How Warts Could Reveal the Immune System's Tiny Flaws and Functions

Medical students have a classic rule of thumb on the subject of choosing their specialty: If you’re undecided between obstetrics and pediatrics, the moment of truth will happen right after you deliver a baby for the first time. In that exhilarating moment of helping a mother welcome a new life, do you want to stay as the obstetrician at the mom’s bedside, or do you want to follow the baby?

Sarah Henrickson, MD, PhD, recalled this maxim when describing a similar moment of clarity she experienced during medical school after she had already metaphorically chosen to follow the baby, with a clinical focus pediatrics. As an MD/PhD student, she wanted to both care for patients and learn from them how to ask optimal questions in the lab — but she remained uncertain what type of questions to ask.

“I had a moment of insight in dermatology clinic that common infections that persisted longer than expected could be a window to understanding chinks in the armor of the immune system — tiny, specific holes, as opposed to the huge gaps in immune function in many classic primary immune deficiencies,” Dr. Henrickson said.

She followed that insight out of dermatology and into immunology, and she has been at work ever since on a study that uses recurrent warts as a natural experiment to understand the normal workings of skin immunity. Dr. Henrickson is now an allergy/immunology fellow at The Children’s Hospital of Philadelphia and a postdoctoral fellow in the lab of E. John Wherry, PhD at the Perelman School of Medicine at the University of Pennsylvania. Her study has recently received new grant support from the Clinical Immunology Society.

Looking at diseases to better understand their relationships to genes and pathways underlying normal biology and physiology is pretty common in science, but Dr. Henrickson is flipping the typical approach upside down.

“Immunology has done an amazing job of focusing on really severe, unusual infections, or patterns of infections, and finding genetic causes,” she said. “But the other way of looking at it is to take really common infections and learn from those as well. You can understand more about how the immune system works if you look at how it can fail to contain something very common. I’m trying to use warts as a test case for that philosophy for looking at immune dysfunction.”

Warts, which are caused by human papilloma virus (HPV) infections in the skin, are so common that most people have probably had one at some point in their lives. Most people’s immune systems fight off the infection naturally or with help from relatively simple remedies that trigger the immune system’s attention.

Dr. Henrickson initially worked with partners at Boston Children’s Hospital (BCH) and Brigham and Women’s Hospital to launch her study while she was a medical student at Harvard. The two hospitals recruited families in which multiple members were prone to recurrent, treatment-resistant viral skin infections, especially HPV. Dr. Henrickson brought the study with her to CHOP and Penn when she transferred during her third year of residency. Kathleen Sullivan, MD, PhD, chief of the division of Allergy and Immunology at CHOP and a professor of Pediatrics at Penn, helped Dr. Henrickson transition the project into a larger collaboration between CHOP, Penn, and BCH, and is the local principal investigator on the project.

By enrolling families with multiple members prone to recurrent infections and their other relatives who did not have these recurrences, Dr. Henrickson hoped to identify specific genes inherited within those families that weakened the skin’s immune response in some individuals. She and her colleagues in Boston sequenced the whole exomes of participants, or the parts of their genome sequence that codes for expressed genes and proteins, and future sequencing will be done at CHOP.

In each of four participating families enrolled in Boston, the team found six candidate genes that could play a role in each of five different pathways involved in skin immunity. These distinct possible chinks in the armor appeared to occur at the point of entry at the skin itself, in the immune cells that pick up viral proteins and other suspicious foreign materials, and in the immune cells that fight viruses once found and identified as a threat. Dr. Henrickson’s next steps are to verify whether the DNA differences in those six genes actually translate to changing each gene’s protein product in a way that affects the body’s ability to fight viruses.

She is clearly in the right place to pursue these next steps because, for each of the six candidate genes she is studying, a lab on the Penn/CHOP campus already specializes in that specific gene.

“I literally could just email people in the Penn/CHOP community, and there are people to talk to about every single gene I want to know about,” she said. “It’s made it really a great environment to follow up.”

Dr. Henrickson credits the project for helping her decide to specialize in immunology. Her other work in Dr. Wherry’s lab focuses on understanding interrelationships of obesity, asthma, and the immune system in children. The skin project’s longevity beyond an intriguing question in medical school, and its progress toward potentially informative results, were both pleasant surprises.

“The reason it’s interesting is that it helps us to both understand skin immunology, as well as understand how those specific viruses interact with our immune system,” she said.