B-cell infiltration distinguishes mucosal from skin patterns of rejection in facial vascularized composite allografts

Rejection monitoring in facial vascularized composite allotransplantation traditionally focuses on skin biopsies. However, mucosal rejection frequently presents with more pronounced signs of immune activity. To explore mechanistic differences between skin and mucosal rejection, rejection and nonrejection biopsies from allograft skin and oral mucosa of 9 facial vascularized composite allotransplantation recipients were retrospectively analyzed using histology, multiplex immunostaining, and gene expression profiling, with peripheral blood mononuclear cells quantified via mass cytometry. Both skin and mucosa exhibited similar patterns of granzyme B expressing (GZMB⁺) T cells, indicating T cell-mediated rejection in both tissues. However, mucosa demonstrated additional CD19⁺ B cell infiltration and occasional plasma cells, which were absent in skin. These intramucosal B cells expressed AHNAK and CD43, suggesting they may be innate-like B cells (Bin cells). CD8⁺/GZMB⁺ cells and B cell populations were enriched in peripheral blood mononuclear cells during combined skin and mucosal rejection but not isolated skin rejection. These findings suggest distinct rejection mechanisms in skin and mucosa, with mucosa uniquely involving B cells. Current skin-focused rejection monitoring may overlook important mucosal rejection events, emphasizing the need to monitor both tissues concurrently. Mucosal biopsies could improve the accuracy in detecting acute rejection.