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Beyond Antibodies

Like lightning, infectious diseases seldom strike twice because the human immune system typically produces cells and antibodies that "remember" a specific virus or bacterium, allowing our bodies to more rapidly fight the invader whenever it reappears. Indeed, many vaccines confer protection by exposing the body to a piece of microbe and prompting the immune system's B cells to produce neutralizing antibodies. But now a new study suggests that although antibodies are essential to prevent reinfection, B cells have other ways of fending off an initial attack by certain viruses. This possibility not only upends prevailing immunological wisdom but also may usher in new treatments for viral diseases.

Immune system's levels of defense. B cells (blue) and T cells (red) fight the vesicular stomatitis virus (green) in a mouse lymph node.
Credit: Ulrich von Andrian, Harvard Medical School, & Mateo Iannacone, San Raffaele Scientific Institute

A team of immunologists led by Matteo Iannacone and Ulrich von Andrian of Harvard Medical School (HMS) in Boston uncovered the B cell surprise by focusing on vesicular stomatitis virus (VSV). The virus, a popular one for lab studies, causes mild illness in cattle, but in mice it swiftly infects the nervous system—making it a good model for brain infections, particularly rabies. "We had been studying VSV for 5 or 6 years, trying to understand how an organism generates an immune response," says Iannacone, who now heads his own lab at the San Raffaele Scientific Institute in Milan, Italy.

When invaded by viruses or bacteria, the immune system usually launches a two-pronged counterattack. In the first wave, certain white blood cells go after the invader directly. Chief among these are macrophages (Greek for "big eaters"), some of which march along blood vessels to gobble up the intruder. A specialized group of macrophages living inside lymph nodes—called subcapsular sinus (SCS) macrophages—act as microscopic flypaper, filtering the lymph and collecting any particles, including viruses. (Up to 99% of infectious viral particles are trapped in lymph nodes in this way.)

Triggering the second phase of defense, SCS macrophages also hand off the virus to antibody-making B cells and so-called T cells, which can directly attack infected cells or support other immune warriors such as the B cells. Studies have shown that mice lacking B cells are particularly vulnerable to viruses such as VSV, so most scientists assumed that antibodies were the key protective element. In 2010, however, Iannacone, von Andrian, and colleagues showed that antibodies were not as crucial to immunity as SCS macrophages: Sixty percent of mice lacking the macrophages died when injected with VSV even though they had as many antibodies as the mice that survived.

Iannacone and von Andrian tackled this puzzle in their latest study by taking advantage of a strain of mice recently developed by Klaus Rajewsky of HMS, which have B cells but can't produce antibodies. These mice survived when injected with VSV, evidence that B cells, not antibodies, are needed for immunity, the team reports online today in Immunity.

So what were the B cells doing to offer viral protection? From previous research, the investigators knew that B cells produce a compound called lymphotoxin, which keeps the numbers of SCS macrophages in balance. To see if this compound played a role in immunity as well, the team treated healthy mice with a lymphotoxin-blocking "decoy" and infected them with VSV. Those rodents succumbed to the virus despite having both B cells and antibodies. Iannacone and von Andrian suggest that disrupting the B cell lymphotoxin signal weakens the ability of SCS macrophages to deal with VSV. Specifically, without lymphotoxin the macrophages can't secrete chemicals called interferons, which block nerves near the lymph nodes from carrying the virus into the central nervous system. "B cells are absolutely critical, but not because they produce antibodies. Instead, their contribution seems to be that they secrete lymphotoxin, which ensures that macrophages can produce interferons, which protect the nervous system," Iannacone explains.

Immunologist Marc Jenkins of the University of Minnesota Medical School in Minneapolis is as surprised as Iannacone and von Andrian were. "The authors have revealed a novel immune mechanism involving B cells and macrophages," he says, adding that the paper is the first to show this effect in response to VSV.

The work adds to a rapidly growing list of talents for B cells that go beyond producing antibodies. Research with parasitic infection shows that B cells can produce cytokines, for example, Jenkins says. The finding may also point to new ways of tackling viral infections of the nervous system, such as rabies, which causes more than 50,000 human deaths per year. "Once infected with the rabies virus, the window of treatment using antibodies is very narrow—a matter of days for humans, and 6 to 8 hours in mice," Iannacone says. "Maybe other things besides antibodies can do the job."