*Purpose: Chronic lung allograft dysfunction (CLAD) remains the major determinant of morbidity and mortality post-lung transplantation (LTx). Bronchiolitis obliterans syndrome (BOS) is the most prevalent presentation of CLAD, but its underlying mechanisms remain poorly understood. We have established a single HLA antigen mismatch model of orthotopic LTx in mice that recapitulates several features of BOS and have identified B cells as major contributors to chronic rejection. However, the extent of B cell heterogeneity and their role in chronic rejection remains unclear.

*Methods: To investigate the specific roles of B and plasma cells in vivo, we performed two different murine models of orthotopic lung transplant (HLA->C57BL/6J and B6D2F1/J->C57BL/6J) and analyzed allografts as well as their syngeneic grafts. To assess the clinical relevance of our findings and their relevance to BOS, we compared explants from patients, who developed BOS and underwent re-transplantation, with healthy controls from retrospective clinical cohorts.

*Results: Our detailed atlas of cell population changes of chronic rejection after LTx in mice showed that Mzb1+ plasma cells (PCs) were the most prominently increased cell population in BOS lungs. In both murine models of lung rejection after LTx, we localized these Mzb1+ PCs populations surrounding the remodeled and obliterated airways, and in areas with dense collagen deposition. In BOS patients, we observed B cell-rich ectopic lymphoid follicles disseminated throughout the lung. Plasma cells, expressing MZB1, were robustly detected in the peribronchial areas in BOS (MZB1+ stained area in BOS 1.24% -vs. 0.16% in donors; p<0.0005), even in the absence of neighboring B cells. Importantly, RNA-sequencing of frozen lung tissue from BOS explants revealed that MZB1 and CXCL13 (encoding a chemokine involved in B cell homing), were amongst the most significantly upregulated genes when compared with control lung samples (increased by 36.50- and 47.10-fold, respectively; p<0.05).

*Conclusions: Our data identify a new role for MZB1+ plasma cells in the pathogenesis of CLAD-associated BOS. These data open an exciting therapeutic approach, in which plasma cells could be specifically targeted to prevent chronic rejection and alleviate tissue remodeling after LTx.

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