Dominant intragraft plasma cells targeting bilirubin implicate local heme catabolism in human cardiac allograft vasculopathy
Year: 2025
Type: article
Abstract: BACKGROUNDCardiac allograft vasculopathy (CAV) is consistently accompanied by immune infiltrates surrounding affected coronary arteries, including antibody-producing plasma cells (PC). The antigenic drivers of these intragraft PC responses remain poorly defined.METHODSWe characterized graft infiltrating PC by single-cell RNA sequencing and immunoglobulin gene profiling. Using immunoglobulin sequences, we generated 37 recombinant monoclonal antibodies (mAb) from dominant intragraft PC clones and 24 control mAb from peripheral blood PC. Antigen reactivity was screened against chemical adducts, including bilirubin, a heme-degradation byproduct. Histologic and tissue analyses assessed bilirubin deposition as well as expression of hemecatabolic enzymes and the presence of Fe2+ in heart explants with CAV.RESULTSA majority of graft-derived mAb (21 of 37; approximately 57%) - but none of the mAb derived from blood PC - reacted to bilirubin. Bilirubin deposition was detected within lymphocytic aggregates in CAV grafts. In coronary arteries with CAV lesions, bilirubin accumulated in the cytoplasm and nuclei of smooth muscle cells in the tunica media, a pattern not observed in healthy heart tissue. Lastly, we detected the expression of heme-oxygenase-1 and biliverdin reductases in graft-infiltrating macrophages along with the presence of Fe2+ ion in the media of arteries with hyperplasia.CONCLUSIONThese findings suggest that local heme catabolism and resultant bilirubin accumulation create a prominent target for intragraft antibody responses in CAV. Bilirubin-specific antibodies and hemecatabolic pathways may contribute to CAV pathogenesis and represent potential mechanistic and therapeutic avenues for further investigation.FUNDINGGrants AI116814, AI154845, AI184963, and AI176507, HL148528, RYC2022-036797-I, P30CA013696, UL1TR001873, S10OD020056.
DOI: 10.1172/jci194138
Authors: Sarah B. See, Talita Aguiar, Max Dietzel, Mattea Ausmeier, Hang T.T. Nguyen, Shunya Mashiko, Laura Donadeu, Hector Cordero, Poulomi Roy, Lorea Roson, Charles C. Marboe, Matthias J. Szabolcs, Maryjane Farr, Jose González-Costello, Aleix Olivella, Yoshifumi Naka, Koji Takeda, Rodica Vasilescu, Kevin J. Clerkin, Gilles Benichou, Joren C. Madsen, R. Glenn King, Oriol Bestard, Evan P. Kransdorf, Emmanuel Zorn
Institutions: Columbia University Irving Medical Center, Martin Luther University Halle-Wittenberg, Vall d'Hebron Hospital Universitari, Universidad de Extremadura, The University of Texas Southwestern Medical Center, Bellvitge University Hospital, Institut d'Investigació Biomédica de Bellvitge, Universitat de Barcelona, Universitat Autònoma de Barcelona, Instituto de Salud Carlos III, Centro de Investigación en Red en Enfermedades Cardiovasculares, Vall d'Hebron Institut de Recerca, Massachusetts General Hospital, University of Alabama at Birmingham, Cedars-Sinai Medical Center, Cedars-Sinai Smidt Heart Institute
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: G4436117340, Functional significance of plasma cell infiltrates of human cardiac allograft vasculopathy, G5036540529, Identifying Novel Diagnostics and Mechanisms for Cardiac Allograft Vasculopathy, Local antibody responses in human cardiac allograft vasculopathy, Contribution of B cells to human cardiac allograft vasculopathy, G7041613273, Functional significance of plasma cell infiltrates of human cardiac allograft vasculopathy
OpenAlex ID: W4416665738