A major role for neutrophils in experimental bullous pemphigoid.
Bullous pemphigoid (BP) is an inflammatory subepidermal blistering disease associated with an IgG autoimmune response to the hemidesmosomal protein, BP180. Using a passive transfer mouse model, our group has shown previously that antibodies to the murine BP180 (mBP180) ectodomain are capable of triggering a blistering skin disease that closely mimics human BP. In this study, we investigated the role of neutrophils in the immunopathogenesis of this disease model. BALB/c mice depleted of circulating neutrophils by treatment with neutrophil-specific antibodies were no longer susceptible to the pathogenic effects of anti-mBP180 IgG. IgG and complement were deposited at the dermal-epidermal junction of these animals, but there was no evidence of inflammatory infiltration or blistering. C5-deficient mice, which are resistant to the pathogenic activity of anti-mBP180 IgG, could be made susceptible to this IgG-mediated blistering disease by intradermal administration of a neutrophil chemoattractant, IL-8 or C5a. Intraperitoneal injection of IL-8, which sequesters neutrophils in the peritoneal cavity, interferes with anti-mBP180-induced neutrophilic infiltration of the skin and prevented the development of BP disease in BALB/c mice. These findings provide the first direct evidence that neutrophils recruited to the skin via a C5-dependent pathway play an essential role in subepidermal blister formation in experimental BP, and suggest new directions for disease intervention.
Liu
Z
Z
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. zhiliu@post.its.mcw.edu
Giudice
G J
GJ
Zhou
X
X
Swartz
S J
SJ
Troy
J L
JL
Fairley
J A
JA
Till
G O
GO
Diaz
L A
LA
D000818:Animals; D003167:Complement Activation; D015936:Complement C5a / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D016209:Interleukin-8 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000502:physiology*; D010391:Pemphigoid, Bullous / Q000276:immunology*; D009195:Peroxidase / Q000378:metabolism; D011817:Rabbits
D007074:Immunoglobulin G; D016209:Interleukin-8; D015936:Complement C5a; D009195:Peroxidase