Hypoxia (lack of enough oxygen) is bad for the body as a whole, but in the neighborhood where infection-fighting antibodies arise, may be important for keeping proper order.
Reporting Aug. 8 in the journal Nature, researchers at Vanderbilt University Medical Center demonstrate in a study in mice that low oxygen in the “germinal centers” of spleens and lymph nodes regulates the quality of antibodies produced against infectious agents.
Because pro-inflammatory antibodies, like IgG2c, are susceptible to oxygen deprivation, hypoxia in the places where antibodies are made may limit inflammation that can damage vulnerable tissues throughout the body if unchecked, said the paper’s senior author, Mark Boothby, M.D., Ph.D.
The availability of oxygen in microenvironments such as the bone marrow and tumors has long been known to affect the production of red blood cells, for example, and the potential for cancers to spread.
This is the first study to demonstrate that hypoxia in the germinal centers of peripheral lymph nodes regulates the qualities of antibody production, said Boothby, professor of Medicine and Pathology, Microbiology and Immunology in the Vanderbilt University School of Medicine.
Normally, B-type white blood cells enter germinal centers into what is called the “dark zone,” where they proliferate and acquire mutations that can change how they bind their targets.
The B cells then move into another compartment in the germinal center called the “light zone,” where they are presented with various antigens, protein markers from infectious agents including bacteria and viruses. This triggers production of antibodies capable of recognizing and attacking specific markers when released into the circulation.
The researchers determined that hypoxia, which predominantly occurs in the light zones, restricts B cell proliferation in a way that selects for survival of the “most suitable” cells, the ones most likely to produce antibodies with a high affinity to bind and destroy infectious agents.
The study was led by Boothby and first author Sung Hoon Cho, Ph.D., research assistant professor of Pathology, Microbiology and Immunology.
Other contributors included Ariel Raybuck, Kristy Stengel, Ph.D., Mei Wei, Ph.D., and Thomas C. Beck, Ph.D., and Vanderbilt faculty members Volker Haase, M.D., Scott Hiebert, Ph.D., James Thomas, M.D., and Emmanuel Volanakis, M.D.
The interplay between metabolism and immunity is a hot topic. In this case, collaboration among Vanderbilt investigators across diverse disciplines led to a new insight about how the availability of oxygen, a metabolic fuel in normal tissues, “affects a process central to vaccines and our relations with microbes,” Boothby said.
