In recent years, it has become apparent that both innate and adaptive immunity contribute to the genesis of hypertension. We have discovered a novel mechanism that underlies activation of adaptive immunity in hypertension, involving the formation of isolevuglandins (isoLGs) in dendritic cells (DCs) and other antigen presenting cells. These lipid oxidation products adduct to proteins, resulting in formation of neoantigens that are processed and presented by major histocompatibility complexes (MHCs). IsoLG-modified proteins are increased in DCs of both mice and humans with hypertension and drive proliferation of subsets of T cells, particularly CD8+ T cells. In this research program, we are examining mechanisms responsible for formation of isoLGs in DCs. We have evidence that isoLGs are formed as a result of both NADPH oxidase activation and by reactive oxygen species generated by the mitochondria in DCs. Using unique mice we have made we are defining potential immunogenic peptides presented in MHC class 1 and determining if there are different peptides derived from mitochondria versus non-mitochondrial sources. Mass spectroscopy will also be employed to determine if similar isoLG modified peptides are presented by monocytes of humans with hypertension. In parallel studies performed in collaboration with Dr. Simon Mallal, the director of the Translational Immunology Core at Vanderbilt, we are characterizing the alpha and beta chain sequences of T cell receptors (TCR? and TCR?) in activated T cells of both mice and humans using single cell sequencing. This will allow us to produce surrogate T cells (transfectomas) that can be used to determine their responsiveness to isoLG-modified proteins and peptides presented in MHC class 1 of hypertensive mice. We have recently shown that hypertensive humans have a striking increase in circulating memory T cells that produce IL-17A and IFN-? compared to matched controls. Data from single cell sequencing will identify the TCR? and TCR? of these cells and to produce transfectomas expressing these sequences and to determine if they are also responsive to isoLG modified proteins presented in the context of APCs from the same individual. Identifying specific neoantigens in hypertension will provide an enormous advance in understanding this disease. These could serve as biomarkers of disease severity and be used to detect pathogenic T cells in hypertension. Ultimately immunization approaches could be employed to treat or prevent hypertension. Specific therapies to reduce isoLG formation have proven effective in experimental models and have substantial promise for treatment of human hypertension.

Public Health Relevance

High blood pressure is an enormous health care burden in the United States, affecting one in three adults. It is a major cause of stroke, heart attack and kidney disease and despite this, the causes of hypertension remain poorly understood and treatment is not always successful. In our proposed studies, we will further define the inflammation that causes hypertension and develop new strategies to prevent this.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
1R35HL140016-01
Application #
9434112
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Maric-Bilkan, Christine
Project Start
2018-02-01
Project End
2024-12-31
Budget Start
2018-02-01
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232