A New Hypothesis About Autoimmunity—Is it Possible
to be Too Clean?
By Jason Socrates Bardi
A group of scientists at The Scripps Research Institute
have found a connection between poor T cell survival in the
body and the development of autoimmunity.
On the basis of this connection, the scientists are proposing
a new hypothesis about the cause of autoimmunity, in which
components of a person's immune system attack his/her own
tissues leading to diseases such as Type 1 diabetes and rheumatoid
arthritis.
"Autoimmunity has [traditionally] been considered a condition
of too much stimulation," says Scripps Research Immunology
Professor Nora Sarvetnick. "What we are seeing is that it
is a condition of too little stimulation."
In an article appearing in this week's issue of the journal
Cell, Nora Sarvetnick and her coauthors in the Department
of Immunology assert that we need a certain level of immune
stimulation to fill the body with immune cells. An understimulated
immune system results in too few T cells, and the body tries
to correct this by inducing a vigorous expansion of the remaining
T cells, creating a more autoreactive population.
The hypothesis explains why childhood bacterial infections
decrease the risk for developing autoimmune diseases and explains
why autoimmunity has been rising in the last half century
in populations with decreased exposure to pathogens.
It also provides a new way for thinking about how to make
autoimmune diseases more preventable. The key to decreasing
the chances of developing autoimmunity may be to stimulate
the immune system by priming people with germs.
Autoimmunity and Lymphopenia
Autoimmune diseases are to biology as friendly fire is to
war.
Normally, the body's immune system is designed to recognize
invading viruses or bacteria and destroy them. But in autoimmune
diseases, the body's response is not limited to pathogens.
Instead, the body manufactures cells and molecules that attack
its own tissues and organs. This assault can have severe consequences
for health and can be lethal.
Take Type 1 (insulin-dependent) diabetes mellitus, for instance.
Type 1 diabetes manifests when T cells become autoreactive
and attack and kill beta cells in the pancreas, the body's
source of insulin. Without insulin, the glucose in the bloodstream
increases and is maintained at levels much greater than normal.
Over time, this can lead to nerve and kidney damage, reduced
eyesight, and an increased risk of developing heart disease
and vascular degeneration. Before the discovery and isolation
of insulin in the 1920s, having this type of chronic metabolic
disease meant certain death. Today, insulin is a reasonable
treatment, but Type 1 diabetes is still a chronic infection
for which there is no prevention and no cure.
According to the new hypothesis that Nora Sarvetnick and
her colleague Cecile King are proposing, the root cause of
autoimmunity is a failure to make an adequate response to
an infection—in other words, an immune system that is
not working hard enough (one that is hyporesponsive). This
hyporesponsiveness creates a condition known as lymphopenia,
where there is a reduction in the number of T cells in the
body. Often people with autoimmune diseases like Type 1 diabetes,
lupus, and rheumatoid arthritis have low T cell numbers.
If the body detects low levels of T cells, it resorts to
homeostatic expansion, a mechanism that has never been associated
with autoimmunity before. Under homeostatic expansion, growth
signals stimulate the existing T cells in the body to divide
and multiply.
This homeostatic process should normally fill the body,
but sometimes that does not happen due to disrupted growth
signals or a viral infection that causes the number of T cells
to go down even as the body is trying to increase their numbers.
These are the conditions that lead to autoimmunity, says Sarvetnick.
Insidious Division
In their current study, Sarvetnick, King, and their colleagues
look at the immune systems of a type of mouse called NOD,
which is genetically prone to developing diabetes. The NOD
mouse has a genetic defect that causes it to produce excessive
amounts of a molecule called interleukin-21, which signals
the growth of T cells without signaling for their survival.
Normally, T cells undergoing homeostatic expansion receive
both signals to grow and signals to stay alive. Since the
NOD mice cannot provide adequate amounts of these latter signals,
their T cells proliferate furiously but do not survive long
term. The NOD mouse's cells turn over too rapidly, leaving
them with lymphopenia—a dearth of T cells.
The body tries to fill the void, and this filling leads
to what Sarvetnick terms insidious division.
The high turnover of T cells presents a selective pressure
that favors the growth of T cells that best recognize the
tissue nearest to where the division is taking place—in
other words, the T cells with the best chance of survival
tend to be the ones that are skewed to recognize self tissue.
Thus, these survivors have a tendency towards autoreactivity,
which can lead to autoimmunity later on when these cells become
activated "effector" cells.
An analogous process is believed to occur when a viral infection
causes lymphopenia. Sarvetnick and other scientists believe
that Type 1 diabetes is often initiated by a common virus
that infects cells in the pancreas. During the viral infection,
the body makes an adaptive immune response, and killer T cells
selectively target and eliminate other cells in the body that
are infected with the virus. However, the T cells themselves
are often lost. Diabetes develops when there is a rapid turnover
of T cells, and the resulting T cell population targets insulin-producing
beta cells.
The Benefits of a Bacterial Swill
In their paper, Sarvetnick and her colleagues showed that
NOD mice can be protected against diabetes by challenging
them with a swill of bacterial cell wall components called
CFA, which increased the T cell count and curtailed the development
of diabetes in the mice.
To show that this effect was due to the increase in T cell
count following the CFA administration and not some other
cause, they passively stimulated the immune systems of NOD
mice by infusing them with T cells. These infusions also prevented
the NOD mice from developing diabetes.
According to Sarvetnick's and King's hypothesis, the protection
against diabetes results from exposure to these pathogens
because it keeps the body full of immune cells. Increased
numbers of T cells act as a buffer against the emergence of
self-reactive T cells by shutting down homeostatic expansion.
This hypothesis could explain a discrepancy in the number
of cases of autoimmune disease in developed and developing
countries. Disease rates have been on the rise in developed
countries in the last 50 years compared to their developing
neighbors, presumably because people in less developed countries
are exposed to more pathogens.
"The cleaner everyone is, the less stimulation their immune
system gets," says Sarvetnick. "Their immune system tends
to be incomplete."
The article, "Immune insufficiency generates autoimmunity"
is authored by Cecile King, Alex Ilic, Kersten Koelsch, and
Nora Sarvetnick and appears in the April 16, 2004 issue of
the journal Cell. The article is available online at
http://www.cell.com/.
The research was funded by the National Institutes of Health
and the Juvenile Diabetes Foundation International.
Send comments to: jasonb@scripps.edu
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