Creative Minds: Exploring the Role of Immunity in Hypertension

Posted on September 7, 2017 by Dr. Francis Collins

Meena Madhur / Credit: John Russell

If Meena Madhur is correct, people with hypertension will one day pay as much attention to their immune cell profiles as their blood pressure readings. A physician-researcher at Vanderbilt University School of Medicine, Nashville, Madhur is one of a growing number of scientists who thinks the immune system contributes to—or perhaps even triggers—hypertension, which increases the risk of stroke, heart disease, kidney disease, and other serious health problems.

About one of every three adult Americans currently have hypertension, yet a surprising number don’t know they have it and less than half have their high blood pressure under control—leading many health experts to refer to the condition as a “silent killer”[1,2]. For many folks, blood pressure control can be achieved through lifestyle changes, such as losing weight, exercising, limiting salt intake, and taking blood pressure medicines prescribed by their health-care provider. Unfortunately, such measures don’t work for everyone, and some people continue to suffer damage to their kidneys and blood vessels from poorly controlled hypertension.

Madhur wants to know whether the immune system might be playing a role, and whether this might hold some clues for developing new, more targeted ways of treating high blood pressure. To get such answers, this practicing cardiologist will use her 2016 NIH Director’s New Innovator Award to conduct sophisticated, single-cell analyses of the immune systems of people with and without hypertension. Her goal is to produce the most comprehensive catalog to date of which human immune cells might be involved in hypertension.

Back in the 1960s, animal studies provided the first indication that the immune system might play a role in hypertension. But with a relatively limited set of tools available then to explore the immune system, limited progress was made over the ensuing few decades. Then, thanks to advances in knowledge and technology arising from the genomic revolution, that line of inquiry began to move forward about a decade ago, starting with more sophisticated studies on the role of immunity and inflammation in hypertension, focusing on genetically engineered rodents.

Now, Madhur is taking the next step with a research project focused on humans. To date, she and her colleagues have collected blood samples from a pilot group of 39 adult volunteers—23 with hypertension and 16 without. These groups are carefully matched for age and body mass index (BMI), two strong risk factors for hypertension.

Caption: Four types of immune T cells from an adult with normal blood pressure cluster on a CyTOF map.
Source: Meena Madhur, Vanderbilt University School of Medicine, Nashville

To get the data, her group will work with Vanderbilt colleague Jonathan Irish, an expert in Cytometry by Time-of-Flight (CyTOF) technology, who will assist in panel design, validation, and data analysis. CyTOF is a form of mass cytometry in which individual antibodies are labeled in the lab with heavy metal tags for visualization, instead of the customary fluorescent tags. This gives Madhur more channels to work with than fluorescence flow cytometry, allowing her team to pack a lot more antibody markers onto each cell, thus increasing the chances of finding something interesting.

CyTOF has been used in cancer studies and to monitor a type of immune T cell that is affected by the human immunodeficiency virus, the cause of AIDS. In the Accelerating Medicines Project (AMP), it’s also being used to look at immune cells in biopsies from patients with rheumatoid arthritis and lupus. But CyTOF has never been applied on such a comprehensive scale to monitor the immune system in hypertension.

Irish has developed a computer software program that employs machine learning to map similarities in the antibody markers attached to the millions of immune cells processed from the blood samples. Each dot plotted on the map represents an individual cell, and the dots cluster into distinct islands of T cell subsets, B cell subsets, and innate immune cells. The more distance between each dot, the more dissimilar their molecular characteristics are. According to Madhur, flow cytometry allows you to find what you are looking for, while CyTOF allows you to find what you never knew existed.

Madhur will look for any unique clusters of cells on the map that come only from people with hypertension. If so, she will pick out eight to 12 features from those cells that will allow isolation by traditional flow sorting and then further characterize these cells in vitro. She will also follow up on her initial leads by opening her study to more volunteers with a wider range of BMIs and age to determine if hypertension associated changes in the immune system track with aging and obesity. It will be interesting to see what implications her work might eventually have for the millions of folks in the United States, not to mention all around the world, who are at risk for this silent killer.

References:

[1] High Blood Pressure Facts. Centers for Disease Control and Prevention, Nov. 30, 2016.

[2] Living with High Blood Pressure. (National Heart, Lung, and Blood Institute/NIH)

Links:

Description of High Blood Pressure (National Heart, Lung, and Blood Institute)

Madhur Lab (Vanderbilt University, Nashville, TN)

Irish Lab (Vanderbilt University)

Madhur Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: National Heart, Lung, and Blood Institute; Common Fund