Autoantibodies to BP180 associated with bullous pemphigoid release interleukin-6 and interleukin-8 from cultured human keratinocytes.
Bullous pemphigoid is an inflammatory subepidermal blistering disease that is associated with auto- antibodies 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 interleukin-6 and interleukin-8, have been implicated in the disease process of both human and experimental murine bullous pemphigoid. This study was 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 bullous pemphigoid IgG, but not control IgG, led to increased levels of interleukin-6 and interleukin-8, but not interleukin-1alpha, interleukin-1beta, tumor necrosis factor-alpha, interleukin-10, or monocyte chemoattractant protein-1, in the culture medium. This effect was concentration- and time-dependent and was abolished by depleting the bullous pemphigoid IgG of reactivity to two distinct epitopes on the BP180 NC16A domain. Upregulation of interleukin-6 and interleukin-8 was found at both protein and mRNA levels. In addition, bullous pemphigoid IgG did not induce the release of interleukin-6 and interleukin-8 from BP180-deficient keratinocytes obtained from a patient with generalized atrophic benign epidermolysis bullosa. These data indicate that bullous pemphigoid-associated autoantibodies to the human BP180 ectodomain trigger a signal transducing event that leads to expression and secretion of interleukin-6 and interleukin-8 from human keratinocytes.
Schmidt
E
E
Department of Dermatology, University of Würzburg, Würzburg, Germany.
Reimer
S
S
Kruse
N
N
Jainta
S
S
Bröcker
E B
EB
Marinkovich
M P
MP
Giudice
G J
GJ
Zillikens
D
D
D001323:Autoantibodies / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology*; D002478:Cells, Cultured; D007074:Immunoglobulin G / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D024041:Non-Fibrillar Collagens; D010391:Pemphigoid, Bullous / Q000097:blood / Q000276:immunology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D012333:RNA, Messenger / Q000502:physiology; D015854:Up-Regulation; D000097805:Collagen Type XVII
D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D015850:Interleukin-6; D016209:Interleukin-8; D024041:Non-Fibrillar Collagens; D012333:RNA, Messenger; D000097805:Collagen Type XVII