Innate B Cell in Humans that Protects Against Infections

MANHASSET, NY — It has long been thought that the human body contains innate immune defense B cells that are present from birth, even before immunization or exposure to infectious organisms. But the question has always been where might these cells be?

Immunologist Thomas L. Rothstein, MD, PhD, and his colleagues from The Feinstein Institute for Medical Research have staked their reputations on finding these so-called “B1 cells” that make “natural” protective antibodies and come online before the adaptive immune system is mature enough to start working. And that is precisely what they have done.

After many years of research, Dr. Rothstein’s team of investigators from the Feinstein Institute has found this unique population of B1 cells, which were hiding in plain sight. It seems that they reside among the same population of B cells that are built one by one when the body comes in contact with millions of infectious bugs over a lifetime – so-called adaptive or memory B cells. The key was finding the particular markers that differentiate B1 cells from every other B cell type. The results of the study were published in the Journal of Experimental Medicine this week.

“The identification of human B1 cells provides a foundation for future studies on the nature and role of these cells in human disease,” the scientists wrote in the study. The lead author, Daniel Griffin, MD, gave up his private physician practice to work toward a doctoral degree in molecular medicine. At any one time, the Feinstein Institute trains about 10 physician-scientists enrolled in the Elmezzi Graduate School of Molecular Medicine. When Dr. Griffin arrived two years ago, Dr. Rothstein laid out several research options. Dr. Rothstein, head of the Feinstein’s Center for Oncology and Cell Biology, told Dr. Griffin about the hunt for human B1 cells, but knew that it would be a big gamble to undertake an uncertain thesis project that may never pan out.

Dr. Griffin didn’t see it that way. He eagerly accepted the challenge and designed a project that he hoped would bear the fruit of the human B1 cell. Several things were in his favor. The Feinstein Institute, through its Tissue Donation Program, provides human blood samples to investigators for research, including umbilical cord blood. Secondly, the Feinstein Institute helped Dr. Rothstein’s lab purchased an expensive piece of equipment that sorts cells. If the B1 cells were present and different enough from memory B cells, the cell sorter would separate the two populations. Then, Dr. Griffin and his colleagues could do the lab work to figure out the nature of the cell populations and whether there really is a human B1 cell.

There was enough evidence from animal studies to suggest that human B1 cells exist. Dr. Rothstein and his colleagues had spent two decades studying mouse B1 cells, so there was a lot of historical information already in place. The big question that generated heated debate was whether innate B1 cells in the mouse exist in humans. In the mouse, CD5 is a good marker for B1 cells. The marker readily distinguishes between mouse B1 and B2 cells. But CD5 is not a good marker for human B1 cells because it is present on many different human B cell types. With the continued inability to identify human B1 cells, scientists began to doubt whether B1 cells exist in humans.

It was against this background that Dr. Griffin, Nichol Holodick, PhD, and Dr. Rothstein undertook a counterintuitive quest to identify human B1 cells. They knew what B1 cells do in mice, so they decided to define a set of functions based on previous work in the mouse system and then ask what B cells in humans carry out these very same functions. In mice, B1 cells secrete antibodies stimulate T cells and are continually signaling. Dr. Griffin began collecting blood samples and running them through the cell sorter. He used fluorescent antibodies to help identify different populations of B cells. In time, he found something rather surprising — a certain percentage of B cells were expressing a marker, CD27, normally seen in so-called memory or adaptive B cells. It turned out that the mysterious population of innate B1 cells was hiding out among the B cell population that is generated in response to vaccination and exposure to infectious agents. But the B1 cells also contained a special marker, CD43, that distinguished them from memory B cells and, in fact, from all other B cells. So by these two distinct markers, CD27 and CD43, human B1 cells can be recognized and studied, and they turned out to have functional characteristics similar to mouse B1 cells.

“Scientists have known that there were protective naturally occurring antibodies in humans but we didn’t know where they were coming from,” said Dr. Rothstein.

Aside from their role in providing an antibody shield against infectious organisms, the antibodies produced by B1 cells help dispose of unwanted cellular debris which, if not removed, can be toxic. In this way, it is speculated that B1 cells may help to counteract heart disease, cancer and neurodegenerative conditions. The Rothstein group has already shown that the number of B1 cells declines with advancing age, which raises the possibility that the loss of B1 cells may contribute to these diseases of the elderly. Most importantly, they will now work to develop treatments to enhance B1 cell numbers, or to provide therapeutic antibodies derived from B1 cells, in order to bolster the normal function of these newly found human B1 cells.

About The Feinstein Institute for Medical Research

Headquartered in Manhasset, NY, The Feinstein Institute for Medical Research is home to international scientific leaders in cancer, leukemia, lymphoma, Parkinson’s disease, Alzheimer’s disease, psychiatric disorders, substance abuse, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, neuroimmunology, and medicinal chemistry. Feinstein researchers are developing new drugs and drug targets, and producing results where science meets the patient, annually enrolling some 10,000 subjects into clinical research programs.