An in Vitro Model of Immune Complex-mediated Basement Membrane Zone Separation Caused by Pemphigoid Antibodies, Leukocytes, and Complement

Gammon, W. Ray; Merritt, Carolyn C.; Lewis, Daniel M.; Sams, W. Mitchell; Carlo, Jaime R.; Wheeler, Clayton E.

doi:10.1111/1523-1747.ep12507222

Cited by 151 publications

(78 citation statements)

References 32 publications

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“…In experimental BP, subepidermal blistering triggered by rabbit antimBP180 IgG depends on neutrophils and neutrophil-released proteolytic enzymes (18,54,55). In human BP, several lines of evidence using in vitro skin culture and cryosections systems demonstrated that dermal-epidermal separation induced by anti-BP180 autoantibodies also depends on neutrophils (58,59). However, another study showed that anti-BP180 autoantibodies are directly pathogenic without the need of neutrophils in the human skin culture system and SCID mice grafted with human skin (60).…”

Section: Discussionmentioning

confidence: 99%

Role of FcRs in Animal Model of Autoimmune Bullous Pemphigoid

Zhao¹,

Trimbeger²,

Li³

et al. 2006

The Journal of Immunology

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Bullous pemphigoid (BP) is a bullous dermatosis associated with autoantibodies directed against the hemidesmosomal Ags BP180 and BP230. Lesional skin is characterized by detachment of the epidermis from the dermis with an intense inflammatory cell infiltrate in the upper dermis. In experimental BP, subepidermal blistering is triggered by rabbit anti-murine BP180 (mBP180) IgG and depends upon complement activation, mast cell degranulation, and neutrophil infiltration. In this study, we determined the role of FcγRs on neutrophils in experimental BP. Mice deficient in FcγRIII (FcγRIII−/−) and those deficient in both FcγRI and FcγRIII (FcγRI&III−/−) but not in FcγRII (FcγRII−/−) were resistant to BP. Pathogenic IgG activated wild-type neutrophils, but not FcγRIII-deficient neutrophils, to secrete proteolytic enzymes. The function of anti-mBP180 IgG depended entirely on its Fc domain; F(ab′)2 of IgG had no pathogenic activities. In wild-type mice injected with pathogenic IgG, an FcγR blocker abolished the BP phenotype and inhibited activation of wild-type neutrophils stimulated by pathogenic IgG. Results from this study establish that FcγRIII plays a critical role in the activation of infiltrating neutrophils and the subsequent blistering in experimental BP.

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Section: Discussionmentioning

confidence: 99%

Role of FcRs in Animal Model of Autoimmune Bullous Pemphigoid

Zhao¹,

Trimbeger²,

Li³

et al. 2006

The Journal of Immunology

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“…These investigators showed that, when cryosections of normal human skin were incubated in an organ culture system with a BP serum plus an exogenous source of complement and human peripheral blood leukocytes, the inflammatory cells migrated and attached to the DEJ in these sections. Moreover, the sections developed focal dermalepidermal separation resembling early BP lesions (15), but only if the inflammatory cells were present. These observations provided the first indication that inflammatory cells, such as the neutrophil, may play a key role in the immunopathogenesis of BP/HG.…”

Section: Introductionmentioning

confidence: 97%

A major role for neutrophils in experimental bullous pemphigoid.

Li¹,

Giudice²,

Zhou³

et al. 1997

J. Clin. Invest.

235

210

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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 dermalepidermal 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 antimBP180 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. ( J.

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“…The positive correlation between the titer of IgG (predominately IgG1 and IgG4) to extracellular epitopes of BP180 and BP disease severity is well recognized. In vitro studies and animal models have demonstrated the critical role of Fc receptor-mediated effects in blister formation [19][20][21]. Liu et al described an animal model in which purified rabbit anti-murine BP180 was passively transferred into neonatal mice.…”

Section: Humoral Immune Responsementioning

confidence: 99%