New theory suggests how hepatitis C may cause rare immune disease

Of the hepatitis alphabet, the C variant may be the nastiest. In 1990, researchers observed that most patients with hepatitis C also develop a rare autoimmune disease called mixed cryoglobulinemia, a condition that frequently leads to cancer, arthritis or both.

Now, researchers at Rockefeller University say that a decade-old explanation of how one disease causes the other is likely wrong, and instead offer a new - albeit controversial - theory of their own: that the pathogen causing the disease zeros in on a specific cellular target that has yet to be identified.

In persons infected with hepatitis C virus, the immune system initially ramps up the production of infection-fighting B cells, which make molecules called antibodies. As these B cells multiply, they make antibodies and release them into the blood where, under normal circumstances, they latch onto the invading pathogens and mark them for destruction. In mixed cryoglobulinemia, there is a problem: the B cells don't stop multiplying, sending the body into a tailspin of pathological conditions that follow a slow, smoldering course.

The uncanny association between hepatitis C and mixed cyroglobulinemia, ever since it was observed, perplexed researchers. Since hepatitis C infects the liver, not B cells, how does it trigger an immune disease? A popular theory proposed that a protein that peppers the outer coat of the virus binds to a receptor called CD81, which is found on the surface of almost every cell in the body, including B cells. If the viral protein directly latches onto the surface of a B cell, it can trigger uncontrolled B cell proliferation.

But scientists led by Lynn Dustin, an associate professor in Charles Rice's Laboratory of Virology and Infectious Disease, reveal that, test after test, the theory came up short. "If the theory were true, then you would expect all different kinds of B cells to be activated and proliferating abnormally - which is what you see in mixed cryoglobulinemia - because CD81 is everywhere," says Dustin. "Instead, every time we analyzed the blood of patients with hepatitis C and mixed cryoglobulinemia, we found that the same B cells were being activated."

In the immune system, billions of B cells are on guard. Each B cell can produce only one kind of antibody, which ordinarily can recognize and fight off only one specific pathogen. Since many of the B cells that Dustin and Edgar Charles, who is a Rockefeller University clinical scholar, isolated from these patients had remarkably similar antibodies as well as many other markers that were similar, the findings suggest that the virus doesn't activate B cells through the ubiquitous CD81 receptor. Otherwise, B cells with different antibody molecules and markers would be activated. "Already, there's a bias in terms of what antigen these B cells are seeing, which kind of rules out this idea that the virus is activating these B cells nonspecifically," says Dustin.

To confirm the findings, which appear in the February 1 edition of Blood, Dustin and Charles enrolled hepatitis C virus-infected patients at Rockefeller University Hospital and looked at their antibody genes, which were identical in the activated B cells from almost every mixed cryoglobulinemia patient. Dustin says this finding is all the more remarkable given that antibody genes must be chopped up and rearranged in order to diversify their repertoire of antibodies and accommodate the ever-growing number of microbes trying to break into the body. "The genes were all rearranged the same way, and the odds of that happening are on the order of one in a billion," says Dustin.

To date, technical obstacles and the nature of the disease prevent scientists from identifying the exact pathogen that triggers mixed cryoglobulinemia, but Dustin and Charles discovered another clue that could help them find the answer: That these antibodies are very similar to rheumatoid factors, which may provide insight into how they cause debilitating autoimmune disease.

In a way, says Charles, the findings signal good news for patients living with hepatitis C and mixed cryoglobulinemia - an estimated 100-170 million worldwide. "It suggests that the survival of these B cells depends on their seeing the pathogen. So finding this elusive pathogen may be the key to preventing these once beneficial B cells from becoming cancerous."

Blood 111(3): 1344-1356 (February 1, 2008)