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J. Biol. Chem., Vol. 282, Issue 24, 17866-17876, June 15, 2007

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Anti-desmoglein 3 (Dsg3) Monoclonal Antibodies Deplete Desmosomes of Dsg3 and Differ in Their Dsg3-depleting Activities Related to Pathogenicity^*

Yukari Yamamoto, Yumi Aoyama, En Shu, Kazuyuki Tsunoda, Masayuki Amagai, and Yasuo Kitajima¹

From the Department of Dermatology, Gifu University School of Medicine, Gifu City 501-1194 and the Department of Dermatology, Keio University School of Medicine, Keio, Tokyo 160-8582, Japan

Pemphigus vulgaris (PV) is an autoimmune blistering disease, characterized by the loss of cell-cell adhesion between epidermal keratinocytes and the presence of autoantibody against desmoglein 3 (Dsg3), which provides adhesive integrity to desmosomes between adjacent keratinocytes. We have previously shown that PV-IgG purified from patients depletes desmosomes of Dsg3. However, PV-IgG contains not only antibodies against a variety of different epitopes of Dsg3 but also against other unknown antigens. Therefore, we examined whether the Dsg3-depleting activity of PV-IgG is generated specifically by anti-Dsg3 activity in a human squamous cell carcinoma cell line (DJM-1) and normal human keratinocytes by using four different pathogenic and nonpathogenic monoclonal antibodies against Dsg3. We demonstrate that these monoclonal antibodies deplete cells and desmosomes of Dsg3, as PV-IgG does. Individual monoclonal anti-Dsg3 antibodies display characteristic limits to their Dsg3-depleting activity, which correlates with their pathogenic activities. In combination, these antibodies exert a cumulative or synergistic effect, which may explain the potent Dsg3-depleting capability of PV-IgG, which is polyclonal. Finally, although Dsg3-depletion activity correlated with AK-monoclonal antibody pathogenicity in mouse models, the residual level of Dsg3, when below 50%, does not correlate with the adhesive strength index in the present study. This may suggest that although the Dsg3 depletion is not indicative for adhesive strength, the level of Dsg3 can be used as a read-out of pathogenic changes within the cell and that the Dsg3 depletion from desmosomes plays an important role in skin fragility or susceptibility to blister formation in PV patients.

Received for publication, August 21, 2006 , and in revised form, March 9, 2007.

^* This work was supported by Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Health and Labor Sciences Research Grants for Research on Measures for Intractable Disease, and the Ministry of Health, Labor and Welfare of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Yanagido 1-1, Gifu City 501-1194, Japan. Tel.: 81-58-230-6390; Fax: 81-58-230-6396; E-mail: yaskitaj{at}gifu-u.ac.jp.

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