Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies.

Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease that occurs in association with underlying neoplasms. Patients with PNP develop characteristic IgG autoantibodies directed against multiple antigens, most of which have been identified as cytoplasmic proteins of the plakin family (desmoplakin I, II, BPAG1, envoplakin, and periplakin). This study identified cell surface target antigens of PNP. We focused on desmoglein (Dsg) 3 and Dsg1, the autoantigens of pemphigus vulgaris and pemphigus foliaceus. ELISA using baculovirus-expressed recombinant Dsgs (rDsg3, rDsg1) has revealed that 25 out of 25 PNP sera tested were positive against Dsg3 and 16 of 25 were positive against Dsg1. All of 12 PNP sera tested immunoprecipitated Dsg3. Removal of anti-Dsg3 autoantibodies by immunoadsorption was sufficient to eliminate the ability of PNP sera to induce cutaneous blisters in neonatal mice in vivo. Furthermore, anti-Dsg3-specific antibodies that were affinity purified from PNP sera were proven to be pathogenic and caused blisters in neonatal mice. These findings indicate that Dsg3 and Dsg1 are the cell surface target antigens in PNP and that IgG autoantibodies against Dsg3 in PNP sera play a pathogenic role in inducing loss of cell adhesion of keratinocytes and causing blister formation.

Anti-p200 pemphigoid has been characterized by autoantibodies to an unidentified 200-kDa protein (p200) of the dermal−epidermal junction. The objective of this study was to identify p200. We performed 2D gel electrophoresis of dermal extracts and immunoblotting with patients' sera, followed by MS analysis of a unique protein band. The protein band corresponded to laminin γ1. Anti-laminin γ1 mAb reacted with the anti-p200 immunoprecipitates by immunoblotting. Sera from 32 patients with anti-p200 pemphigoid showed 90% reactivity to the recombinant products of laminin γ1. None of the healthy control sera reacted with laminin γ1. By immunoblotting, reactivity of a patient's serum with p200 was competitively inhibited by adding anti-laminin γ1 C -terminus mAb. Purified anti-p200 IgG also inhibited the reactivity of this mAb to dermal laminin γ1. Most laminin γ1-positive sera showed reactivity with recombinant laminin γ1 C -terminal E8 fragment. Reactivity of patients' sera and purified IgG to dermal laminin γ1 was higher than reactivity to blood vessel laminin γ1 under reducing conditions. These results suggest that laminin γ1 is the autoantigen for patients with anti-p200 pemphigoid. The autoantibodies may specifically recognize dermal laminin γ1 with unique posttranslational modifications. The epitope is localized to the 246 C -terminal amino acids within the coiled-coil domain. The 9 C -terminal residues are known to be critically involved in laminin recognition by integrins.

Pemphigus vulgaris (PV) is an autoimmune blistering disease of skin and mucous membranes caused by autoantibodies to the desmoglein (DSG) family proteins DSG3 and DSG1, leading to loss of keratinocyte cell adhesion. To learn more about pathogenic PV autoantibodies, we isolated 15 IgG antibodies specific for DSG3 from 2 PV patients. Three antibodies disrupted keratinocyte monolayers in vitro, and 2 were pathogenic in a passive transfer model in neonatal mice. The epitopes recognized by the pathogenic antibodies were mapped to the DSG3 extracellular 1 (EC1) and EC2 subdomains, regions involved in cis-adhesive interactions. Using a site-specific serological assay, we found that the cis-adhesive interface on EC1 recognized by the pathogenic antibody PVA224 is the primary target of the autoantibodies present in the serum of PV patients. The autoantibodies isolated used different heavy- and light-chain variable region genes and carried high levels of somatic mutations in complementary-determining regions, consistent with antigenic selection. Remarkably, binding to DSG3 was lost when somatic mutations were reverted to the germline sequence. These findings identify the cis-adhesive interface of DSG3 as the immunodominant region targeted by pathogenic antibodies in PV and indicate that autoreactivity relies on somatic mutations generated in the response to an antigen unrelated to DSG3.