The Genetic I.D. of Lupus
By Jason Socrates
Bardi
"Know
Thyself"
—A
saying often attributed to Socrates and inscribed at the
entrance of the ancient temple of Apollo at Delphi
The patient is ten times more likely to be female, often
a young adult in her 20s. She has a slightly higher chance
of being of African, Native American, or Asian descent and
often no one in her immediate family has had a history of
medical problems. She herself may have enjoyed perfect health
until, suddenly, there was any one of a thousand things wrong
with her. Perhaps she was hospitalized with seizures. Perhaps
she has painful swelling in the small joints of her hands.
Perhaps she has red rashes on her hands and face, or anemia...
If her doctor knows enough to refer her to a rheumatologist
who defines her illness as lupus, she is one of the lucky
ones. Lupus is often misdiagnosed.
Even the name "lupus" is a mischaracterization of sorts.
The word lupus, which means "wolf" in Latin, was first used
in the Middle Ages to describe a chronic rash on the skin.
The name may have been chosen because the rash on the skin
resembled the effects of a bite from one of these wild animals.
Or, some believe the name arises from the fact that the rash
was common about the cheeks, giving lupus victims a werewolf-like
appearance.
Whichever the case, the disease is not the bite of a Canis
lupus, but the bite of a person's own immune system.
Lupus is a chronic, inflammatory autoimmune disease caused
by multiple genetic, environmental and other factors, most
of which are unknown. It is a complicated disease that may
appear a thousand different ways in a thousand different people.
The Lupus Foundation of America estimates that approximately
1,400,000 Americans have a form of lupus, a disease that ranges
widely case-by-case, has a long list of symptoms, and affects
a wide variety of tissues—especially the skin, joints,
blood, and kidneys.
Lupus occurs when a person's own B cells produce antibodies
that are directed against "self" tissue. These antibodies—secreted
proteins also called "immunoglobins" that help the body clear
infections—normally target foreign pathogens in the bloodstream
or those displayed on infected cells. But in lupus, the antibodies
target the body's own molecules instead.
For instance, many people who have lupus produce an antibody
that targets red blood cells, which are a vital oxygen-transporting
component of blood. The antibodies coat the red blood cells,
and these are then taken up and destroyed by macrophages.
This can lead to a deficit of red blood cells and anemia.
Two researchers at The Scripps Research Institute (TSRI)
are investigating the causes of lupus and looking for possible
targets for intervention. Immunology Professor Argyrios Theofilopoulos
has studied lupus for over 25 years—since soon after
he came to TSRI as a postdoctoral fellow in the laboratory
of Frank Dixon, then the director of the institute, in 1972.
Now Theofilopoulos works closely with his colleague, Associate
Professor Dwight Kono, who arrived at TSRI in 1989.
Treatment Largely Unchanged Since the 50s
The victims of lupus have yet to reap the benefits of the
genomic revolution. There are tests that will determine if
you have the disease, but there are no genetic screens to
tell you if you have an increased susceptibility. In fact,
the genes that contribute to lupus are not even known.
"It's clear genes play a big part and it's complex," says
Kono. "We don't know what they are yet. We're still mapping
the genome to find out where they are located."
Not all genes contribute to the disease equally. Many act
in concert with one another and it is the sum effect that
causes the disease. "In these diseases you have not only multiple
genes but environmental and other stochastic influences,"
says Theofilopoulos. "Knowing one of them may not be sufficient
to change the disease process. Yet some genes may have a greater
effect than others, and if we can identify them, we may be
able to intervene."
Instead of viewing diseases like lupus as one disease, one
might be able to identify a sub-group of patients with a particular
genetic defect that contributes to their particular form of
the disease.
"Then we would be much better off designing treatments,"
says Theofilopoulos. Such an accomplishment would be a major
advance, he adds, because no new treatments for lupus have
been found since the 1950s, and these treatments have a high
incidence of side effects.
The hope is that instead of giving non-specific drugs as
is the case now, one could design specific drugs to treat
a specific form of lupus. Additionally, if scientists know
the genes that lead to the formation of the disease, they
may be able to predict who is susceptible.
Lupus was rigorously described and defined as a medical
condition in the early 1800s, but it was not until the latter
half of that century that real progress was made in defining
the full clinical spectrum of this disease. The first positive
step was when doctors recognized that the disease could be
systemic and could cause damage to the kidneys and other internal
organs distinct from and sometimes in the absence of its defining
rashes.
More importantly, at the turn of the 20th century, doctors
discovered the effectiveness of anti-inflammatory and anti-malaria
drugs as a treatment for lupus. But the real breakthrough
came decades later, in the early 1950s, when doctors began
using corticosteroids to treat lupus with even greater success.
Although a few other treatments have been developed in the
last 50 years, corticosteroids, anti-inflammatories, and anti-malarials
are still the main therapies for the disease today.
Models of the Disease
One of the key tools that has allowed so much research to
be carried out at TSRI and elsewhere has been the identification
and availability of murine models for lupus.
Dixon and Theofilopoulos characterized several murine models
in the 1970s that developed symptoms resembling lupus. They
spent the next several years analyzing these models, trying
to understand the basic pathogenesis of lupus and writing
some of the first detailed descriptions of the serological,
cellular, and histological characteristics of the disease.
Theofilopoulos was interested both in the basic immunological
assessment of the disease—its relationship to T cells,
B cells, organs like the thymus, antibodies—and in finding
specific molecules important for its pathogenesis.
"Then," says Theofilopoulos, "when molecular cloning began,
we started defining the structural characteristics of the
autoantibodies implicated in lupus."
He discovered that the genes that encode these pathogenic
antibodies were not very different from those encoding regular
immunoglobins against foreign antigens. His goal became identifying
all the other genetic components of the disease, something
Theofilopoulos and Kono have been working on for the last
several years.
Specifically, they became interested in identifying the
"effector" genes that predispose a person to getting lupus
or that lead normal genes to be involved in the disease process.
To be important for therapy, these genes could be a root cause
of lupus or simply a contributing factor. Some genes are not
necessarily malfunctioning in lupus patients, but may nevertheless
contribute to the pathogenesis of the disease.
"If you block these effector genes, you will still have
a good therapeutic effect," says Kono.
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