In the early 1990s, Harley and James were studying the particular autoantigen that the immune system first targeted in lupus. The antibodies were mistaking this protein for a foreign invader, and the pair wanted to know why.

Over time, Harley and James determined that the antibodies always initiated their attacks by binding to a very specific site on the autoantigen. This site consisted of a sequence of eight specific amino acids from the autoantigen. By searching a database of amino acid sequences, they realized that this eight-acid sequence bore a striking resemblance to another protein sequence that scientists had previously identified: the Epstein-Barr virus.

Known as “the kissing virus,” Epstein-Barr is transmitted through saliva and infects over 90 percent of the population by adulthood. In most, it causes only cold or flu-like symptoms. In more severe cases, it gives rise to mononucleosis. Once infected, we carry the virus with us for life.

Based on the nearly identical structure of the two protein sequences, James suggested that she and Harley investigate a possible link between the virus and lupus. But Harley knew that researchers had already tried to blame the virus for a host of diseases, including lupus, and that none of the theories had panned out. “I told Judith, ‘If we go after Epstein-Barr, we’ll probably lose all of our funding because nobody will believe us,’” recalls Harley. Still, he was intrigued.

He and James decided that the best way to explore the link between Epstein-Barr and lupus was to immunize lab animals with key portions of the virus and see how their immune systems responded. And though the sample size was small—they immunized only two animals—one developed a syndrome that looked a lot like lupus. Harley and James published their findings in the Annals of the New York Academy of Sciences. Although the paper generated significant skepticism, the scientists now had experimental data to support a working theory: Exposure to the Epstein-Barr virus can trigger lupus in some individuals.

Armed with these results, Harley wrote a grant proposal to the National Institutes of Health seeking funding to explore further the connection between Epstein-Barr and lupus. The application was not well-received.

“We were body-slammed,” remembers Harley. “The scientists who reviewed our proposal wrote inflammatory reviews about how wrong this had to be, how it had been explored before and discarded as a hypothesis.” But he would not be deterred.

The next step was to establish a similar chain of causation in humans. Harley and James concluded that the best way was to study children and teens, the only slice of the population where the “kissing virus” has yet to infect almost everyone.

When the researchers took blood samples from healthy children and teens, they found that roughly 70 percent of them were infected with Epstein-Barr. But when they examined lupus patients from the same age group, they saw that virtually every one of them tested positive for Epstein-Barr exposure. These results, published in The Journal of Clinical Investigation in 1997, provided strong evidence the virus plays a key role in the development of lupus.

As satisfying—and vindicating—as these results were, they created almost as many questions as they answered. For instance, does Epstein-Barr actually cause lupus? If so, why does this virus only cause the disease in a minuscule portion of the population? And if the virus does trigger the disease, how can we stop it?

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