Studying autoimmune-mediated heart disease with iPSC-derived engineered cardiac tissue models

In Systemic Lupus Erythematosus (SLE), heart failure rates are 2-3-fold higher compared to the general population, suggesting that the autoimmune response intrinsic to SLE drives this increased risk. Interestingly, while in certain SLE patients no cardiac pathology is observed, others are diagnosed with cardiac dysfunction of varying severities. The immunological mechanisms that lead to different cardiac phenotypes in SLE patients remain unknown. Current experimental tools such as 2D cell culture and animal models have limited ability to recapitulate the biological complexity of SLE, and lack patient-specificity. Here, we developed 3D tissue models of the human heart muscle, engineered from iPSCs-derived cardiac cells, to investigate patient-specific autoimmune mechanisms of heart disease.

We investigated a cohort of SLE patients with well-characterized cardiac disease status. We observed that autoantibodies isolated from patients with high levels of cardiac inflammation showed increased binding to the iPSC-derived cardiac tissues, with distinctive patterns of cardiac autoantigen specificity. We further demonstrated that the autoantibodies directly led to altered tissue contractility and calcium handling. This effect was enhanced under stress conditions, suggesting that cardiac stress leads to enhanced autoantibody reactivity and subsequently cardiac dysfunction. Importantly, we demonstrated that the cardiac tissues, cultured with patient autoantibodies, recapitulated autoimmune-mediated cardiac dysfunction in a patient-specific context. Furthermore, by using proteomic analysis, we identified autoantibodies that drive cardiac tissue dysfunction, and may play a role in disease pathogenesis. This study provides a personalized approach toward a mechanistic understanding of autoimmune-mediated heart disease and identifies potential heart disease-aggravating autoantibodies and associated therapeutic targets.