The Anti-C1s Antibody TNT003 Prevents Complement Activation in the Skin Induced by Bullous Pemphigoid Autoantibodies

To the Editor
Chronic skin inflammation, subepidermal blistering, and severe itching are the clinical hallmarks of bullous pemphigoid (BP). The disease is caused by autoantibodies against type XVII collagen (COL17, BP180), more specifically, the extracellular fraction of the 16th noncollagenous domain of the protein (NC16A) (Schmidt and Zillikens, 2013). Two pathways are thought to drive BP pathogenesis. First, autoantibody binding to COL17 leads to activation of the complement cascade, evidenced by the detection of complement deposits along the dermal-epidermal junction in patients with BP (Jordon et al., 1967, Jordon et al., 1975) and in mouse models of the disease (Iwata et al., 2015). For example, blockade of C1q or use of noncomplement activating mutant IgG as well as C4- and C5-deficient mice (Nelson et al., 2006) protected from anti-COL17 IgG transfer-induced blistering, thus underscoring the key relevance of the classical pathway of complement in BP pathogenesis (Li et al., 2010, Nelson et al., 2006). Second, noncomplement-dependent pathways lead to a depletion of COL17 (Ujiie et al., 2014), facilitated by protein kinase C-regulated micropinocytosis (Iwata et al., 2016). It is currently unclear which of these two mechanisms drives inflammation and blistering in patients with BP. Yet, the clinical description of an inflammatory and a noninflammatory BP phenotype (Izumi et al., 2016) provokes the assumption that complement-mediated blistering may be one of the driving disease pathways in patients with inflammatory BP.