Autoantibody Profile Differentiates between Inflammatory and Noninflammatory Bullous Pemphigoid Kentaro Izumi, Wataru Nishie, Yosuke Mai, Mayumi Wada,

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Autoantibody Profile Differentiates between Inflammatory and Noninflammatory Bullous Pemphigoid Kentaro Izumi, Wataru Nishie, Yosuke Mai, Mayumi Wada, Ken Natsuga, Hideyuki Ujiie, Hiroaki Iwata, Jun Yamagami, Hiroshi Shimizu Journal of Investigative Dermatology Volume 136, Issue 11, Pages 2201-2210 (November 2016) DOI: 10.1016/j.jid.2016.06.622 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Characterization of recombinant human COL17. (a) Schematic of full-length, intracellular, and C-terminal recombinant COL17. Limited digestion sites with plasmin (arrowheads) and epitopes of mouse monoclonal and rabbit polyclonal Abs are illustrated. (b) Coomassie Blue staining of full-length COL17 shows 540-kDa and 180-kDa bands (left). Immunoblotting of recombinant full-length COL17 using anti-DDDDK mouse monoclonal Ab and domain-specific rabbit polyclonal Abs, including the intracellular domain (08003) and the NC16A (R7) of COL17 (right). (c) Coomassie Blue staining and immunoblotting of limited digested fragments of COL17 by plasmin. The 180-kDa band corresponds to full-length COL17 (left); the 120-kDa (arrows) and 97-kDa (arrowheads) polypeptides are digested COL17 ectodomains (right). Ab 08003 fails to recognize digested ectodomains. Ab R7 detects both 120-kDa and 97-kDa ectodomains, whereas Ab C17-C1 recognizes only the 120-kDa ectodomain. Ab, antibody; COL17, collagen XVII; NC16A, noncollagenous 16A domain. Journal of Investigative Dermatology 2016 136, 2201-2210DOI: (10.1016/j.jid.2016.06.622) Copyright © 2016 The Authors Terms and Conditions

Figure 2 The diagnostic performance of ELISA using full-length recombinant human COL17. (a) Receiver operating characteristic (ROC) analysis to determine a cutoff value for full-length COL17 ELISA. The arrow indicates the point at which the Youden Index is the maximum. Full-length COL17 ELISA has a sensitivity of 83.5% and a specificity of 94.3%. (b) Scatterplot representation of the full-length COL17 ELISA index. (c) Full-length COL17 ELISA indices are plotted for the active and the CR phases. The ELISA index is significantly lower for the CR phase (mean ± SD 45.8 ± 25.6 vs. 8.2 ± 11.5, P = 0.0010). (d) NC16A ELISA indices are plotted for the active and the CR phases. The ELISA index is significantly lower for the CR phase (mean ± SD 94.8 ± 60.7 vs. 33.1 ± 34.8, P = 0.0005). BP, bullous pemphigoid; COL17, collagen XVII; CR, complete remission; non-AIBD, nonautoimmune blistering disease; NC, normal controls; NC16A, noncollagenous 16A domain; PF, pemphigus foliaceus; PV, pemphigus vulgaris. Journal of Investigative Dermatology 2016 136, 2201-2210DOI: (10.1016/j.jid.2016.06.622) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Clinical and histopathological relationship between “Full with NC16A-BP” and “Full without NC16A-BP”. (a) Clinical manifestations of representative case of “Full with NC16A-BP” (#2) and “Full without NC16A-BP” (#96). (b) BPDAI (urticaria/erythema) scores among different BP subgroups. Each plot shows BPDAI (urticaria/erythema) of “Full with NC16A-BP” (n = 12), “Full without NC16A-BP” (n = 5), and NC16A-BP (n = 3). There are significant differences between “Full with NC16A-BP” and “Full without NC16A-BP” (P = 0.0003) using the Mann-Whitney test. (c) (#2): Histopathological findings of representative “Full with NC16A-BP” (#2) and “Full without NC16A-BP” (#96). Hematoxylin and eosin staining, original magnification ×100, scale bar = 100 μm (left). The black square indicates the area of high-power field (HPF), original magnification ×400, scale bar = 20 μm (right). (d) Comparison of the number of infiltrating eosinophils between “Full with NC16A-BP” and “Full without NC16A-BP.” “Full without NC16A-BP” reveals significantly less eosinophilic infiltration (mean ± SD 22.7 ± 14.1 vs. 4.3 ± 4.0, P = 0.0170 using the Mann-Whitney test). Clinical photographs published with patients' consent. BP, bullous pemphigoid; BPDAI, Bullous Pemphigoid Disease Area Index; NC16A, noncollagenous 16A domain. Journal of Investigative Dermatology 2016 136, 2201-2210DOI: (10.1016/j.jid.2016.06.622) Copyright © 2016 The Authors Terms and Conditions

Figure 4 Epitope mapping of IgG autoAbs in “Full with NC16A-BP” and “Full without NC16A-BP” patients targeting various regions of recombinant mammalian cell-derived COL17 proteins. (a) Immunoblotting of “Full with NC16A-BP” and “Full without NC16A-BP” using N-50K cell lysate. (upper) #: “Full with NC16A-BP” sera, (lower) #: “Full without NC16A-BP” sera, P: anti-DDDDK Ab. Arrows and dotted frames indicate N-50K. (b) Immunoblotting of “Full with NC16A-BP” and “Full without NC16A-BP” using C-22K cell lysate. (Upper) #: “Full with NC16A-BP” sera, (lower) #: “Full without NC16A-BP” sera, P: anti-DDDDK Ab. Arrows and dotted frames indicate C-22K. (c) Coomassie Blue staining and immunoblotting of the mixture samples including 180 kDa full-length COL17 and plasmin-digested 120-kDa and 97-kDa ectodomains. (d) Immunoblotting of “Full without NC16A-BP” (left) and NC16A-BP (right) using the mixture of full-length COL17 and limited digestion fragments with plasmin. The dotted frame indicates the plasmin-digested 97-kDa COL17. autoAbs, autoantibodies; BP, bullous pemphigoid; COL17, collagen XVII; NC16A, noncollagenous 16A domain. Journal of Investigative Dermatology 2016 136, 2201-2210DOI: (10.1016/j.jid.2016.06.622) Copyright © 2016 The Authors Terms and Conditions