IgE Basement Membrane Zone Antibodies Induce Eosinophil Infiltration and Histological Blisters in Engrafted Human Skin on SCID Mice

Zone, John J.; Taylor, Tomaro; Hull, Christopher M.; Schmidt, Linda; Meyer, Laurence

doi:10.1038/sj.jid.5700681

Cited by 96 publications

(75 citation statements)

References 34 publications

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“…Passive transfer of IgE autoantibodies, purified from patient sera, into human skin grafts on nude mice was shown to induce lesions in the grafted skin that reproduce the early phases of BP lesion development, including mast cell degranulation, eosinophil influx, formation of erythematous plaques, and histological separation at the BMZ (19). Zone and colleagues (21) made similar observations after s.c. injection of a murine IgE hybridoma specific for the shed ectodomain of human BP180 (LABD97) in SCID mice with engrafted human skin.…”

supporting

confidence: 57%

“…Although inflammation and skin fragility at the level of the BMZ were observed in the IgG passive transfer models, other hallmarks of BP that were absent included urticarial plaque formation, recruitment of eosinophils, and spontaneous subepidermal blistering (6,7,14). These shortcomings of the IgG-based models led to investigations into the role of IgE class autoantibodies in the BP disease process (17,(19)(20)(21). Passive transfer of IgE autoantibodies, purified from patient sera, into human skin grafts on nude mice was shown to induce lesions in the grafted skin that reproduce the early phases of BP lesion development, including mast cell degranulation, eosinophil influx, formation of erythematous plaques, and histological separation at the BMZ (19).…”

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confidence: 99%

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FcR-Independent Effects of IgE and IgG Autoantibodies in Bullous Pemphigoid

Messingham

Srikantha

DeGueme

et al. 2011

The Journal of Immunology

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Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by IgE and IgG class autoantibodies specific for 180-kDa BP Ag 2 (BP180), a protein involved in cell-substrate attachment. Although some direct effects of BP IgG have been observed on keratinocytes, no study to date has examined direct effects of BP IgE. In this study, we use primary cultures of human keratinocytes to demonstrate Ag-specific binding and internalization of BP IgE. Moreover, when BP IgE and BP IgG were compared, both isotypes stimulated FcR- independent production of IL-6 and IL-8, cytokines critical for BP pathology, and elicited changes in culture confluence and viability. We then used a human skin organ culture model to test the direct effects of these Abs on the skin, whereas excluding the immune inflammatory processes that are triggered by these Abs. In these experiments, physiologic concentrations of BP IgE and BP IgG exerted similar effects on human skin by stimulating IL-6 and IL-8 production and decreasing the number of hemidesmosomes localized at the basement membrane zone. We propose that the Ab-mediated loss of hemidesmosomes could weaken attachment of basal keratinocytes to the basement membrane zone of affected skin, thereby contributing to blister formation. In this article, we identify a novel role for IgE class autoantibodies in BP mediated through an interaction with BP180 on the keratinocyte surface. In addition, we provide evidence for an FcR-independent mechanism for both IgE and IgG class autoantibodies that could contribute to BP pathogenesis.

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supporting

confidence: 57%

mentioning

confidence: 99%

FcR-Independent Effects of IgE and IgG Autoantibodies in Bullous Pemphigoid

Messingham

Srikantha

DeGueme

et al. 2011

The Journal of Immunology

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“…Interestingly, the passive transfer models for BP using only IgG antibodies do not totally replicate human BP because eosinophil infiltration, a characteristic finding of human BP, is not detected in those models. 29,35 Zone et al 44 has successfully induced the itchy erythematous lesions in engrafted human skin on severe combined immunodeficiency (SCID) mice using IgE antibodies against LABD97, which is a component of the shed ectodomain of hCOL17. They developed an IgE hybridoma to the LABD97 antigen, and this hybridoma was injected s.c. in SCID mice with engrafted human skin.…”

Section: Ige Autoantibodies In Bpmentioning

confidence: 99%

What’s new in bullous pemphigoid

Ujiie

Shibaki

Nishie

et al. 2010

The Journal of Dermatology

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Bullous pemphigoid (BP) is the most common autoimmune blistering disease. BP patients have autoantibodies against type XVII collagen (COL17, also called BP180 or BPAG2), a type II transmembrane protein that spans the lamina lucida and projects into the lamina densa of the epidermal basement membrane. The non-collagenous 16A domain of COL17 is considered to contain pathogenic epitopes of BP. The transfer of immunoglobulin (Ig)G from BP patients fails to cause blisters on mouse skin probably due to differences between humans and mice in the amino acid sequence of NC16A pathogenic epitope of COL17. Passive transfer of rabbit IgG antibodies against the murine homolog of human COL17 NC16A triggers immune reactions to COL17 in mice, including complement activation, mast cell degranulation and neutrophilic infiltration, resulting in dermal-epidermal separation. Recent studies using COL17-humanized mice that express human COL17 but lack murine COL17 were the first to demonstrate the pathogenicity of anti-COL17 human BP IgG autoantibodies in vivo. These new findings provide a greater understanding of BP pathomechanisms and facilitate the development of novel specific and efficient therapeutic strategies for BP.

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“…All experimental animals used in this study were under a protocol approved by the Institutional Animal Care and Use Committee of the University of Utah. Human foreskin was grafted to mice as previously described (8,9). Immunopathological evaluation of the grafted skin with Abs to mouse IgG, IgM, IgA, and C3 showed no evidence of a mouse humoral immune response to the human skin graft.…”

Section: Laboratory Animalsmentioning

confidence: 99%

“…Biopsies were processed for histopathology with H&E staining and for direct immunofluorescence as described previously (9).…”

Section: Passive Transfer Of Goat Anti-tg3 Ab and Evaluation Of Graftsmentioning

confidence: 99%

Dermatitis Herpetiformis Sera or Goat Anti–Transglutaminase-3 Transferred to Human Skin-Grafted Mice Mimics Dermatitis Herpetiformis Immunopathology

Zone

Schmidt

Taylor

et al. 2011

The Journal of Immunology

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Dermatitis herpetiformis (DH) is characterized by deposition of IgA in the papillary dermis. However, indirect immunofluorescence is routinely negative, raising the question of the mechanism of formation of these immune deposits. Sárdy et al. (2002. J. Exp. Med. 195: 747–757) reported that transglutaminase-3 (TG3) colocalizes with the IgA. We sought to create such deposits using passive transfer of Ab to SCID mice bearing human skin grafts. IgG fraction of goat anti-TG3 or control IgG were administered i.p. to 20 mice. Separately, sera from seven DH patients and seven controls were injected intradermally. Biopsies were removed and processed for routine histology as well as direct immunofluorescence. All mice that received goat anti-TG3 produced papillary dermal immune deposits, and these deposits reacted with both rabbit anti-TG3 and DH patient sera. Three DH sera high in IgA anti-TG3 also produced deposits of granular IgA and TG3. We hypothesize that the IgA class anti-TG3 Abs are directly responsible for the immune deposits and that the TG3 is from human epidermis, as this is its only source in our model. These deposits seem to form over weeks in a process similar to an Ouchterlony immunodiffusion precipitate. This process of deposition explains the negative indirect immunofluorescence results with DH serum.

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IgE Basement Membrane Zone Antibodies Induce Eosinophil Infiltration and Histological Blisters in Engrafted Human Skin on SCID Mice

Cited by 96 publications

References 34 publications

FcR-Independent Effects of IgE and IgG Autoantibodies in Bullous Pemphigoid

FcR-Independent Effects of IgE and IgG Autoantibodies in Bullous Pemphigoid

What’s new in bullous pemphigoid

Dermatitis Herpetiformis Sera or Goat Anti–Transglutaminase-3 Transferred to Human Skin-Grafted Mice Mimics Dermatitis Herpetiformis Immunopathology

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