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Regulatory B Cells Do Exist -- and Pack a Punch

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Duke Health News 919-660-1306

DURHAM, N.C. – Researchers at Duke University Medical Center
have uncovered definitive evidence that a small but potent
subset of immune system B cells is able to regulate
inflammation.

Using a new set of scientific tools to identify and count
these cells, the team showed that these B cells can block
contact hypersensitivity, the type of skin reactions that many
people have when they brush against poison ivy.

The findings may have large implications for scientists and
physicians who develop vaccines and study immune-linked
diseases, including cancer. Once the cells that regulate
inflammatory responses are identified, scientists may have a
better way to develop treatments for many diseases,
particularly autoimmune diseases such as arthritis, type 1
diabetes and multiple sclerosis.

"While the study of regulatory T cells is a hot area with
obvious clinical applications, everyone has been pretty
skeptical about whether regulatory B cells exist," said Thomas
F. Tedder, Ph.D., chairman of the Immunology Department and
lead author of the study published in the May 16 issue of
Immunity. "I am converted. They do exist."

Koichi Yanaba and Jean-David Bouaziz identified this unique
subset of small white blood cells, which they call B10 cells,
in the Tedder laboratory.

The researchers found that B10 cells produce a potent
cytokine, called IL-10 (interleukin-10), a protein that can
inhibit immune responses. The B10 cells also can affect the
function of T cells, which are immune system cells that
generally boost immune responses by producing cytokines. T
cells also attack tumors and virus-infected cells.

The study was supported by grants from the NIH, the
Association pour la Recherche contre le Cancer (ARC),
Foundation Rene Touraine, and the Philippe Foundation.

Depleting B10 cells may enhance some immune responses,
Tedder said. Enhancing B10 cell function may inhibit
inflammation and immune responses in other diseases, like
contact hypersensitivity.

"Now that we have been able to identify this regulatory B
cell subset, we have already developed treatments that deplete
these cells in mice. We are moving to translate these findings
to benefit people," he said.

"The discovery of the ability to identify this potent
regulatory cell type should provide important clues to how the
immune system regulates itself in response to vaccines as well
as infectious agents," says Barton F. Haynes, M.D., leader of
the international Center for HIV/AIDS Vaccine Immunology
(CHAVI), a consortium of universities and academic medical
centers, and director of the Duke Human Vaccine Institute.
"This information should enable researchers to design ways to
help the immune system control infections more effectively, and
could be a useful advance as we refine approaches to preventing
HIV infection."

There's a huge initiative underway to look at regulatory T
cells in autoimmune disease, HIV infection, and cancer
therapy," Tedder said. "What we have also shown is that it is
not only regulatory T cells, but also regulatory B cells that
could prevent a person from making effective immune responses
in HIV and many other diseases, particularly cancer."

The Duke researchers developed a way to mark the B10 cells
so that they could see that just these cells were producing
IL-10. Previously, scientists could only purify a population of
B cells and see whether IL-10 could be produced by some of
these cells in the population.

In this study, they found that the B10 cells represented
only 1-2 percent of all of the B cells in the spleen of a
normal mouse. Before this, no one had definitively identified
this B cell subset or such regulatory B cells in normal mice,
although B cell regulatory function had been described in some
genetically altered mice with chronic inflammation.

"In this study, we could directly look at the B cells that
were producing IL-10, and figure out what their cell surface
molecules looked like, so that we could isolate them. This
allowed us to show that this rare subset of B cells controlled
immune responses by producing IL-10, which inhibits T cell
inflammatory responses," Tedder said.

The scientists studied a special mouse (CD19-deficient) with
altered genes that give them an increased contact
hypersensitivity reaction. As it turned out, these mice lacked
B10 cells, which resulted in exaggerated inflammation reaction.
"This allowed us to show that giving CD19-deficient mice a few
B10 cells had a big effect on reducing inflammation," Tedder
said.

They found that depleting all B cells in the mice also
resulted in worse inflammation. Since total B cell depletion
therapies are now being used to treat people with B cell
cancers and autoimmune disease, these findings help to further
explain how these therapies treat disease. They also open the
door to creating new therapies that take advantage of the power
of B10 cells.

This is the first of several papers that will describe cases
in which regulatory B10 cells help control immune responses,
Tedder said.

Karen Haas and Jonathan Poe of the Duke Department of
Immunology, and Manabu Fujimoto of the Department of
Dermatology at Kanazawa University Graduate School of Medical
Science in Ishikawa, Japan, were the paper's other authors.

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