Tambur, A. R. | bioRxiv Science

bioRxiv2026

Autoreactive antibody production by intrarenal B cells in mouse kidney allograft rejection

Antibody-mediated rejection (AMR) is a major cause of kidney allograft failure, with donor HLA-specific antibodies (DSA) recognized as primary drivers of AMR pathology. However, a significant proportion of AMR diagnoses lack detectable DSA, thus implicating DSA-independent mechanisms. In support, we previously reported on the accumulation of autoreactive B cells in rejecting renal biopsies, which raised the possibility that autoreactive IgG produced within the allograft contributes to graft pathology. In this study, we used mouse models to show that rejecting kidney allografts preferentially promoted a breach in autoreactive B cell tolerance, leading to the local production of autoreactive antibodies. Notably, autoreactive IgG responses were uncoupled from DSA production, indicative of distinct regulation. Organoid cultures confirmed that autoantibody production was observed in the rejecting kidney, whereas DSAs were produced in both the lymph node and graft. Intrarenal B cells expressing Nur77 were enriched for autoreactivity, consistent with in situ antigen recognition. Finally, autoreactive antibodies are pathogenic, since inhibiting autoantibody production with transient anti-IL-15 and CTLA-4Ig led to preserved kidney allografts. These unique features of in situ autoantibody responses may be relevant to diverse diseases with chronic tissue inflammation beyond transplantation.

immunology↗

bioRxiv2024

Compartmentalization of Transcripts During Antibody Mediated Rejection in Renal Transplants

We used Digital Spatial Profiling to localize transcripts in glomeruli and tubulointerstitial compartments in a series of 4 biopsies from a patient diagnosed with acute antibody-mediated rejection (AMR). The 4 biopsies included: a baseline protocol biopsy 25 days after transplantation; a 3 month biopsy diagnosed as acute AMR; a biopsy 4 months after treatment with intravenous immunoglobulin (IVIg) showing ongoing AMR with a mild increase in tubulointerstitial fibrosis; and a biopsy 7 months later with resolution of glomerulitis. Glomeruli were captured in regions of interest (ROIs) for whole exome sequencing. Compared to baseline glomeruli, 17 transcripts were increased and 39 decreased in the 3 subsequent biopsies (> 2-fold and p < 0.005). Increased signatures for macrophages correlated with increased numbers of CD68 positive cells imaged in the corresponding glomeruli. The Human Cell Atlas classified the 39 transcripts decreased during the initial rejection as characteristic of podocytes and this gene signature did not recover in the subsequent 2 biopsies. Additional ROIs encompassing areas of tubulointerstitial fibrosis disclosed signatures for memory B cells in the acute AMR sample. Treatment with IVIg did not eliminate the B cell signal in the subsequent biopsy. Collectively these data demonstrate a compartmentalization of injury processes. Innate immune cells including macrophages were located in glomerular and tubulointerstitial compartments, whereas, adaptive immune cells including memory B cells localized to the tubulointerstitial compartment. Furthermore, podocyte transcripts were decreased in glomeruli and did not recover with treatment indicating a vulnerability of these cells to acute AMR.

pathology↗