A Pathogenic Role for IgE in Autoimmunity: Bullous Pemphigoid IgE Reproduces the Early Phase of Lesion Development in Human Skin Grafted to nu/nu Mice

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A Pathogenic Role for IgE in Autoimmunity: Bullous Pemphigoid IgE Reproduces the Early Phase of Lesion Development in Human Skin Grafted to nu/nu Mice Janet A. Fairley, Christopher T. Burnett, Chang-Ling Fu, David L. Larson, Matthew G. Fleming, George J. Giudice Journal of Investigative Dermatology Volume 127, Issue 11, Pages 2605-2611 (November 2007) DOI: 10.1038/sj.jid.5700958 Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Purified BP IgE binds to basal epidermal keratinocytes and dermal mast cells by IF, and to the NC16A region of BP180 by immunoblotting. Following purification, IgE from serum BP-W7714 was tested by indirect immunofluorescence for its ability to bind to components of human skin. (a) A cryosection of normal human skin was labeled with the purified BP IgE followed by FITC-anti-human IgE. Staining can be seen at the BMZ (arrowheads), as well as on some dermal cells (arrows). (b) This is an immunoblot of GST-NC16A fusion protein and GST (designated “N” and “G”, respectively) labeled with either the unfractionated BP-W7714 serum (left two lanes) or IgE purified from BP-W7714 (right two lanes). The secondary antibody used for all four lanes was horseradish peroxidase-anti-human IgE. The two arrowheads to the left of the blot indicate the positions of GST-NC16A (upper) and GST (lower). IgE reactivity with the GST-NC16A fusion protein is seen in the first and third lanes. Identical results were seen with BP-G5554. Bar=100μm. Journal of Investigative Dermatology 2007 127, 2605-2611DOI: (10.1038/sj.jid.5700958) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Human skin grafts injected with BP or control IgE. (a and c) Grafts injected with 6ng of BP IgE show a well-developed urticarial plaque (11/11). (b and d) No elevation or erythema was seen, the control grafts injected with 6ng of normal IgE. Journal of Investigative Dermatology 2007 127, 2605-2611DOI: (10.1038/sj.jid.5700958) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Histology of skin grafts injected with BP IgE. (a) The low-power view of a human skin graft injected with 6ng of BP IgE. Mild congestion of the vessels is seen (arrow) and a granulocytic infiltrate. (b) Area of dense infiltration showing the granulocytic character of the infiltrate. (c) Two of the three human skin grafts receiving 47ng of BP IgE split along the basement membrane zone. (d) Control grafts that received normal IgE show no abnormalities. Immunofluorescent mapping with antibodies to (e) BPAG1 and (f) type VII collagen indicated the split was predominantly through the lamina lucida/lamina densa region. Bar=100μm. Journal of Investigative Dermatology 2007 127, 2605-2611DOI: (10.1038/sj.jid.5700958) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 IgE, IgG, and C3 labeling in grafts injected with BP IgE. Following harvest of the grafts 24hours after injection with 6ng of BP IgE, cryosections were labeled with FITC-conjugated anti-human IgE, IgG or anti-murine C3. (a) Anti-human IgE revealed weak staining at the BMZ. (b) Mast cells were also labeled by anti-IgE as indicated by double labeling with anti-human mast cell tryptase. (c and d) No BMZ staining was seen with anti-human IgG or anti-murine C3. Bar=50μm. Journal of Investigative Dermatology 2007 127, 2605-2611DOI: (10.1038/sj.jid.5700958) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Electron micrographs of the infiltrate induced by BP IgE. The infiltrate was composed of (a) mast cells, many of which have empty granules (arrows), indicating recent degranulation. (b) Eosinophils, recognized by their characteristic granules and bilobed nucleus, were also present, as were (c) neutrophils and lymphocytes (data not shown). Bar=1μm. Journal of Investigative Dermatology 2007 127, 2605-2611DOI: (10.1038/sj.jid.5700958) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions