How Does Aging Affect Innate Immunity?

Cellular immunologist Ruth Montgomery, PhD, is an expert in using novel technology in human translational studies. Her research identifies individual differences in immune responses that lead to divergent infection outcomes. Her group focuses on the effects of aging and age-associated diseases on innate immunity, among other areas.

Worldwide, the population is getting older, so it’s imperative to understand the cell changes that come with age, stresses Montgomery, who is a professor of medicine (rheumatology) at Yale School of Medicine, and of epidemiology (microbial diseases) at Yale School of Public Health. “Older people are more susceptible to infectious diseases and less responsive to vaccines,” she said.

During her time at Yale, Montgomery has studied individual variations that influence susceptibility to West Nile, dengue, Zika, and COVID-19 infections. Her recent work includes inflammatory profiling of patients with sickle cell disease, who suffer from specific but poorly understood forms of immunosuppression.

In a Q&A, Montgomery discusses the effects of aging on innate immunity, a surprising discovery about West Nile virus, and how advanced technology influences her research.

The innate immune system consists of white blood cells, including neutrophils, which are the first responders to infection. In humans, 75% of the white cells in the blood are neutrophils. These specialized cells are born every day and live about 24 hours.

Even though these cells are born new every day, they respond differently to stimuli depending on whether they are from an older person or a younger one. In our studies, we enroll people under 35 and over 60 into two distinct groups, and then we test what the cells are able to do, what functions they have, and how they respond to stimulation. In other studies, we look at cells from individuals with severe disease compared to those who have an asymptomatic infection to identify differences between the two groups.

My work is focused on using the most in-depth technology to do detailed immune profiling of patient samples to understand the differences in cells and responses to viruses. In addition to the cell function assays that we've been doing for longer, we are currently studying the metabolites and proteins in the blood and bringing all of that together. We want to understand not only how you turn on the immune system but also how you regulate it and turn it down when it's not needed. Sometimes, the over-exuberance of the immune response makes it difficult for a patient to recover. That's been true in COVID, and it's also true in some cases of West Nile virus infection.

I'm always excited and surprised when we discover something about how cells work. For example, in a young person, when cells get infected with West Nile virus, they bring down the level of one of the molecules that recognizes the virus receptors to avoid an over-exuberant immune response. However, in an older person, that level stays high, so the cells continue to progress in an activation pathway, which can be difficult for the patient. It’s a striking difference, and I didn’t expect it.

Our most recent project is centered on patients with sickle cell disease. We identify differences in the immune cell pathways at two different time points—at baseline and when they have a crisis. We then compare the responses to those of household contacts who don't have sickle cell disease. We want to understand which pathways are relevant to the difficulty in immune responses that these patients have. Quite a lot is understood about how you get sickle cell and what it means for your red blood cells, but there's little information on how the immune system works in that patient group. It’s an exciting new area.

Every few years, there's a revolution in how we study cells, and we use the latest techniques when we move to a new project. We don't go back and repeat the old ways of doing things. Currently, we do single-cell RNA sequencing, and we also use a technique called CyTOF, a multi-parameter cell identification system that I launched at Yale in 2013. With CyTOF, we measure 50 parameters at the same time in the cell when we used to be limited to 8 or 10. And we not only look at what the cell is doing but also the environment. More and more now, if we can, we study the tissue of the host, not just the circulating blood. A lot of what goes on in immunity is in the tissues of the body.

With each project, we learn new and more in-depth ways to study how the immune response works.

The Department of Internal Medicine at Yale School of Medicine is among the nation's premier departments, bringing together an elite cadre of clinicians, investigators, educators, and staff in one of the world's top medical schools. To learn more, visit Internal Medicine.