|
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, whose research was supported by the National Institutes of
Health Clinical and Translational Science Award.
To confirm the findings, which appear in the February 1 edition of Blood,
Dustin and Charles enrolled hepatitis C virus-infected patients at The
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.”
http://newswire.rockefeller.edu/?page=engine&id=755
 |
Information 
Subscribe to this comment's feed