Investigating the role of SLE serum factors in neonatal lupus cardiac fibrosis 

Autoantibodies, a hallmark of systemic lupus erythematosus (SLE), are antibodies that mistakenly target a person’s own cells and tissues, leading to inflammation and organ damage. Expectant mothers with certain autoantibodies, including two called anti-Ro/SSA and anti-La/SSB, have an increased risk of having infants with a heart condition called congenital heart block (CHB). A feature of CHB is fibrosis, which refers to the thickening and scarring of tissue resulting from injury.

The reasons why mothers with anti-Ro and anti-La autoantibodies are more likely to have infants with CHB, and the role of other contributing factors, remain unclear. There is a need for a model to study this disease more accurately and to understand the onset and progression of fibrosis. Additionally, since anti-Ro and anti-La autoantibodies are not the only factors that increase the risk of CHB, Dr. Horton aims to pinpoint other factors present in the blood of women with anti-Ro and anti-La autoantibodies associated with SLE that promote the onset or progression of fibrosis.

Dr. Horton developed a microtissue platform (an engineered system that mimics the structure and function of heart tissues) called congenital cardiac fibrosis chip (CCFC). The CCFC mimics heart tissue and allows her to study how various factors affect it. Dr. Horton will use the CCFC platform to determine whether pro-inflammatory and/or pro-fibrotic factors in blood from women with SLE contribute to the onset and progression of fibrosis in CHB. She predicts that exposure to cytokines (molecules that cause inflammation in lupus) and autoantibodies will lead to harmful cell changes, an increase in fibrosis-related gene expression, and issues in electrical conduction (the heart’s electrical signals that control the heart rate/rhythm).

Lastly, she will study how activated macrophages, immune cells that promote scarring in CHB, contribute to fibrosis and heart disease associated with this condition.

What this means for people with lupus
With her novel model, Dr. Horton aims to find biomarkers and therapeutic targets for SLE-related cardiac diseases, ultimately improving the clinical outlook for infants with CHB.

Expectant mothers testing positive for Ro/SSA and La/SSB autoantibodies associated with lupus have a higher risk of having infants with congenital heart block (CHB). Current works suggest that Ro/SSA and La/SSB autoantibodies localize to apoptotic fetal cardiomyocytes. This leads to an accumulation of macrophages which may contribute to a proinflammatory and pro-fibrotic microenvironment. Many in vitro models fail to recapitulate features of the native microenvironment and are often focused on a single cell type. There is a need for tools to capture in vivo features and allow for the assessment of cardiac fibrosis. The PI has developed congenital cardiac fibrosis on a chip (CCFC) model to mechanistically assess cardiac fibrosis in autoantibody mediated CHB. The chip contains two chambers; an endothelium chamber, containing cardiac endothelial cells and macrophages which will be exposed to physiological flowrates, and a cardiac chamber containing cardiomyocytes and fibroblasts. The chambers are linked by a permeable membrane which allows cross talk between the different cellular constituents. The CCFC will facilitate probing the dynamic interactions between the endothelium and myo-fibro tissue to determine the direct and indirect effect of the maternal autoantibodies, paracrine signaling on neonatal cardiac fibrosis. We hypothesize that pro-inflammatory and/or pro-fibrotic factors in serum of SLE women potentiate autoantibody positivity to manifest fibrosis onset and progression in CHB. The model will be challenged with cytokines, autoantibodies, and SLE serum to investigate cardiac fibrosis. The following aims are proposed:

Aim 1: To utilize the CCFC to determine the temporal interrelationships of cytokine and autoantibody stimulation on fibrosis associated with CHB in neonatal lupus.

Aim 2: To identify other systemic derived pro-fibrotic factors in Ro and La positive sera that may potentiate fibrosis leading to CHB in neonatal lupus using the CCFC.

Aim 3: To determine the mechanism by which macrophages contribute to fibrosis and cardiac dysfunction associated with CHB in neonatal lupus.

The CCFC can be used to improve our current understanding of the fibrosis mechanism. Further, the chip can be used as a testbed for drug candidates which can lead to improved clinical outlook. Lupus is a complex disease, the CCFC is poised to conduct interrogations related to heterogeneity associated with lupus and the heart. While conducting the translational research, the candidate will advance her knowledge in immunology and technical skills such as multiplexing and improve professional competencies related to grantsmanship, mentoring, and leadership. Throughout the project mentoring by a team of senior-level autoimmunity, cardiovascular disease, and regenerative medicine experts will help ensure that the candidate successfully meets the milestones and realize the long-term goal of identifying novel therapeutic targets for fibrosis within CHB.