Sick and tired: The plight of an aging immune system

Derya Unutmaz

JAX professor Derya Unutmaz, a renowned expert in HIV, launches a bold initiative to examine how immune system aging contributes to chronic diseases.

Through the wonders of evolution, humans come equipped with a built-in bodyguard — the immune system. Like any defender, it must identify and neutralize threats, and do so in a precise, measured way. And like most defenders, it has imperfections, sometimes taking aim at the wrong targets or weakening with age.

Despite its flaws, the body’s natural defenses emerge from a vast network of cells, tissues and organs that together make up the immune system. For the last 25 years, Derya Unutmaz, M.D., has studied these components and their complex behaviors. Unutmaz, who joined The Jackson Laboratory as a professor in January 2015, has his sights set squarely on the immune system in humans, motivated by a personal mission to translate his findings as quickly as possible to the clinic.

“I like to say, ‘The patient is always right,’” says Unutmaz. “You can have the most beautiful theories or hypotheses or results from the lab, but if they don’t fit what we see in the patient, they don’t mean very much.”

Over the last several years, he and his colleagues have revealed deep insights into the human immunodeficiency virus (HIV), specifically how it perturbs the immune system and causes disease. Now, as he establishes his roots at The Jackson Laboratory for Genomic Medicine, Unutmaz is applying that expertise to a new set of questions — how does the human immune system age, and how does that maturity contribute to chronic disorders, such as cancer, cardiovascular disease, and Alzheimer’s disease?

For love of the immune system

Unutmaz trained as a physician, earning his MD from the Marmara University Medical School in Istanbul, Turkey. Although he has not treated patients since he graduated in 1991, he remains deeply focused and committed to research that can improve health.

Unutmaz was first exposed to immunology as a medical student. But he detested the topic — it seemed boring. One day, while studying in the library, he opened a textbook written by the famed immunologist Ivan Roitt. It was unlike any Unutmaz had seen, decorated with vividly colored drawings and illustrations that conveyed the inner workings of the immune system.

“I immediately fell in love,” recalls Unutmaz. “I realized how beautiful this system is, how complicated and intricate. I switched from hating it to loving it.”

That love grew deeper as his professors recognized his passion and helped nurture it. He suspended his medical studies for a year to work as an immunology research intern, first at Novartis, a global pharmaceutical company headquartered in Basel, Switzerland, and later at University College in London, England. Those early forays led Unutmaz to accept a postdoctoral position at Novartis following graduation. There his work centered on cellular immunology and the myriad types of immune cells, specifically a subset of human immune cells called T cells that orchestrate the immune response.

As he became well versed in the ways of these immune cells, Unutmaz also became interested in the molecular side of immunology. He accepted a second postdoctoral position, this time at New York University in the laboratory of Dan Littman. There he developed a keen interest in HIV, a type of virus known as a retrovirus, which inserts itself into its host’s genome by copying its own genetic material, made of RNA, into a DNA version. (This RNA to DNA conversion reverses the typical flow of biological information, thus the name “retro”-virus.)

“I thought, ‘HIV probably knows more immunology than I do,’ so I needed to study that,” he says. “It was, and still is, an important problem.”

Unraveling the biology of HIV

HIV is a relatively new pathogen, leaving little time, evolutionarily speaking, for humans to adapt and evolve effective defenses. As a result, HIV exploits weaknesses in the immune system, allowing it to infect and persist in human populations. In fact, the virus infects the very immune cells that are programmed to attack it — so-called CD4+ T cells. As HIV infection unfolds, these CD4+ cells are progressively destroyed, disrupting the body’s response against the virus as well as many other pathogens.

Through decades of fundamental research, including key discoveries from Unutmaz’s own lab, the biomedical research community has developed effective strategies for fighting back. Now, many people who are infected with HIV receive anti-retroviral therapy, which can keep the virus in check, transforming a once fatal disease into a chronic, but manageable, condition.

Despite this progress in HIV, some important challenges remain. Even in patients whose viral levels remain low and well controlled, immunological changes unfold over time that leave some patients more vulnerable to chronic, inflammatory diseases.

“There is a sort of accelerated aging of the immune system that causes inflammatory diseases,” says Unutmaz. “So, a 50-year-old with HIV has a much higher risk of heart attack, for example, than someone who is not infected.”

Imagine a group of very seasoned soldiers who have been at war for many years. They are extremely experienced. But they can also be quite dangerous — mercenaries, for example — and inflict significant harm. This is analogous to what happens in an aging immune system. Very powerful immune cells, known as effector cells, accumulate over time. These cells are typically eliminated shortly after infections, but in chronic conditions they persist, growing in number and in their collective strength.

Unutmaz is now embarking on an effort to unlock the basis of this immune aging process, seeking to understand how it contributes to HIV as well as other chronic diseases, including cancer, cardiovascular disease, and Alzheimer’s disease. His work is part of a newly expanded program at JAX, led by Jacques Banchereau, Ph.D., which delves into the biology of the human immune system and its role in various diseases and conditions.

Focused on translation

Unutmaz is taking a broad approach by collecting samples from as many patients and disease types as possible. Through his extensive network of collaborators, he has gathered samples representing various forms of cancer, including breast cancer, Hodgkins lymphoma, and multiple myeloma, as well as other chronic diseases, such as coronary artery disease and chronic fatigue syndrome.

To analyze these samples, Unutmaz and his colleagues turn to immune profiling methods, which allow them to deeply and thoroughly characterize the immune cells present in each patient sample. Single-cell techniques, such as RNA sequencing, are particularly powerful, enabling the scientists to analyze immune cells that are present at varying frequencies — even very low frequencies. By probing these rare cells, they can uncover completely new classes of cells or reveal previously unknown molecular markers, casting important light on disease biology.

One of Unutmaz’s closest and longest-running collaborations is with Oral Alpan, a clinical immunologist based in Fairfax, Virginia. The pair has worked together for nearly a decade, studying patients with allergic conditions as well as other immune disorders. Their findings are yielding detailed molecular information that can improve the diagnosis and treatment of puzzling, poorly understood immune disorders.

For Alpan, the collaboration is both rewarding and enlightening — a mutual exchange not just of samples, but also of transformative ideas and insights.

“Derya is very diligent and detail-oriented,” says Alpan. “He’s someone who can easily dissect a good scientific question from a bad one. At the same time, he’s very open, and willing to share all the information he has.”

For Unutmaz, his partnership with Alpan is just one example of how he hopes his work at JAX will impact patients. “Although I don’t see patients, my goal as a trained physician is to be able to translate our knowledge back to the patients,” says Unutmaz. “We have a responsibility to push forward as quickly as we can.”

Nicole Davis, Ph.D., is a freelance writer and communications consultant specializing in biomedicine and biotechnology. She has worked as a science communications professional for nearly a decade and earned her Ph.D. studying genetics at Harvard University.