B cells, traditionally seen as largely pathogenic contributors to autoimmune diseases, also play important roles as regulators, processors, and presenters of autoantigens. At least one subset of regulatory B cells is moving toward human trials.
“About a decade ago, investigators working on B cell regulation of autoimmune and inflammatory disease started observing things happening that weren’t fitting the classic paradigm of B cells just making autoantibodies, being proinflammatory, and causing disease,” said Thomas F. Tedder, PhD, Alter E. Geller Professor for Research in Immunology at Duke University. “There were good clues that regulatory B cells are real.”
Dr. Tedder will kick off a Sunday basic science symposium, New Perspectives on B Cells in Autoimmunity, on Sunday from 12:30 – 2:00 pm.
Multiple labs have uncovered regulatory B cells, with the subset that secretes IL-10, dubbed B10 cells by the Tedder lab. B10 cells resemble typical B cells, but they activated a specific functional program in response to specific antigens and receptor signaling with their environment.
“These cells are absolutely antigen-specific,” Dr. Tedder said. “Appropriate signaling through their antigen receptor is the most critical event in their functional programming to become B10 cells. That makes for an exquisitely well-regulated system so that B10 cells don’t induce general immunosuppression, as they are only inhibiting immune responses to the right antigens.”
In mice, B10 cells treat experimental autoimmune encephalomyelitis (EAE), a common model for multiple sclerosis and other human demyelinating diseases. A newly developed B10 culture system that starts with a single mouse spleen can generate enough B10 cells to treat 21,000 mice with EAE in just nine days. In humans, the same system can expand B cells extracted from one mL of whole blood to a potentially therapeutic dose of about four billion B10 cells in the same nine days.
“Everything we have seen says that there are going to be other functional programs and other regulatory B cell subsets,” Dr. Tedder said. “We, the field, are on the way to defining a lot more heterogeneity in B cell function than we currently appreciate.”
Other pathways also play roles in lupus. A biological defect can prevent lysosomes from degrading apoptotic debris that is trafficked into cells. As a result, the apoptotic cargo targeted for degradation is never degraded and eventually is transported back to the cell surface. The mix of nuclear antigens ends up displayed on the surface hematopoietic cells, including B cells.
The defect is relatively straightforward, said Barbara Vilen, PhD, Associate Professor of Microbiology/Immunology at the University of North Carolina in Chapel Hill. Lysosomes fail to mature and reach the pH needed to activate hydrolases to degrade apoptotic debris. The biologic trash that should have been degraded is instead recycled back on the cell surface, including autoantigens seen in lupus.
“This lysosomal defect promotes the accumulation of apoptotic antigens that can activate the adaptive immune responses, and the leaking of nuclear antigens in the cytosol to activate the innate immune system. We find this defect to be upstream of the production of autoantibodies and cytokines that are associated with lupus,” Dr. Vilen said. “In lupus mice and in human lupus patients with active disease, their cells are coated with nuclear antigens from their own apoptotic debris. However, in patients with inactive disease, the levels of nuclear antigens on the cell surface are low.
B cells are also opening new insights into the immunologic pathways that contribute to lupus. One of the persistent questions is whether patients with lupus are ever immunologically quiet, even when disease symptoms are quiet.
“The whole process of B cell activation and transformation into plasma B cells and the generation of antibodies is supposed to be one of the central issues in the pathology of lupus,” said Iñaki Sanz, MD, Mason I. Lowance Professor of Medicine and Pediatrics, Chief of Rheumatology, Director of the Lowance Center for Human Immunology and Georgia Research Alliance Eminent Scholar in Human Immunology at Emory University.
“We have been trying to characterize what happens, what type of B cells may contribute to both the initiation and the ongoing process in lupus, and whether that immunological pathway ever stops. The traditional approach has been to measure the endpoint, which is B cell activation and antibodies, but the whole process leading to that point has never been properly understood. We have identified new pathways of B cell activation that lead to the generation of autoantibodies. Understanding that process should give us information about how to measure immunological activation and disease heterogeneity and will help design newer and more precise treatments and monitoring strategies.”
BASIC SCIENCE TRACK
New Perspectives on B Cells in Autoimmunity
12:30 – 2:00 pm Sunday • Room 140A