Bullous Pemphigoid: Using Animal Models to Study the Immunopathology

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Bullous Pemphigoid: Using Animal Models to Study the Immunopathology Zhi Liu Journal of Investigative Dermatology Symposium Proceedings Volume 9, Issue 1, Pages 41-46 (January 2004) DOI: 10.1111/j.1087-0024.2004.00841.x Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Human and mouse BP180. (A) Sequence comparison of human and murine BP180 proteins. A schematic representation of the structural organization of the human BP180 protein is shown at the top. The orange arch designates the transmembrane domain. The red oval designates the NC16A antigenic site recognized by BP autoantibodies. The COOH-terminal extracellular region is made up of 15 interrupted collagen-like domains (yellow rectangles). The box (in red) at the bottom shows the amino acid sequence alignment of the human and murine BP180 within the BP epitope. Identical residues are designated by double dots, and conservative substitutions are marked by a single dot. An unusually high degree of sequence divergence is seen in the epitope region. (B) Characterization of anti-BP180 antibody cross-species reactivity. Rabbit antimurine BP180 (α-mBP180) and rabbit antihuman BP180 (α-hBP180) NC16A domain antisera were analyzed by immunoblotting (IB) using recombinant human BP180 (H, lanes 1 and 3) or recombinant murine BP180 (M, lanes 2 and 4) and indirect immunofluourescence (IIF) using human (panels a and b) or murine (panels c and d) skin sections. Anti-hBP180 autoantibodies react with the recombinant human BP180 (lane 1) and human skin (panel a), but fail to cross-react with recombinant mBP180 (lane 2) and mouse skin (panel c). Conversely, anti-mBP180 antibodies react with mBP180 (lane 4) and stain mouse skin (panel d), but do not bind hBP180 (lane 3) or human skin (panel b). (C) Passive transfer of rabbit anti-mBP180 IgG. Neonatal Balb/c mice were injected intradermally with rabbit antimurine BP180 IgG. After 24 hours, gentle friction elicits persistent epidermal wrinkling, producing the “epidermal detachment” sign (panel a). Direct immunofluorescence analysis shows deposition of anti-BP180 IgG (panel b) and murine C3 (panel c) at the basement membrane zone. Histological examination of lesional skin reveals dermal–epidermal junction separation with an inflammatory infiltrate (panel d). Journal of Investigative Dermatology Symposium Proceedings 2004 9, 41-46DOI: (10.1111/j.1087-0024.2004.00841.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Cellular events in the IgG passive transfer model of BP. (A) Quantification of inflammatory cell recruitment in the dermis of mice injected with pathogenic anti-BP180 IgG. Neonatal mice were injected i.d. with pathogenic (black bars) or control IgG (gray bars). The skin sections at the IgG injection site were obtained 24 hours postinjection and processed to recover infiltrating cells. The different populations of inflammatory cells were identified by staining and flow cytometry. The data shown are the mean±SE. *p<0.05 and **p<0.01, Student t-test for paired samples. PMN, neutrophils; Mφ, macrophages; T, T lymphocytes; B, B lymphocytes; eos, eosinophils. (B) Clinical and histological examination of neonatal mice deficient in different inflammatory cells injected with pathogenic anti-mBP180 IgG. Neonatal mice were injected i.d. with anti-mBP180 IgG. Twelve hours later, wild-type C57BL/6J (WT), T and B cell–deficient (T & B(–)) mice developed subepidermal blisters. In contrast, mast cell–deficient (MC(–)), macrophage-deficient (MΦ(–)), and neutrophil-deficient (PMN(–)) mice injected i.d. with pathogenic IgG showed no evidence of skin disease. Journal of Investigative Dermatology Symposium Proceedings 2004 9, 41-46DOI: (10.1111/j.1087-0024.2004.00841.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Functional relationship between complement, mast cells, and neutrophils in the IgG passive transfer model of BP. Neonatal mice were injected i.d. with pathogenic anti-mBP180 IgG and clinically examined at different time points. The skin sections at each time point were analyzed by mast cell (MC)-specific staining (toluidine blue staining) for MC identification and quantification and by myeloperoxidase (MPO) activity assay for neutrophil infiltration. (A) Complement (C′) activation causes MC degranulation. C5-sufficient mice (panel a) show extensive MC degranulation at 2 hours and develop blisters at 12 hours post-injection. In contrast, C5-deficient mice (panel b) exhibit minimal MC degranulation and no skin lesions. d, dermis. (B) Time course of MC degranulation and neutrophil infiltration. MC degranulation reaches the peak level at 1–2 hours after IgG injection (panel a), whereas PMN infiltration appears at 2 hours and reaches the peak level at 8 hours post-injection. (C) Local reconstitution of neutrophils restores the pathogenic activity of anti-mBP180 antibodies in MC-deficient mice. Injection of pathogenic anti-mBP180 IgG causes BP in MC-sufficient, but not MC-deficient, mice. MC-deficient mice reconstituted with neutrophils (by intradermal administration) injected with anti-mBP180 IgG develop BP. MC-deficient mice pretreated intradermally with IL-8 or TNF-α also become susceptible to experimental BP (data not shown). Journal of Investigative Dermatology Symposium Proceedings 2004 9, 41-46DOI: (10.1111/j.1087-0024.2004.00841.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Proteolytic events in the IgG passive transfer model of BP. (A) Neutrophil elastase produces DEJ separation in mouse skin in vitro. Neonatal mouse skin sections were incubated in medium alone (panel a), with purified neutrophil elastase (NE) (panel b), or with gelatinase B (GB) (panel c) at 37°C for 24 hours and were examined by routine histology. DEJ separation is seen in sections treated with NE but not GB or medium control. Epidermis (e), dermis (d), blister vesicle (v), site of basal keratinocytes (arrow). (B) In vivo BP180 degradation depends on neutrophil elastase (NE) activity. Neonatal wild-type (WT), NE-deficient (NE-), and GB-deficient (GB-) mice were injected i.d. with pathogenic IgG alone or with neutrophils and were examined 12 hours after injection. The skin extracts were analyzed by immunoblotting using the anti-mBP180 IgG. The wild-type mice injected with pathogenic IgG develop BP blisters and both intact and degraded BP180 are present in lesional skin extracts (lane 1). In contrast, NE-deficient mice injected with pathogenic IgG show no skin lesions and no degraded BP180 was found in skin samples (lane 2). GB-deficient mice locally reconstituted with 2.5 million GB-deficient (but NE-sufficient) neutrophils and then injected i.d. with pathogenic IgG develop BP, and cleaved BP180 is detected in their lesional skin extracts (lane 3). In contrast, GB-deficient mice locally reconstituted with the same number of NE-deficient (but GB-sufficient) neutrophils and then injected i.d. with pathogenic IgG fail to develop BP, and extracts from their skin show only intact BP180 (lane 4). As a negative control, wild-type mice injected i.d. with normal IgG show no skin lesions and no degraded BP180 is seen in skin extract samples (data not shown). mPMN: mouse neutrophils. Journal of Investigative Dermatology Symposium Proceedings 2004 9, 41-46DOI: (10.1111/j.1087-0024.2004.00841.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions