Pathogenic relevance of autoantibodies to BP180/type XVII collagen on keratinocytes
Project management at the University of Würzburg:
Bullous pemphigoid (BP) is an inflammatory subepidermal blistering disease that is associated with autoantibodies to the keratinocyte surface protein, BP180. In addition to the binding of autoantibodies, the infiltration of inflammatory cells is necessary for blister formation. Cytokines, including IL-6 and IL-8, have been implicated in this disease process in both human and experimental murine BP. The present studies aimed at testing the hypothesis that the binding of anti-BP180 antibodies to their target antigen triggers a signal transduction event that results in the secretion of these pro-inflammatory cytokines. Consistent with this hypothesis, treatment of cultured normal human epidermal keratinocytes with BP IgG, but not control IgG, led to increased levels of IL-6 and IL-8, but not IL-1alpha, IL-1beta, TNFalpha, IL-10, or MCP-1, in the culture medium. This effect was dose and time-dependent and was abolished by depleting the BP IgG of reactivity to two distinct epitopes on the BP180 NC16A domain. Up-regulation of IL-6 and IL-8 was found at both protein and mRNA levels. In addition, BP IgG did not induce the release of IL-6 and IL-8 from BP180-deficient keratinocytes obtained from a patient with generalized atrophic benign epidermolysis bullosa. These data indicate that BP-associated autoantibodies to the human BP180 ectodomain trigger a signal transducing event that leads to expression and secretion of IL-6 and IL-8 from human. Further studies demonstrated that the BP180-mediated release of IL-8 is inhibited by dapsone, which is commonly used to treat BP. In contrast, dapsone did not affect the IL-8 synthesis. This observation suggests that dapsone inhibits the IL-8 relase from cultured keratinocytes, induced by autoantibodies, by mechanisms at the post-transcritional level.
Projekt period: from 03.2000 to 02.2002
DFG ( Zi 439/4-1 ) ,Granting date: 22.01.2000
IZKF Z 4-4