An engineered human cardiac tissue model reveals contributions of systemic lupus erythematosus autoantibodies to myocardial injury
Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease that affects multiple organs, including the heart. The mechanisms of myocardial injury in SLE remain poorly understood. In this study, we engineered human cardiac tissues and cultured them with IgG from patients with SLE, with and without myocardial involvement. IgG from patients with elevated myocardial inflammation exhibited increased binding to apoptotic cells within cardiac tissues subjected to stress, whereas IgG from patients with systolic dysfunction exhibited enhanced binding to the surface of live cardiomyocytes. Functional assays and RNA sequencing revealed that, in the absence of immune cells, IgG from patients with systolic dysfunction altered cellular composition, respiration and calcium handling. Phage immunoprecipitation sequencing (PhIP-seq) confirmed distinctive IgG profiles between patient subgroups. Coupling IgG profiling with cell surfaceome analysis identified four potential pathogenic autoantibodies that may directly affect the myocardium. Overall, these insights may improve patient risk stratification and inform the development of new therapeutic strategies.
Authors
- Martin Liberman (ORCID: https://orcid.org/0000-0001-5922-4912)
- Christine E. Seidman (ORCID: https://orcid.org/0000-0001-6380-1209)
- Youngbin Kim (ORCID: https://orcid.org/0000-0003-1919-1575)
- Jonathan G. Seidman (ORCID: https://orcid.org/0000-0002-9082-3566)
- Gabriela Venturini (ORCID: https://orcid.org/0000-0003-2913-2296)
- Trevor R. Nash (ORCID: https://orcid.org/0000-0003-4555-7577)
- Sharon Fleischer (ORCID: https://orcid.org/0000-0002-9852-6697)
- Roberta I. Lock
- Daniel Naveed Tavakol (ORCID: https://orcid.org/0000-0003-0451-0617)
- Vanessa Li
- Richard A. Friedman (ORCID: https://orcid.org/0000-0003-3046-1505)
- ROBERT J. WINCHESTER (ORCID: https://orcid.org/0000-0002-7543-8037)
- Manuel A. Tamargo (ORCID: https://orcid.org/0000-0003-1675-1880)
- Margaretha Morsink (ORCID: https://orcid.org/0000-0001-5511-6105)
- Pamela L. Graney (ORCID: https://orcid.org/0000-0003-0428-2634)
- Gordana Vunjak‐Novakovic (ORCID: https://orcid.org/0000-0002-9382-1574)
- Rajesh K. Soni (ORCID: https://orcid.org/0000-0002-4556-4358)
- Laura Geraldino‐Pardilla (ORCID: https://orcid.org/0000-0001-6082-4077)
- Richard Z. Zhuang (ORCID: https://orcid.org/0000-0002-3959-5094)
- Jaron Whitehead
- Morgan J. Lamberti
Institutions
- Brigham and Women's Hospital (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Columbia University Irving Medical Center (US)
- Columbia University (US)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1038/s44161-024-00525-w
- Citations
- 12
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 4.85
Funders
- American Heart Association
- National Heart, Lung, and Blood Institute
- National Institute of Biomedical Imaging and Bioengineering