Chen Rao, Powell Juliana S, Shufesky William J, Bardhi Elissa, Sullivan Mara L G, Tkacheva Olga A, Camirand Geoffrey, Goncalves Zoe, Stolz Donna Beer, Chalasani Geetha, Catz Sergio D, Watkins Simon C, Larregina Adriana T, Morelli Adrian E
T.E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Sport Medicine, Peking University Third Hospital, Beijing, China; Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
T.E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Cell Rep. 2025 Jun 24;44(6):115832. doi: 10.1016/j.celrep.2025.115832. Epub 2025 Jun 12.
B cells play fundamental roles in transplant rejection. However, how allogeneic (allo)-antigens (Ags) are transported from allografts to follicular dendritic cells (FDCs) in lymphoid tissues for development of B cell responses remains unknown. We demonstrated that graft allo-Ags are relayed to FDCs via small extracellular vesicles (sEVs), which activate complement via immunoglobulin M (IgM) bound to vesicle phospholipids. Complement-opsonized allo-sEVs bind splenic marginal-zone B cells that shuttle the vesicles to FDCs, which retain and recycle the allo-sEVs so they are recognized by B cells. Accordingly, graft release of allo-sEVs promoted allo-major histocompatibility complex (MHC) accumulation in FDCs, germinal center formation, Ig switch and affinity maturation, and donor-specific antibodies, which decreased in allografts with impaired sEV secretion or when allo-Ags were delivered via disrupted sEVs. Importantly, human spleen FDCs bound allo-sEVs opsonized with human serum bearing active complement. Our findings provide insight into the mechanisms that lead to antibody-mediated rejection, for which there are no FDA-approved therapies.
B细胞在移植排斥反应中发挥着重要作用。然而，同种异体（allo）抗原（Ag）如何从移植物转运至淋巴组织中的滤泡树突状细胞（FDC）以引发B细胞反应仍不清楚。我们证明，移植的同种异体抗原通过小细胞外囊泡（sEV）传递给FDC，这些小细胞外囊泡通过与囊泡磷脂结合的免疫球蛋白M（IgM）激活补体。补体调理的同种异体小细胞外囊泡与脾边缘区B细胞结合，后者将囊泡穿梭至FDC，FDC保留并循环利用同种异体小细胞外囊泡，使其被B细胞识别。因此，同种异体小细胞外囊泡的移植释放促进了FDC中同种异体主要组织相容性复合体（MHC）的积累、生发中心形成、Ig类别转换和亲和力成熟以及供体特异性抗体的产生，而在小细胞外囊泡分泌受损的移植物中或当同种异体抗原通过破裂的小细胞外囊泡递送时，这些反应会减弱。重要的是，人脾FDC结合了被含有活性补体的人血清调理的同种异体小细胞外囊泡。我们的研究结果为导致抗体介导的排斥反应的机制提供了见解，目前针对该反应尚无FDA批准的治疗方法。
