Single-cell RNA-seq atlas of peripheral blood and kidney graft immune cells in chronic antibody-mediated rejection

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. High-resolution spatial transcriptomics localized this fibroblast–immune architecture to perivascular regions marked by endothelial activation and stromal remodeling, and placed CAMR-associated immune states within adjacent immune-rich neighborhoods, supporting a CXCL12-CXCR4 axis that may be associated with local immune accumulation. Comparisons with large-scale blood immune reference data and spatial transcriptomic datasets from rheumatoid arthritis and systemic lupus erythematosus suggested partial recurrence of related immune states and fibroblast–immune organization. Together, this study links circulating CAMR immune remodeling to a spatially organized CXCL12-CXCR4 fibroblast-immune niche, and suggests that elements of this niche recur across alloimmune and autoimmune inflammation.