The autoimmune disease pemphigus vulgaris (PV) manifests as loss of keratinocyte cohesion triggered by autoantibody binding to desmoglein (Dsg)3, an intercellular adhesion molecule of mucous membranes, epidermis, and epidermal stem cells. Here we describe a so far unknown signaling cascade activated by PV antibodies. It extends from a transient enhanced turn over of cell surfaceexposed, nonkeratin-anchored Dsg3 and associated plakoglobin (PG), through to depletion of nuclear PG, and as one of the consequences, abrogation of PG-mediated c-Myc suppression. In PV patients (6/6), this results in pathogenic c-Myc overexpression in all targeted tissues, including the stem cell compartments. In summary, these results show that PV antibodies act via PG to abolish the c-Myc suppression required for both maintenance of epidermal stem cells in their niche and controlled differentiation along the epidermal lineage. Besides a completely novel insight into PV pathogenesis, these data identify PG as a potent modulator of epithelial homeostasis via its role as a key suppressor of c-Myc.

BP showed a mean incidence of 12.1 new cases per million people per year. Its incidence increased significantly after the age of 70 years, with a maximal value after the age of 90 years. The female/male ratio was 1.3. The age-standardized incidence of BP using the European population as reference was, however, lower, with 6.8 new cases per million people per year, reflecting the ageing of the Swiss population. In contrast, both PV and PF were less frequent. Their combined mean incidence was 0.6 new cases per million people per year. CONCLUSIONS; This is the first comprehensive prospective study analysing the incidence of autoimmune bullous diseases in an entire country. Our patient cohort is large enough to establish BP as the most frequent autoimmune bullous disease. Its incidence rate appears higher compared with other previous studies, most likely because of the demographic characteristics of the Swiss population. Nevertheless, based on its potentially misleading presentations, it is possible that the real incidence rate of BP is still underestimated. Based on its significant incidence in the elderly population, BP should deserve more public health concern.

Bullous pemphigoid, the most common autoimmune subepidermal bullous disorder, is associated with autoantibodies targeting antigenic sites clustered within the extracellular domain of BP180. To investigate epitope and subclass specificity of autoantibodies in bullous pemphigoid, we developed an enzyme-linked immunosorbent assay utilizing baculovirus-expressed recombinant forms of the NH2- and COOH-terminal regions of the extracellular domain of BP180 and examined sera obtained from patients with active bullous pemphigoid (n=116) and controls (n=100). Ninety-three (80%) and 54 (47%) of the 116 bullous pemphigoid sera recognized the NH2- and COOH-terminal regions, respectively, of the extracellular domain of BP180. Detailed analysis demonstrates that (i) this novel enzyme-linked immunosorbent assay is highly specific (98%) and sensitive (93%) as 108 of 116 bullous pemphigoid sera reacted with at least one of the baculovirus-derived recombinants, (ii) in active bullous pemphigoid, autoantibodies against the NH2-terminus of the extracellular domain of BP180 were predominantly of the IgG1 class, whereas a dual IgG1 and IgG4 response to this region was related to a more severe skin involvement, (iii) autoreactivity against both the NH2- and COOH-terminal regions was more frequently detected in patients with mucosal lesions, and (iv) levels of IgG (and IgG1) against the NH2-terminal, but not against the COOH-terminal portion of the extracellular domain of BP180, reflected disease severity indicating that autoantibodies against the NH2-terminus are critical in the pathogenesis of bullous pemphigoid. In conclusion, this novel enzyme-linked immunosorbent assay represents a highly sensitive and specific assay for rapid diagnosis of bullous pemphigoid and related disorders and may provide predictive parameters for the management of bullous pemphigoid patients.

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Although numerous chemokines act on monocytes, none of them is specific for these cells. Here, we show that breast and kidney–expressed chemokine (BRAK) is a highly selective monocyte chemoattractant. Migration efficacy and Bordetella pertussis toxin–sensitive Ca2+ mobilization responses to BRAK were strongly enhanced after treatment of monocytes with the cyclic AMP–elevating agents prostaglandin E2 and forskolin. BRAK is the first monocyte-selective chemokine, as other types of blood leukocytes or monocyte-derived dendritic cells and macrophages did not respond. Expression in normal skin keratinocytes and dermal fibroblasts as well as lamina propria cells in normal intestinal tissues suggests a homeostatic rather than an inflammatory function for this chemokine. In addition, macrophages were frequently found to colocalize with BRAK-producing fibroblasts. We propose that BRAK is involved in the generation of tissue macrophages by recruiting extravasated precursors to fibroblasts, which are known to secrete essential cytokines for macrophage development.

Bullous pemphigoid is a subepidermal blistering disease associated with auto-antibodies (auto-ab) to BP180 and BP230. We developed ELISAs utilizing baculovirus-encoded recombinant proteins of BP230 and BP180 and studied their diagnostic and prognostic values by assessing the profile of the auto-ab response in 127 patients with BP. 39 patients had focal involvement, whereas 88 had generalized disease; 51 individuals served as controls. The results indicate: (1) BP180 IgG reactivity was associated with an overall sensitivity of 0.953 and specificity of 0.940; (2) 105 of 127 BP patients also displayed BP230 auto-reactivity, the global diagnostic performance of which, however, was moderate compared to BP180-auto-reactivity (sensitivity 0.815 vs 0.953, specificity 0.648 vs 0.940); (3) 101 patients (79.5%) had concordant BP180 and BP230 reactivity; (4) the association between the presence of BP230 auto-reactivity and focal involvement was stronger than in generalized disease (odds ratio (OR) 17.7 vs 10.2), independently from BP180 auto-ab profile; (5) correlation of total IgG with IgG1 and IgG4 was variable for both BP180 and BP230. Collectively, the global diagnostic properties of the BP180-ELISA outperform those of the BP230-ELISA. Presence of BP230 auto-reactivity, however, supports the diagnosis of BP and might be indicative for the extent of the disease.

The presence of IgG and IgA autoantibody responses to BP180 in patients with three clinically distinct autoimmune bullous diseases indicates that an autoimmune response to the same distinct adhesion protein may lead to different clinical manifestations. It is therefore conceivable that variable epitopes of BP180 are targeted by the different autoantibody isotypes, resulting in the distinct clinical pictures.

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