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We engineered a therapeutic fusion protein consisting of the pathogenic domains of Dsg3 linked to either human immunoglobulin G1 (IgG1) or mouse IgG2a (Dsg3-Fc). In vitro, Dsg3-Fc selectively eliminated Dsg3-autoreactive B cells. In vivo, Dsg3-Fc effectively depleted human B cells expressing patient-derived anti-Dsg3 B cell receptors, even in the presence of circulating autoantibodies. Moreover, Dsg3-Fc inhibited both disease initiation and progression in a polyclonal, active pemphigus vulgaris model in immunocompetent mice. In addition, Dsg3-Fc rapidly neutralized pathogenic autoantibodies without inducing systemic toxicity. These findings demonstrate that targeting pathogenic B cells and neutralizing autoantibodies through autoantigen-Fc fusion proteins may represent a promising therapeutic strategy for pemphigus vulgaris and potentially other autoantibody-mediated diseases without the need for global immunosuppression.<\/jats:p>","DOI":"10.1126\/scitranslmed.adk6484","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T17:58:41Z","timestamp":1756317521000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["Antigen-Fc fusion therapy reduces severity of a model of pemphigus vulgaris without systemic immunosuppression"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6765-8830","authenticated-orcid":true,"given":"Soheil","family":"Tavakolpour","sequence":"first","affiliation":[{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 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