Functional Evidence for Complement-activating Immune Complexes in the Skin of Patients with Bullous Pemphigoid

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

doi:10.1111/1523-1747.ep12497912

Cited by 41 publications

(6 citation statements)

References 21 publications

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“…This resulted, in fact, in an increased in¯ux of neutrophils into the upper dermis of the graft, but not in subepidermal blisters. In contrast to acantholysis in pemphigus, blister formation in BP requires in¯ammatory cells and mediators in addition to autoantibodies [27,31,32]. One may speculate that SCID mice lack suf®cient numbers of in¯ammatory cells, necessary for BP blister formation.…”

Section: Discussionmentioning

confidence: 99%

Antibodies to desmogleins 1 and 3, but not to BP180, induce blisters in human skin grafted onto SCID mice

et al. 2001

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Pemphigus and bullous pemphigoid (BP) are blistering skin diseases associated with IgG autoantibodies to desmosomal and hemidesmosomal components. When autoantibodies to desmogleins 1 and 3 from patients with pemphigus foliaceus (PF) and pemphigus vulgaris (PV) or rabbit antibodies against the murine hemidesmosomal component BP180 are passively transferred into neonatal mice, they induce blisters in the skin of the mice. To develop an animal model that would duplicate the findings in the skin of the patients more closely, full-thickness human skin from healthy volunteers was grafted onto SCID mice. Injection of the purified IgG fraction from the serum of PF and PV patients led to subcorneal and suprabasal splits in the human grafts and human IgG was deposited intercellularly in the upper and lower layers of the epidermis, respectively. Interestingly, anti-BP180 autoantibodies purified from the serum of BP patients and from a rabbit immunized with recombinant human BP180 strongly bound to the basement membrane zone of the grafts (n=32), fixed murine complement, led to the recruitment of neutrophils to the upper dermis of the graft, but did not induce subepidermal blisters. We report a novel experimental model for PF and PV which should greatly facilitate further studies to dissect the immunopathological mechanisms in these diseases. Specifically, this model can be used to identify pathogenically relevant epitopes on human desmogleins 1 and 3 and to develop novel strategies for the treatment of pemphigus.

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Section: Discussionmentioning

confidence: 99%

Antibodies to desmogleins 1 and 3, but not to BP180, induce blisters in human skin grafted onto SCID mice

et al. 2001

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“…Manipulations that interfered with complement activation also resulted in a drastic reduction of neutrophil influx into the dermis of the animals (13), suggesting that neutrophils may play a key role in blister formation in the experimental BP/HG model. Previous findings reported by Gammon et al (14) using an in vitro model of BP led to the hypothesis that subepidermal blistering in BP is dependent upon antibody binding to an antigen of the DEJ, complement activation and an inflammatory infiltration of lesional skin. 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.…”

Section: Introductionmentioning

confidence: 98%

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 differential expression of intensity between IgG and C3 among the above disorders is not understood. [81][82][83] Multiple deposits at the BMZ. This pattern of deposition strongly favors EBA (Fig 4, A) and bullous SLE over the pemphigoid group of diseases.…”

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confidence: 99%