Dominant intragraft plasma cells targeting bilirubin implicate local heme catabolism in human cardiac allograft vasculopathy
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.
Authors
- Emmanuel Zorn (ORCID: https://orcid.org/0000-0001-9985-8389)
- R. Glenn King (ORCID: https://orcid.org/0000-0001-6522-0053)
- Talita Ferreira Marques Aguiar (ORCID: https://orcid.org/0000-0003-0202-6848)
- Max Dietzel
- E. Kransdorf (ORCID: https://orcid.org/0000-0002-0507-2412)
- Koji Takeda (ORCID: https://orcid.org/0000-0001-8263-1911)
- Kevin J. Clerkin (ORCID: https://orcid.org/0000-0001-8351-9219)
- José González‐Costello (ORCID: https://orcid.org/0000-0002-7437-3630)
- Oriol Bestard (ORCID: https://orcid.org/0000-0001-9468-7920)
- Maryjane Farr (ORCID: https://orcid.org/0000-0003-1066-9368)
- A. Olivella (ORCID: https://orcid.org/0000-0003-4912-2343)
- Gilles Bénichou (ORCID: https://orcid.org/0000-0003-1356-3171)
- Shunya Mashiko (ORCID: https://orcid.org/0000-0002-4829-535X)
- Sarah B. See (ORCID: https://orcid.org/0000-0002-4208-317X)
- Hang Thi Thu Nguyen (ORCID: https://orcid.org/0000-0001-7431-5126)
- Charles C. Marboe (ORCID: https://orcid.org/0000-0001-6844-209X)
- Héctor Cordero (ORCID: https://orcid.org/0000-0002-0420-0478)
- Laura Donadeu (ORCID: https://orcid.org/0000-0002-5089-5047)
- Joren C. Madsen (ORCID: https://orcid.org/0000-0003-2724-1333)
- Poulomi Roy (ORCID: https://orcid.org/0000-0001-9445-9709)
- Yoshifumi Naka (ORCID: https://orcid.org/0000-0003-1808-7063)
- Mattea Ausmeier
- Rodica Vasilescu
- Matthias Szabolcs
- Lorea Roson
Institutions
- Hebron University (PS)
- Cedars-Sinai Medical Center (US)
- Columbia University Irving Medical Center (US)
- Bellvitge University Hospital (ES)
- University of Alabama at Birmingham (US)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Massachusetts General Hospital (US)
- Vall d'Hebron Institut de Recerca (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Cedars-Sinai Smidt Heart Institute (US)
- Martin Luther University Halle-Wittenberg (DE)
- Universidad de Extremadura (ES)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-11-25
- DOI
- https://doi.org/10.1172/jci194138
- Citations
- 1
- Primary Topic
- Transplantation: Methods and Outcomes
- Type
- article
- Field-Weighted Citation Impact
- 2.01
Funders
- Vagelos College of Physicians and Surgeons, Columbia University