Vol. 4 Issue 13 / Apr 19, 2004
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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