Monovalent Fab' immunoglobulin fragments from endemic pemphigus foliaceus autoantibodies reproduce the human disease in neonatal Balb/c mice.

Rock, Barbara; Labib, Ramzy S.; Díaz, Luis A.

doi:10.1172/jci114426

Cited by 127 publications

(69 citation statements)

References 12 publications

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“…The finding that scFv mAbs can induce blisters in mice clinically and histologically similar to those observed in pemphigus patients and also interfere with the adhesive function of Dsg1 and Dsg3 in cultured human keratinocytes is consistent with direct disruption of desmoglein interactions by pemphigus autoantibodies, as shown in previous studies using serum-derived Fab′ fragments (17,18). Epitope mapping data using pemphigus IgG or pathogenic mAbs isolated from an adoptive transfer mouse model of pemphigus show that almost all pathogenic autoantibodies bind conformational epitopes in the desmoglein amino-terminal extracellular domain that is predicted to form the intercellular trans-adhesive interface (20,21,33).…”

Section: Discussionsupporting

confidence: 85%

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Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display

et al. 2005

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Pemphigus is a life-threatening blistering disorder of the skin and mucous membranes caused by pathogenic autoantibodies to desmosomal adhesion proteins desmoglein 3 (Dsg3) and Dsg1. Mechanisms of antibody pathogenicity are difficult to characterize using polyclonal patient sera. Using antibody phage display, we have isolated repertoires of human anti-Dsg mAbs as single-chain variable-region fragments (scFvs) from a patient with active mucocutaneous pemphigus vulgaris. ScFv mAbs demonstrated binding to Dsg3 or Dsg1 alone, or both Dsg3 and Dsg1. Inhibition ELISA showed that the epitopes defined by these scFvs are blocked by autoantibodies from multiple pemphigus patients. Injection of scFvs into neonatal mice identified 2 pathogenic scFvs that caused blisters histologically similar to those observed in pemphigus patients. Similarly, these 2 scFvs, but not others, induced cell sheet dissociation of cultured human keratinocytes, indicating that both pathogenic and nonpathogenic antibodies were isolated. Genetic analysis of these mAbs showed restricted patterns of heavy and light chain gene usage, which were distinct for scFvs with different desmoglein-binding specificities. Detailed characterization of these pemphigus mAbs should lead to a better understanding of the immunopathogenesis of disease and to more specifically targeted therapeutic approaches.

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Section: Discussionsupporting

confidence: 85%

“…The relationship of the valence of autoantibodies to pathogenicity has been examined (17,18). Fab′ monovalent fragments, prepared by proteolytic degradation and alkylation/ reduction of whole IgG from both PF and PV sera, cause histologically typical disease when passively transferred to neonatal mice.…”

Section: Introductionmentioning

confidence: 99%

Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display

et al. 2005

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“…Each animal received a total dose of 12.5 g of inhibitor. After 18 h, the skin of neonatal mice from the test and control groups was examined clinically and histologically as described (1,25). Perilesional skin biopsies were examined by direct immunof luorescence (IF) for the presence of PV IgG bound to the epidermal epithelium.…”

Section: Resultsmentioning

confidence: 99%

“…In this model, the IgG fraction from patients and control nonaffected normal individuals is purified and passively transferred into neonatal mice (1,25), reproducing the clinical and histological features of the human disease. We now demonstrate that inhibitors of p38MAPK prevent blister formation in this PV mouse model.…”

mentioning

confidence: 99%

p38MAPK inhibition prevents disease in pemphigus vulgaris mice

Berkowitz¹,

Hu²,

Warren³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

206

197

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Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering skin disease characterized by detachment of keratinocytes (acantholysis). It has been proposed that PV IgG might trigger signaling and that this process may lead to acantholysis. Indeed, we recently identified a rapid and dose-dependent phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and heat shock protein (HSP) 27 after binding of PV antibodies to cultured keratinocytes. In human keratinocyte cultures, inhibitors of p38MAPK prevented PV IgG-induced phosphorylation of HSP27 and, more importantly, prevented the early cytoskeletal changes associated with loss of cell-cell adhesion. This study was undertaken to (i) determine whether p38MAPK and HSP25, the murine HSP27 homolog, were similarly phosphorylated in an in vivo model of PV and (ii) investigate the potential therapeutic use of p38MAPK inhibition to block blister formation in an animal model of PV. We now report that p38MAPK inhibitors prevented PV blistering disease in vivo. Targeting the end-organ by inhibiting keratinocyte desmosome signaling may be effective for treating desmosome autoimmune blistering disorders.autoimmune ͉ signaling P emphigus vulgaris (PV) is a life-threatening autoimmune blistering disease where the autoimmune response targets the epidermis and mucosal epithelia, resulting in f laccid blisters and erosions. The loss of epithelial integrity disrupts the skin barrier function, putting patients at risk for infection as well as f luid and electrolyte imbalance. Before the introduction of systemic corticosteroids, the disease was highly lethal. Although the mortality has been reduced through the use of steroids and potent immunosuppressive drugs, the disease remains lethal, and patients often suffer from and may succumb to the secondary effects of the medications used to treat the disease.In PV, IgG autoantibodies that bind to the surface of epithelial cells are pathogenic. IgG purified from PV patient sera causes blistering in mouse models (1, 2). In the PV IgG passive transfer model, autoantibodies purified from patient sera bind to keratinocyte desmoglein 3 (dsg3) (3-5) and induce loss of cell-cell adhesion, reproducing the clinical and histological features of the human disease (1, 2). In both the human disease and the PV mouse model, gentle friction of perilesional skin causes sloughing of epidermal sheets (Nikolsky's sign). Although the model mimics aspects of the disease, the molecular mechanisms of blister formation remain unresolved. In the passive transfer model, the epidermal cell-cell detachment induced by PV autoantibodies is neither Fc-(6), complement-(7), nor plasminogen activator-dependent (8). Thus, the PV passive transfer mouse model represents an end-organ damage model triggered by anti-dsg3 autoantibodies.It has been proposed that PV IgG might trigger signaling and that this process may lead to acantholysis (9 -16). Indeed, we recently identified a rapid and dose-dependent phosphorylation of p38 mitogen-activated protein kinase (p38MA...

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“…The majority of these patients possess anti-desmoglein-1 (Dsg1) IgG autoantibodies that are predominantly of the IgG4 subclass (15). Passive transfer of FS anti-Dsg1 IgG into neonatal mice reproduces the key features of the human disease in the epidermis of these experimental animals (16,17). Dsg1 is a desmosomal glycoprotein that belongs to the cadherin family of cell adhesion molecules (18,19).…”

mentioning

confidence: 99%

Desmoglein-1–specific T lymphocytes from patients with endemic pemphigus foliaceus (fogo selvagem)

Lin¹,

Fu²,

Aoki³

et al. 2000

J. Clin. Invest.

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Monovalent Fab' immunoglobulin fragments from endemic pemphigus foliaceus autoantibodies reproduce the human disease in neonatal Balb/c mice.

Cited by 127 publications

References 12 publications

Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display

Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display

p38MAPK inhibition prevents disease in pemphigus vulgaris mice

Desmoglein-1–specific T lymphocytes from patients with endemic pemphigus foliaceus (fogo selvagem)

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