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Gene-Altered Mouse Is Model for Rare Autoimmune Syndrome

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Duke Health News 919-660-1306

DURHAM, N.C. -- By knocking out a single gene in mice,
immunologists at Duke University Medical Center have mimicked a
little-understood autoimmune disorder in humans. In the
puzzling disorder, called Sjögren's syndrome, the person's tear
and salivary glands are affected, causing dry eyes and mouth,
as they are damaged by an attack of the person's own immune
cells.

According to researchers, the achievement not only offers
insight into Sjögren's syndrome, but into the general
developmental machinery of the immune system.

The immunologists, Yuan Zhuang, HongMei Li and MeiFang Dai,
published their findings in the October 2004 issue of the
journal Immunity. The work was sponsored by the National
Institutes of Health and the Leukemia and Lymphoma Society.

In a preview of the article, immunologist Marjan Versnel
wrote that the new mouse model "offers a wonderful opportunity
to study in detail the relationship between the immune system
and autoimmunity occurring in the context of only a single
genetic lesion." Versnel is at Erasmus Medical Center in the
Netherlands.

According to Zhuang, while Sjögren's syndrome is not well
known, affecting up to 0.6 percent of the population. It
manifests itself in middle age, mostly in women.

"Most patients do not see a physician unless it becomes very
serious or other problems arise, such as fatigue, arthritis, or
inflammation of the lungs, kidneys or blood vessels," he said.
Treatment for the disorder involves lubricant drops for the
eyes and drugs that increase production of saliva.

"Basically nothing was known about the genetic basis of the
disease," said Zhuang. "It was only known that the patients
showed infiltration of lymphocytes into lachrymal and salivary
glands and the production of certain autoantibodies."
Lymphocytes are white blood cells -- T cells and B cells --
that are major components of the immune system. T cells are
those that directly attack invaders such as bacteria and
viruses, while B cells are the armament factories of the immune
system, producing antibodies that recognize and attack such
invaders.

While other genetically altered mouse models had been
produced that showed similar symptoms, those animals showed
other pathologies that do not mimic Sjögren's syndrome, said
Zhuang. Also, they did not arise from a single genetic
mutation, so it is difficult to determine the initial cause of
the disease in these complex animal models, he said.

Zhuang and his colleagues did not set out to produce a mimic
of Sjögren's syndrome in their studies. Rather they were
exploring the role of a regulatory protein, called Id3, that
previous studies in Zhuang's laboratory had revealed to be key
to the development of lymphocytes.

"In our basic studies, we suspected that if we developed
animal models lacking the gene we would not only better
understand its role in immune development, but see disease
characteristics as well," said Zhuang. "We had no prior
knowledge that we would produce such a precise model of
Sjögren's syndrome."

Indeed, he said, the mice lacking the gene had all the
characteristics of the disease, including reduced tear and
saliva secretion and infiltration of lymphocytes into their
tear and salivary glands. The animals also showed production of
the antibodies that indicated the immune system was activated
to attack the animals' own tissues.

Also, the researchers found that they could induce symptoms
of the syndrome in normal mice by transferring bone marrow
cells from the genetically altered mice. Bone marrow is the
source of immune cells that could cause the disorder. The
researchers' experiments with the Id3-deficient mice also
revealed that T cells play a dominant and essential role in
generating the pathology of the disorder.

According to Zhuang, development of the model will now
enable the researchers to explore the complexities of the
disease and the immune system in general.

"This model really tells us that the biology of Id3 and the
immune system is more complex than was suspected," he said.
"For example, we need to understand why autoimmunity so
specifically affects the lachrymal and salivary glands when the
Id3 gene is very broadly expressed in many cell types."

Thus, the researchers are exploring the mechanism by which
the Id3 mutation compromises early development of T cells and
produces an autoimmune response.

Importantly, said Zhuang, genetic analysis can be further
applied to this animal model. For example, the defect in Id3
may cause different effects in different strains of mice with
other genetic deficiencies -- offering even further opportunity
for understanding the intricacies of immune system
development.

Zhuang and his colleagues are also collaborating with
medical center rheumatologists Drs. William St. Clair and Rob
Geletka to determine whether Id3 deficiency plays a role in the
disease in humans. They have begun to screen blood samples from
patients with the disorder.

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