How Autoantibodies Attack the Heart in Lupus Patients

Cardiovascular disease is the leading cause of death in patients with lupus, an autoimmune disease in which our immune system attacks our own tissues and organs—the heart, blood, lungs, joints, brain, and skin. Lupus myocarditis, an inflammation of the heart muscle, can be very serious because it alters the regularity of the heart’s rhythm and strength. However, the mechanisms underlying this complex disease are poorly understood and difficult to study.

A recurring question about lupus is why some patients develop myocarditis while others do not. And why the clinical manifestations of affected patients vary widely, 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 tissues or organs, with different specificities for different molecules. Like our genes, they may explain why different people have different symptoms.

Researchers have long suspected that specific autoantibody signatures may hold the key to the puzzling clinical variations observed in lupus patients. Until now, identifying the autoantibodies involved in cardiac damage has been extremely difficult due to the lack of experimental models capable of reproducing heart disease in lupus patients. Current animal models are inadequate due to differences in cardiac physiology, while human cell cultures simply cannot capture the complexity and function of the human heart.

Study shows autoantibodies may directly affect heart disease in lupus patients

In a new study, published August 15 in Cardiovascular research on natureA 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 patients with lupus.

The researchers engineered millimeter-sized heart tissues from healthy adult human stem cells, matured them using metabolic and electromechanical signals, and then incubated them with autoantibodies present in the blood of lupus patients with and without myocarditis.

The team found that the patterns of patient autoantibodies binding to heart tissue depended on the type and severity of their myocardial damage. A subset of patients with severe myocarditis had unique autoantibody populations that primarily targeted dying heart cells, while patients with impaired heart pump function had autoantibodies that primarily targeted the surface of living cells.

Interestingly, the team found that autoantibodies that bind to living heart cells are able to exert powerful biological effects on tissues in the absence of immune cells, revealing new mechanisms that could potentially contribute to heart failure in lupus patients.

The study also identified four autoantibodies that may directly affect the heart muscle. These findings could help identify lupus patients at greatest risk of developing heart disease, inform the development of new therapeutic strategies, and extend the study to other autoimmune diseases.

“This discovery is the first demonstration that autoantibodies can directly promote myocardial injury in this complex autoimmune disease,” said team leader Gordana Vunjak-Novakovic, university professor and Mikati Foundation Professor of Biomedical Engineering, Medical Sciences and Dentistry at Columbia.

“It is amazing that these tiny heart tissues that we have created using human stem cells and organ-on-a-chip technology have the ability to mimic organ function in a patient-specific way, and for such a complex disease. We now live in an era of studying disease progression and treatment using seemingly simple but highly controllable and predictive human organ models. It feels like we are living in the future.”

Engineers and clinicians use a collaborative approach

Vunjak-Novakovic, a bioengineer known for her pioneering work in engineering functional human tissues for 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.

Physicians provided blood samples containing lupus autoantibodies and detailed clinical data for the lupus patient cohort. This allowed the Columbia engineering team to assess the effects of patient-specific autoantibodies on heart function using engineered heart tissue and correlate these effects with clinical symptoms.

“Myocarditis can be a difficult to diagnose and sometimes clinically worrisome disease of lupus. The development of this functional model of mature cardiac tissue already opens new avenues to advance our understanding and, ultimately, the clinical management of this enigmatic autoimmune process,” Winchester noted.

To learn more about potential therapeutic targets, Vunjak-Novakovic’s team also worked closely with Drs. Christine and Jonathan Seidman of Harvard University. The team is now exploring ways to use their findings to better understand the underlying mechanisms of heart disease in lupus patients and to improve the diagnosis and treatment of this complex and challenging disease.

“What’s really exciting 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 a novel approach to solving long-standing questions about heart disease in lupus patients,” said Sharon Fleischer, first author of the study and a postdoctoral fellow in Vunjak-Novakovic’s lab. “The new framework we established in this study for studying autoantibody interactions with human organs opens up unprecedented 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, a recent graduate of the Vunjak-Novakovic lab and an MD candidate in the Medical Scientist Training Program at the Vagelos College of Physicians and Surgeons.