Despite the rising incidence of autoimmunity, therapeutic options for patients with autoimmune disease still rely on decades-old immunosuppressive strategies that risk severe and potentially fatal complications. Thus, novel therapeutic approaches for autoimmune diseases are greatly needed in order to minimize treatment-related toxicity. Such strategies would ideally target only the autoreactive immune components to preserve beneficial immunity. Here, we review how several decades of basic, translational, and clinical research on the immunology of pemphigus vulgaris (PV), an autoantibody-mediated skin disease, have enabled the development of targeted immunotherapeutic strategies. We discuss research to elucidate the pathophysiology of PV and how the knowledge afforded by these studies has led to the preclinical and clinical testing of targeted approaches to neutralize autoantibodies, to induce antigen-specific tolerance, and to specifically eliminate autoreactive B cells in PV.
Christoph T. Ellebrecht, Aimee S. Payne
Potential mechanisms of disease relapse after B cell depletion therapy.
Relapse after rituximab therapy of pemphigus vulgaris may be due to incomplete B cell depletion and recurrence of the same anti-DSG3 B cells observed during initial disease, a model best supported by the current data. Alternatively, disease relapse may be triggered by the appearance of a new anti-DSG3 B cell repertoire after complete B cell depletion. Production of anti-DSG3 antibodies by long-lived plasma cells, which are CD20– and hence not targeted by rituximab, appears not to play a significant role for many patients, given the serologic remissions of disease observed after rituximab therapy. Illustrated by Rachel Davidowitz.