Disease-specific and therapy-driven alterations in immunoglobulin G heavy-chain repertoire in peripheral blood mononuclear cells from pemphigus vulgaris and bullous pemphigoid patients

BACKGROUND: Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are two subtypes of autoimmune bullous disorders (AIBD), characterized by abnormal B cell activation and autoantibody production. Glucocorticoids (GC) and rituximab (RTX) are main treatment agents for AIBD. However,the effects of GC and RTX therapies on B cell receptor (BCR) repertoire need clarification. METHODS: The study included 18 AIBD patients (13 PV, 5 BP) and 9 healthy controls (HC). Of 13 PV, 9 were newly diagnosed/relapsed (4 responsive to GC monotherapy), 4 were GC-refractory but responsive to RTX-GC therapy. All BP were newly diagnosed/relapsed (4 responsive to GC). High throughput profiling of immunoglobulin G heavy-chain (IGHG) repertoire in peripheral blood mononuclear cells of all subjects was done.Comparative analysis identified differential changes in IGHG repertoire features between treatment-naïve/relapsed AIBD patients and HC, as well as pre- and post-therapeutic interventions. RESULTS: AIBD patients differed from HC in skewed IGHV/D/J usage, decreased clone diversity (more dominant clones), and distinct CDR3 amino acid patterns of IGHG repertoire. GC-responsive BP/PV patients had slight changes in IGHG repertoire profiles between pre- and post-treatment. However, the four GC-refractory PV patients who responded to GC-RTX combination therapy showed notable decreased clone diversity, elevated proportions of dominant clones, high interindividual clonal heterogeneity, and reduced public clones when compared to the pre-treatment states. CONCLUSIONS: PV and BP patients exhibited disease-specific IGHG repertoire alterations. GC-RTX therapy has stronger effects than GC monotherapy, leading to more pronounced IGHG repertoire remodeling. This study offers valuable insights for both immunopharmacological investigations and immunotherapy development in autoimmune bullous disorders.