blister formation in bullous pemphigoid has been believed to be complement-dependent. Therefore, the role of IgG4 autoantibodies on blister formation in bullous pemphigoid remains controversial. Here, we examine the progress of research on the mechanisms of blister formation in autoimmune bullous diseases. We focus on the complement-dependent and independent blistering in bullous pemphigoid using comparisons between pemphigus diseases. In addition, we review the current understanding of the role of IgG4 antibodies in bullous pemphigoid.

Dainichi T ，Chow Z ，Kabashima K 《-》

Comparison of IgG subclasses and complement binding activity of autoantibodies from patients with bullous pemphigoid and pemphigus.

Brooks WS ，Lee YY ，Abell E ，Deng JS ... -  《JOURNAL OF CLINICAL LABORATORY ANALYSIS》

Human IgG1 monoclonal antibody against human collagen 17 noncollagenous 16A domain induces blisters via complement activation in experimental bullous pemphigoid model.

Li Q ，Ujiie H ，Shibaki A ，Wang G ，Moriuchi R ，Qiao HJ ，Morioka H ，Shinkuma S ，Natsuga K ，Long HA ，Nishie W ，Shimizu H ... -  《-》

Bullous pemphigoid autoantibodies directly induce blister formation without complement activation.

Complement activation and subsequent recruitment of inflammatory cells at the dermal/epidermal junction are thought to be essential for blister formation in bullous pemphigoid (BP), an autoimmune blistering disease induced by autoantibodies against type XVII collagen (COL17); however, this theory does not fully explain the pathological features of BP. Recently, the involvement of complement-independent pathways has been proposed. To directly address the question of the necessity of the complement activation in blister formation, we generated C3-deficient COL17-humanized mice. First, we show that passive transfer of autoantibodies from BP patients induced blister formation in neonatal C3-deficient COL17-humanized mice without complement activation. By using newly generated human and murine mAbs against the pathogenic noncollagenous 16A domain of COL17 with high (human IgG1, murine IgG2), low (murine IgG1), or no (human IgG4) complement activation abilities, we demonstrate that the deposition of Abs, and not complements, is relevant to the induction of blister formation in neonatal and adult mice. Notably, passive transfer of BP autoantibodies reduced the amount of COL17 in lesional mice skin, as observed in cultured normal human keratinocytes treated with the same Abs. Moreover, the COL17 depletion was associated with a ubiquitin/proteasome pathway. In conclusion, the COL17 depletion induced by BP autoantibodies, and not complement activation, is essential for the blister formation under our experimental system.

Ujiie H ，Sasaoka T ，Izumi K ，Nishie W ，Shinkuma S ，Natsuga K ，Nakamura H ，Shibaki A ，Shimizu H ... -  《-》

Diagnosis and classification of pemphigus and bullous pemphigoid.

Pemphigus and bullous pemphigoid represent the two major groups of autoimmune blistering diseases. Pemphigus has three major variants: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus and is characterized by autoantibodies directed against the cell surface of keratinocytes, producing acantholysis that in turn leads to intraepithelial blisters in the skin and/or mucous membranes. In bullous pemphigoid, the autoantibodies are present at the dermo-epidermal junction and attack the hemidesmosomes, causing subepidermal blister formation. The classification of the major variants of both the pemphigus group and bullous pemphigoid can be based on the combination of clinical, histopathological and immunopathological criteria. Many tools are available for the diagnosis of these entities including biopsy, direct and indirect immunofluorescence, immunoprecipitation, immunoblotting and ELISA. However, currently there are no generally accepted criteria for the diagnosis of these disorders. The present review provides a proposal for diagnostic criteria.

Kershenovich R ，Hodak E ，Mimouni D 《-》