The Thomsen-Friedenreich Antigen-Binding Lectin Jacalin Interacts with Desmoglein-1 and Abrogates the Pathogenicity of Pemphigus Foliaceus Autoantibodies.

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The Thomsen-Friedenreich Antigen-Binding Lectin Jacalin Interacts with Desmoglein-1 and Abrogates the Pathogenicity of Pemphigus Foliaceus Autoantibodies In Vivo Ning Li, Moonhee Park, Minglang Zhao, Julio Hilario-Vargas, David M. McInnes, Phillip S. Prisayanh, Zhi Liu, Luis A. Diaz Journal of Investigative Dermatology Volume 130, Issue 12, Pages 2773-2780 (December 2010) DOI: 10.1038/jid.2010.209 Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Jacalin (Jac) binds desmoglein-1 (Dsg1). (a) Binding to recombinant Dsg1 ectodomain (rDsg1). rDsg1 was incubated with Jac-agarose (lanes 1, 3–6) or protein G/A-agarose beads (lane 2). Bound-Dsg1 was released by boiling in SDS sample buffer (lanes 1–2 and 5–6) or eluted with Jac-inhibiting sugars (lane 3: 0.1M melibiose; lane 4: 0.8M D-galactose). In one set of experiments, Jac beads were preincubated with 0.8M D-galactose (lane 5) or buffer (lane 6) before adding the pemphigus foliaceus serum to further show the sugar-dependency binding. Released Dsg1 was analyzed by immunoblotting (IB) using anti-histidine antibodies. (b) Binding to epidermal Dsg1. Tissue lysates from human (H) or mouse (M) epidermis were incubated with Jac-agarose (lanes 1 and 2) or protein G/A-agarose beads (lanes 3 and 4) followed by IB using anti-Dsg1 antibodies. Journal of Investigative Dermatology 2010 130, 2773-2780DOI: (10.1038/jid.2010.209) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Jacalin (Jac) inhibits pemphigus foliaceus (PF) autoantibody binding to desmoglein-1 (Dsg1). (a) ELISA assay showing dose-dependent inhibitory effect of Jac. Dsg1-coated microplates were preincubated with Jac (100, 250, and 500μgml−1) followed by incubating with PF-1 serum. Cutoff value: 0.421. (b) Reverse effects of D-galactose on Jac inhibition. Recombinant Dsg1 ectodomain (Dsg1)-microplates were preincubated with tris-buffered saline-Ca2+ buffer (left column), Jac (100μgml−1) (center), or Jac (100μgml−1) plus D-galactose (0.8M) (right) before adding PF-1 serum. (n=3, *P<0.05 (Student's t-test)). (c) Immunoprecipitation (IP) results showing dose-dependent inhibitory effect of Jac. rDsg1 was preincubated with Jac (0, 10, and 100μgml−1) before IP. (d) Representative IP showing that 100μgml−1 of Jac (even-numbered lanes) inhibits the interaction of rDsg1 with eight PF/Fogo Selvagem sera compared with the controls that were preincubated with buffer (odd-numbered lanes). Journal of Investigative Dermatology 2010 130, 2773-2780DOI: (10.1038/jid.2010.209) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 N-glycosylation is not involved in desmoglein-1 (Dsg1)/jacalin (Jac) and Dsg1/pemphigus foliaceus (PF) IgG binding. Baculovirus expressed Dsg1 ectodomain produced in the presence or absence of tunicamycin (0.5mgml−1) was used for the experiments. (a) Immunoblotting shows that tunicamycin treatment reduced the molecular weight of Dsg1 (untreated in lane 1 vs. treated in lane 2). Concanavalin A (ConA)-beads precipitated poorly with Dsg1 produced in the presence of tunicamycin (lanes 3) compared with nontreated Dsg1 (lane 4). In contrast, Jac-agarose precipitated both the tunicamycin-treated (lane 6) and nontreated Dsg1 (lane 5). (b) Representative immunoprecipitation shows that five PF/Fogo Selvagem sera reacted with tunicamycin-treated Dsg1 (even-numbered lanes) as well as nontreated Dsg1 (odd-numbered lanes). Journal of Investigative Dermatology 2010 130, 2773-2780DOI: (10.1038/jid.2010.209) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Jacalin (Jac) protects mice from developing pemphigus foliaceus (PF). (a) Representative results showing that mice preinjected with control buffer (n=4) developed clinical and histological blisters upon injection with IgG from PF-1 (A, B). In contrast, mice pretreated with Jac (80μgg−1 body weight, n=4; 160μgg−1 body weight, n=4) did not develop skin blisters clinically and histologically (D, E). Direct immunofluorescence staining showed a significant reduction of IgG binding to the epidermis in mice treated with Jac (F) compared with buffer-treated controls (C). Bars=100μm (B, E) and 10μm (C, F), respectively. (b) Jac inhibits PF blistering in a dose-dependent manner. Animals were pretreated (s.c.) with different doses of Jac and then injected (s.c.) with the same dose of pathogenic PF IgG. Clinical disease was scored for each group of experimental mice. (n=4; *P<0.05, **P<0.01 (Student's t-test).) Journal of Investigative Dermatology 2010 130, 2773-2780DOI: (10.1038/jid.2010.209) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Peanut agglutinin (PNA), but not vicia villosa-B4 (VVL-B4), binds to Dsg1 and abolishes the pathogenicity of PF autoantibodies. (a) Lectin pull-down assay. Tissue lysates from human epidermis (lanes 1 and 2) or mouse skin (lanes 3 and 4) were incubated with PNA-agarose (lanes 1 and 3) or VVL-B4-agarose beads (lanes 2 and 4). Dsg1 was detected by immunoblotting using anti-Dsg1 antibodies. PNA but not VVL-B4 was able to pull-down the epidermal Dsg1. (b) IgG passive transfer. Neonatal mice pretreated with PNA (160μgg−1 body weight, n=9) or VVL-B4 (160μgg−1 body weight, n=3), followed by subcutaneous injection of pathogenic IgG from PF-1. Injected mice were examined 20hours after IgG injection. PNA (A and B), but not VVL-B4 (C and D), inhibits PF IgG-induced skin blisters in mice. Bar=50μm. Journal of Investigative Dermatology 2010 130, 2773-2780DOI: (10.1038/jid.2010.209) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions