Nichol Holodick, PhD, has always enjoyed asking questions.
It wasn’t until she first stepped into a research lab as an undergraduate student at Northeastern University, however, that everything began to click.
“I was taking a microbiology class, and I was asking my professor questions when he said, ‘You know, you don't have to know the answer.’ I thought, ‘What? No, I want to know the answer,’” Dr. Holodick said. “I didn't know it at the time, but that's what research is. It’s asking questions, anything your mind can think of. You must have somewhat of an imagination -- at least I think so -- to ask all these questions, and you're searching through literature. You never know what you're going to find and what you're going to read. It's a puzzle and you're reading other people's contribution to the puzzle, and you can get new ideas from that.”
That curiosity has led to more than two decades of studying B cells and their immune response in the body for Dr. Holodick, now an associate professor in the Department of Investigative Medicine and researcher in the Center for Immunobiology at ͷ University Homer Stryker M.D. School of Medicine (WMed).
B-1 cells are a specific subset of white blood cells that make proteins called antibodies, which are able to bind to and facilitate the clearance of bacteria. Dr. Holodick’s research focuses on the loss of protective antibodies against pneumococcal bacteria with advancing age and the role of sex in determining differences in protection from infection between males and females.
“B-1 cells make natural antibodies, which are antibodies made before your body has seen any invading outside antigen or foreign thing, and this antibody can recognize the bacteria or virus that you're being attacked by,” Dr. Holodick said. “That recognition allows other immune cells to clear the infection immediately. That natural antibody basically gives you an initial defense to allow the other arm of the immune system to kick in and make a specific defense against invading bacteria. My lab’s interest is understanding how natural antibody and the B-1 cells that make natural antibody change with age or in the context of disease, such as sickle cell disease.”
Dr. Holodick obtained her PhD in Immunology from Boston University in 2009, working on signaling and development of B-1 cells. She expanded her work on B-1 cells during a postdoctoral fellowship at the Feinstein Institute for Medical Research in Manhasset, New York, focusing her research on the role of B-1 cells in infection during aging.
Dr. Holodick’s lab at WMed is supported by research associate Naomi Tsuji, postdoctoral fellow Sarah Webster, PhD, research assistant Daken Heck, M4 Morgan Helmich, and M4 Jordan Terry. Since joining the medical school in 2016, Dr. Holodick has been successful in obtaining grant funding for a variety of projects examining the influence that biological sex has on health and disease.
Studies have shown that infection of Streptococcus pneumoniae, a type of bacteria that causes pneumonia, claims the lives of adults over the age of 65 eight times more frequently than those aged 5 to 49, Dr. Holodick said. In both mice and humans, there is a greater incidence and susceptibility to pneumococcal infection in males. B-1 cells provide protection from the bacteria through the production of natural antibody, but her studies have shown the natural antibody in aged male mice does not protect against Streptococcus pneumoniae infection.
Dr. Holodick has shown B-1 cells and the natural antibody protection they afford deteriorates with advancing age in males but remains highly effective in females. Dr. Holodick is currently examining how hormones regulate B cells and the antibodies they make over time.
A research project led by Dr. Holodick and fellow researchers in the Center for Immunobiology -- Tom Rothstein, MD, PhD, and Momoko Yoshimoto, MD, PhD -- titled “The Role of Biological Sex in the Self-renewal of B1 Cells into Old Age in Mice and Humans,” is being supported by a five-year, $3.8 million R01 grant from the National Institutes of Health (NIH).
Dr. Yoshimoto, a professor in the Department of Investigative Medicine, has shown that most B-1 cells originate from fetal progenitor cells, even in old mice. Dr. Rothstein, who serves as director of the Center for Immunobiology and is professor and chair of the Department of Investigative Medicine, has shown that in humans, as in mice, B-1 cells decline with advancing age.
This research has raised an intriguing hypothesis that females can better maintain fetal-derived B-1 cells and thus produce more protective natural antibodies into old age. As such, the combination of immunological and hematological approaches by Drs. Holodick, Rothstein, and Yoshimoto synergize and create an attractive new research direction. This latest NIH-funded research project will offer the opportunity to explore possible reasons for this sex-associated disparity.
“I think we've only scratched the surface of what we know about B-1 cells,” Dr. Holodick said. “This subset of B cells provides immediate and essential protection from infection. Understanding how these cells change with age, disease, or even between different biological sexes is crucial. By knowing how these B cells function and change in these contexts, we can hopefully enhance immunity against a range of threats, including bacterial, viral, and fungal infections, as well as autoimmune diseases, where our immune system mistakenly attacks our own body.
“B-1 cells play many different roles in fighting infection, and the more we learn about their function in normal, diseased, and aging conditions, the better we can address issues when they arise,” Dr. Holodick added. “If we can understand what's gone wrong, then we can work to provide solutions.”