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Tiny Killers: How Autoantibodies Attack the Heart in Lupus Patients
Columbia University School of Engineering and Applied Science News
New York, NY — Cardiovascular disease is the leading cause of death in patients suffering from lupus, an autoimmune disease in which our immune system attacks our own tissues and organs, the heart, blood, lung, joints, brain, and skin. Lupus myocarditis can be very serious because the inflammation alters the regularity of the rhythm and strength of the heartbeat. However, the mechanisms underlying this complex disease are poorly understood and difficult to study.
A long-standing question about lupus is why some patients develop myocarditis while others remain unaffected. And why the clinical manifestations of affected patients range so dramatically, from no symptoms at all to severe heart failure. Lupus is characterized by a large number of autoantibodies, immune proteins that mistakenly target a person's own tissues or organs, with different specificities for various molecules. Like our genes, they may explain why different individuals experience different symptoms.
Researchers have long suspected that specific autoantibody signatures could hold the key to the puzzling clinical variations they observe in lupus patients. Thus far, identifying autoantibodies involved in heart damage has been incredibly challenging due to the lack of experimental models that can replicate the cardiac disease in lupus patients. The currently used animal models fall short because of differences in cardiac physiology, while human cell cultures simply cannot capture the complexity and function of the human heart.
New study shows that autoantibodies can directly affect heart disease in lupus patient
In a new study, published August 15 in Nature Cardiovascular Research, a team of researchers from Columbia Engineering, Columbia University Vagelos College of Physicians and Surgeons, and Harvard University report that autoantibodies alone directly affect heart function in lupus patients.
The researchers engineered millimeter-sized cardiac tissues from healthy adult human stem cells, matured them using metabolic and electromechanical signals, and then incubated them with the autoantibodies found in the blood of lupus patients with and without myocarditis. The team found that the binding patterns of the patients’ autoantibodies to heart tissue depend on the type and severity of their myocardial damage. A subset of patients with severe myocarditis had unique autoantibody populations that primarily targeted dying cardiac cells, whereas patients with weakened heart pump function had autoantibodies that mostly targeted the surface of live cells. Interestingly, the team discovered that the autoantibodies that were binding to live cardiac cells were able to exert potent biological effects on the tissues in the absence of immune cells, revealing potentially new mechanisms that could contribute to heart failure in lupus patients.
The study also identified four such autoantibodies that may directly affect the heart muscle. These findings may help identify lupus patients with the greatest risk of developing heart disease, inform the development of new therapeutic strategies, and allow extension to other autoimmune diseases.
“This finding is the first demonstration that autoantibodies can directly mediate myocardial injury in this complex autoimmune disease,” said the team’s leader Gordana Vunjak-Novakovic, University Professor and the Mikati Foundation Professor of Biomedical Engineering, Medical Sciences, and Dental Medicine at Columbia. “It’s astounding that these tiny heart tissues we’ve engineered using human stem cells and ‘organs-on-chip’ technology have the ability to emulate organ-level functions in a patient-specific way, and for such a complex disease. We now live in the era of studying the progression and treatment of diseases using apparently simple yet highly controllable and predictive models of human organs. It feels like living in the future.”
Engineers and clinicians use collaborative approach
Vunjak-Novakovic, a bioengineer renowned for her pioneering work in engineering functional human tissue for use in regenerative medicine, and her group have spent three decades working on modeling heart injury and disease and engineering tissues to combat them. For this study, the bioengineers teamed up with two physicians, Robert Winchester and Laura Geraldino-Pardilla, both rheumatologists at NewYork-Presbyterian/Columbia University Irving Medical Center. The physicians provided blood samples containing lupus autoantibodies and detailed clinical data for the cohort of lupus patients. This enabled the Columbia Engineering team to assess the effects of patient-specific autoantibodies on heart function using engineered heart tissues and to correlate these effects to clinical symptoms.
”Myocarditis can be a diagnostically elusive and sometimes clinically ominous feature of lupus. The development of this functional mature cardiac tissue model is already opening multiple new pathways to advance our understanding and ultimately clinical management of this enigmatic autoimmune process,” Winchester noted.
To learn more about the potential therapeutic targets, Vunjak-Novakovic’s team also worked closely with Drs Christine and Jonathan Seidman from Harvard University. The team is now exploring ways to use their findings to better understand the underlying mechanisms of cardiac disease in lupus patients and to improve diagnostics and treatment of this complex and challenging disease.
"What’s really cool about this study is that by leveraging our expertise in engineering and stem cells to develop models of the human heart, we were able to take an innovative approach to solving long-standing questions surrounding heart disease in lupus patients,” said the study’s first author Sharon Fleischer, who is a postdoc in Vunjak-Novakovic’s lab. “The new framework we established in this study to investigate autoantibody interactions with human organs opens up unparalleled opportunities for understanding organ damage, not just in lupus but across a spectrum of autoimmune diseases.”
“It was wonderful to be part of such a collaborative team that included engineers, physicians, and biologists working together to investigate a challenging clinical problem,” said Trevor Nash, one of the study’s co-first authors who is a recent graduate from the Vunjak-Novakovic lab and a MD/PhD candidate in the Medical Scientist Training Program at the Vagelos College of Physicians and Surgeons.
About the Study
Journal: Nature Cardiovascular Research
The study is titled “An engineered human cardiac tissue model reveals contributions of systemic lupus erythematosus autoantibodies to myocardial injury.”
Authors are: Sharon Fleischer1,*, Trevor R. Nash1,*, Manuel A. Tamargo1, Roberta I. Lock1, Gabriela Venturini2, Margaretha Morsink1, Pamela L. Graney1, Vanessa Li1, Morgan J. Lamberti1, , Martin Liberman1, Youngbin Kim1, Daniel N. Tavakol1, Richard Z. Zhuang1, Jaron Whitehead1, Richard A. Friedman3,4, Rajesh K. Soni5, Jonathan G. Seidman2, Christine E. Seidman2,6,7, Laura Geraldino-Pardilla8, Robert Winchester8,9 and Gordana Vunjak-Novakovic1,8,10,‡
1Department of Biomedical Engineering, Columbia University, New York, NY, USA
2Department of Genetics, Harvard Medical School, Boston, MA, USA
3Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
4Department of Biomedical Informatics, Columbia University, New York, NY, USA
5Proteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
6Division of Cardiovascular Medicine, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA, USA
7Howard Hughes Medical Institute, Chevy Chase, MD, USA
8Department of Medicine, Columbia University, New York, NY, USA
9Columbia Center for Translational Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA
10College of Dental Medicine, Columbia University, New York, NY, USA
The study was supported by. National Institutes of Health (P41EB027062 and 3R01HL076485 to G.V-N.), the American Heart Association (19TPA34910217 to R.W.), a Pfizer Aspire research award (WI237809 2018 ASPIRE US Rheumatology to R.W.), and the National Science Foundation (NSF1647837 to G.V-N.).
The authors declare no financial or other conflicts of interest.
Nature Cardiovascular Research, DOI: 10.1038/s44161-024-00525-w
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