A Subset of Pemphigus Foliaceus Patients Exhibits Pathogenic Autoantibodies Against Both Desmoglein-1 and Desmoglein-3 Luis A. Arteaga, Philip S. Prisayanh,

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A Subset of Pemphigus Foliaceus Patients Exhibits Pathogenic Autoantibodies Against Both Desmoglein-1 and Desmoglein-3 Luis A. Arteaga, Philip S. Prisayanh, Simon J.P. Warren, Zhi Liu, Luis A. Diaz, Mong-Shang Lin Journal of Investigative Dermatology Volume 118, Issue 5, Pages 806-811 (May 2002) DOI: 10.1046/j.1523-1747.2002.01743.x Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Molecular structure of the extra cellular region of dsg1 and dsg3. dsg1 and dsg3 exhibit five major cadherin-like domains (EC-1, EC-2, EC-3, EC-4, and EC-5), stretching from the N-terminus (EC-1) to the C-terminus (transmembrane domain). The six-histidine tag is attached to the C-terminus. The black strips represent Ca2+ binding motifs. The recombinant ectodomains of rdsg1 and rdsg3 are expressed in the baculovirus system as a soluble glycopeptide of approximately 66 kDa. Journal of Investigative Dermatology 2002 118, 806-811DOI: (10.1046/j.1523-1747.2002.01743.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Sera from PV patients specifically react with rdsg3 using the dsg3 ELISA. The cut-off value for this assay was set at the mean of 50 normal human sera plus 3 SD, equal to 0.48 OD units. All 50 normal sera were negative, as were 20 patients with bullous pemphigoid (BP), 19 with systemic lupus erythematosus (SLE), and 23 with herpes gestationis (HG). Eighty-two of 83 patients with PV were positive. The one PV patient that was negative was also in clinical remission. Journal of Investigative Dermatology 2002 118, 806-811DOI: (10.1046/j.1523-1747.2002.01743.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 All 19 patients with antibodies to dsg3 by ELISA were also positive by immunoprecipitation. The autoradiogram shows immunoprecipitates analyzed by sodium dodecyl sulfate–polyacrylamide gel electrophoresis. Lane P: PV patient included as a positive dsg3 control. Lane C: Normal human serum included as a negative control. Lanes 1–19: All 19 patients with PF or FS with antibodies to dsg3 by ELISA. Journal of Investigative Dermatology 2002 118, 806-811DOI: (10.1046/j.1523-1747.2002.01743.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Competitive inhibition of the dsg1 and dsg3 ELISA by soluble recombinant dsg1 and dsg3. PF or FS serum was incubated with rdsg1 or rdsg3 (0–8 µg) and then tested in the dsg1 and dsg3 ELISA. (A) Purified rdsg3 was capable of absorbing anti-dsg3 activity, but not anti-dsg1 activity. (B) Purified rdsg1 was capable of absorbing ant-dsg1 activity but not anti-dsg3 activity. The asterisk sign indicates that the ELISA titers of samples are below the cut-offs. Journal of Investigative Dermatology 2002 118, 806-811DOI: (10.1046/j.1523-1747.2002.01743.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Anti-dsg1 and anti-dsg3 autoantibody fractions from patients with PF and FS are pathogenic. Neonatal BALB/C mice were injected intradermally with affinity purified anti-dsg1 autoantibodies (A–C) or anti-dsg3 autoantibodies (D–F), respectively. The clinical, immunologic, and histologic evaluations were performed 18 h post-IgG injection. Mice injected with anti-dsg1 autoantibodies developed blisters (A), which were located in the subcorneal region of the epidermis (B). The anti-dsg1 autoantibodies were detected bound to the epidermal ICS by direct IF (C). Mice injected with anti-dsg3 autoantibodies developed blisters (D), which were located in the suprabasilar region of the epidermis (E). Autoantibodies were detected bound to the epidermal ICS by direct IF (F). The pathogenicity of the anti-dsg3 and anti-dsg1 autoantibodies fractions was blocked by preincubation of these fractions with purified rdsg3 and rdsg1, respectively (data not shown). Journal of Investigative Dermatology 2002 118, 806-811DOI: (10.1046/j.1523-1747.2002.01743.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 The purified total IgG fraction from PF and FS patients with antibodies to both dsg1 and dsg3 produce clinical and histologic features of PF in the mouse model. The total IgG fraction from two patients with endemic PF and one with nonendemic PF were purified by ammonium sulfate precipitation and injected intradermally into neonatal mice. All three sera reproduced the clinical (A) and histologic features (B) of PF, namely superficial blistering with subcorneal acantholysis. Journal of Investigative Dermatology 2002 118, 806-811DOI: (10.1046/j.1523-1747.2002.01743.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions