WARS1, TYMP and GBP1 display a distinctive microcirculation pattern by immunohistochemistry during antibody-mediated rejection in kidney transplantation

Abstract

Antibody-mediated rejection (ABMR) is the leading cause of allograft failure in kidney transplantation. Defined by the Banff classification, its gold standard diagnosis remains a challenge, with limited inter-observer reproducibility of the histological scores and efficient immunomarker availability. We performed an immunohistochemical analysis of 3 interferon-related proteins, WARS1, TYMP and GBP1 in a cohort of kidney allograft biopsies including 17 ABMR cases and 37 other common graft injuries. Slides were interpreted, for an ABMR diagnosis, by four blinded nephropathologists and by a deep learning framework using convolutional neural networks. Pathologists identified a distinctive microcirculation staining pattern in ABMR with all three antibodies, displaying promising diagnostic performances and a substantial reproducibility. The deep learning analysis supported the microcirculation staining pattern and achieved similar diagnostic performance from internal validation, with a mean area under the receiver operating characteristic curve of 0.89 (± 0.02) for WARS1, 0.80 (± 0.04) for TYMP and 0.89 (± 0.04) for GBP1. The glomerulitis and peritubular capillaritis scores, the hallmarks of histological ABMR, were the most highly correlated Banff scores with the deep learning output, whatever the C4d status. These novel immunomarkers combined with a CNN framework could help mitigate current challenges in ABMR diagnosis and should be assessed in larger cohorts.

Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection

“…Using microdissection on formalin-fixed kidney allograft biopsies combined with mass spectrometry-based proteomics, it was recently reported that 77 proteins were deregulated in glomerulitis compared to stable grafts, particularly involved in cellular stress mediated by interferons type I and II, leukocyte activation and microcirculation remodeling 55 . Also here, WARS1 protein was overexpressed in leucocytes infiltrating the glomeruli as well as in endothelial cells during ABMR 55,56 . Furthermore, our cell-to-cell communications analysis suggested that CXCL10 overexpression by FcγRIII+ monocytes may recruit CXCR3 + T cells and activate ACKR1+ endothelial cells composing the peritubular capillaries.…”

Identification of RNA-binding protein genes associated with renal rejection and graft survival

“…Increased mRNA levels of WARS are reported to be associated with renal rejection [ 52 ]. Using a proteomic approach, one study found that high expression of the interferon associated protein WARS1 could be used as a specific indicator of endothelial stress along with TYMP and GBP1 to aid in the diagnosis of ABMR [ 53 , 54 ]. Our study also demonstrates its important potential diagnostic value in kidney transplant rejection and long-term prognosis.…”

Identification of Key Genes and Exploration of Immune Activation Pathways in T-cell Mediated Rejection through Integrated Bulk and Single-Cell RNA-Seq Analysis with Machine Learning

“…GBP1 is highly expressed in macrophages, endothelial cells, and epithelial cells, with continued high expression levels in T cells after IFN-γ stimulation induced by interferon-γ (IFN-γ) 32 . In several studies of renal transplant rejection, researchers have con rmed through transcriptomic analysis and tissue biopsies that GBP1 may serve as a biological characteristic and predictive model for acute rejection [33][34][35] . Recent research have found that GBP1 binds to lipopolysaccharide (LPS) during bacterial infection, mediating the recruitment and activation of in ammatory caspase-4 through cleavage of GSDMD to induce pyroptosis 36,37 .…”