A single-cell and spatial immune atlas of chronic antibody-mediated rejection reveals autoimmune-shared immune states and a CXCL12-CXCR4 fibroblast-immune niche

Chronic antibody-mediated rejection (CAMR) is a leading cause of late kidney allograft failure and shares features of chronic immune activation with systemic autoimmune diseases, but how circulating immune states connect to spatially organized graft injury and whether related immune features recur in autoimmune inflammation remain unclear. Here, we integrated single-cell profiles from peripheral blood and kidney graft samples from patients with CAMR or stable allograft function and healthy controls with independent transplant cohorts, bulk transcriptomic datasets, spectral flow cytometry, multiplex immunofluorescence, high-resolution spatial transcriptomics, and a large blood immune reference spanning autoimmune and inflammatory diseases.

CAMR was associated with reproducible myeloid expansion and enrichment of SLC8A1+ monocytes/macrophages, ANK3+CD4+ memory T cells, ZEB2hi T cells, and CD16+ NK cells. These subsets exhibited migratory and tissue-interacting programs characterized by the recurrent expression of CXCR4 and ZEB2. In graft tissue, CXCL12-expressing fibroblasts and CXCR4-expressing immune cells were increased in CAMR.