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A New Hypothesis About Autoimmunity. Is It Possible To Be Too Clean?

Date:
April 16, 2004
Source:
Scripps Research Institute
Summary:
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.

Administration of adjuvant prevents diabetes but does not inhibit islet infiltration. A representative section of a pancreas immunostained for insulin from a 20 week old NOD mouse that was immunized with complete freunds adjuvant at 3 weeks of age. The section shows the islet surrounded by a sea of infiltrating mononuclear cells.
Credit: Image courtesy Scripps Research Institute

La Jolla, CA. April 12, 2004 - 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, Ph.D. "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, Ph.D. 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 ԤeffectorԬ 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. After April 16, the article will be available online at http://www.cell.com/.

The research was funded by the National Institutes of Health and the Juvenile Diabetes Foundation International.

About The Scripps Research Institute

The Scripps Research Institute in La Jolla, California, is one of the world's largest, private, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases and synthetic vaccine development.


Story Source:

The above story is based on materials provided by Scripps Research Institute. Note: Materials may be edited for content and length.


Cite This Page:

Scripps Research Institute. "A New Hypothesis About Autoimmunity. Is It Possible To Be Too Clean?." ScienceDaily. ScienceDaily, 16 April 2004. <www.sciencedaily.com/releases/2004/04/040416014249.htm>.
Scripps Research Institute. (2004, April 16). A New Hypothesis About Autoimmunity. Is It Possible To Be Too Clean?. ScienceDaily. Retrieved April 18, 2014 from www.sciencedaily.com/releases/2004/04/040416014249.htm
Scripps Research Institute. "A New Hypothesis About Autoimmunity. Is It Possible To Be Too Clean?." ScienceDaily. www.sciencedaily.com/releases/2004/04/040416014249.htm (accessed April 18, 2014).

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