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A Delicate Balance: What Changes in the Immune System Trigger Type 1 Diabetes?

BOSTON — November, 2000 — Like a carefully balanced house of cards, one or more changes in the body’s immune system can trigger a cascade of events that lead to type 1 (juvenile onset or insulin-dependent) diabetes. It’s only after the cards have collapsed and the immune system has gone awry that one can observe the destruction done: The body can no longer control blood sugar (glucose) levels and daily insulin injections are required for the individual to live.

What triggers the immune system to attack its own insulin-producing beta cells in the pancreas, throwing off track the body’s system for controlling blood sugar levels and obtaining energy from food? Why does type 1 diabetes often develop in young children, while in others it may take decades to develop?

These are some of the questions being explored by Christophe O. Benoist, M.D., Ph.D., and Diane J. Mathis, Ph.D., who head the Section on Immunology and Immunogenetics at Joslin in Boston. Drs. Benoist and Mathis recently moved their world renowned research laboratories from the Institute of Genetics and Molecular and Cell Biology in Strasbourg, France, to Joslin. They also are professors of medicine at Harvard Medical School.

Since 1984 the husband-wife research team and their colleagues have been studying the intricate cellular and genetic mechanisms that cause the immune system to turn against itself, resulting in type 1 diabetes and other autoimmune diseases.

"The immune system has an element of chance. Immune receptors are randomly generated so each person’s immune system develops differently," says Dr. Benoist.

"So in fact, we now know that even identical twins do not, over time, have ‘identical’ immune systems. Studies have found that it’s like shooting dice whether identical twins will develop type 1 diabetes," Dr. Mathis adds.

An estimated 800,000 Americans have type 1 diabetes. Each year, 13,000 new cases of type 1 diabetes are diagnosed in children and teenagers, making it one of the most common chronic diseases in American children. Yet, it frequently occurs in people in their 30s and beyond. About 85 percent of newly diagnosed cases of type 1 have no family history of the disease, making it difficult on the surface to predict who will develop it.

"Once type 1 diabetes has been diagnosed, 95 percent of the insulin-producing islet cells already have been destroyed. We want to understand the mechanisms so we can intervene early and prevent the islet cells from dying. The ultimate goal is to diagnose children before signs of the disease are even evident, and to then treat and alter the autoimmune cascade," Dr. Benoist says.

A look at the body’s immune system

 The body’s immune system is an extremely complex network of different types of cells working together to fight disease. When something like bacteria or a cold virus infects the body, it invades healthy cells and takes over. In response to this invasion, the body recognizes these invaders as foreign and marshals a large arsenal of forces to kill the invading organism and the cells it has invaded. Scientists still have a lot to learn about exactly how the immune system works, but some of the key types of cells and their functions have been identified.

There are several different types of cells involved in the immune system response. T cells (or T lymphocytes), seem to be largely in charge of the immune system, telling other types of cells to mount an attack.

How does the process cause diabetes? Basically, the immune system makes the mistake of thinking an insulin-producing cell is a foreign invader and T-cells activate an attack against them, killing off the healthy islet cells instead of just killing invading organisms.

Targeting T-Cells

Drs. Benoist and Mathis have focused their efforts over the last two decades on the actions of T lymphocytes, and the genes that control how aggressive these cells are in the body. Certain T-cells recognize molecules (auto-antigens) that target cells in the pancreas, and therefore bring about the destruction of the insulin-producing beta cells. Why do T-cells target pancreatic cells at all? "This is a million dollar question. We have ideas and clues, but no real answers," Dr. Benoist says. Drs. Mathis and Benoist have found that a critical part of T-cells’ involvement in the destructive process are certain receptors on the cell surface known as T-cell receptors, which interact with molecules on the target cells (known as MHC class I or class II molecules). It is the interplay between the T-cell receptors and the MHC targets that determines the onset the immune system’s attack. "Why people with diabetes cannot control these aggressive receptors and cells is the key question," Dr. Benoist adds.

Researchers in the Mathis/Benoist lab also have shown that a number of "dampening" genes help control the actions of the T-cells. Some have been clearly identified. The existence of others has been proven by genetic analysis, but their exact identity has yet to be formally pinpointed.

The Benoist/Mathis lab uses transgenic methods to modify the genetic composition of NOD mice, (which frequently develop a form of diabetes similar to that in humans) to create a series of mouse models having varying severity of diabetes depending on their genetic makeup. Some of the mice, for example, have resistance-inducing MHC class II molecules and, therefore, have less severe diabetes. In others the mice are protected from diabetes when a crucial subpopulation of T-cells, important to triggering the start of the disease, are eliminated. In some mice, the diabetes is more aggressive, including those in which the effect of dampening molecules is reduced. The researchers have also produced mice in which all T-cells make a receptor directed against the beta cells, making it much easier to study the cells’ behavior. "We try to simplify the model of disease used in the laboratory to understand it more fully," Dr. Benoist says. Some of these transgenic mouse models of diabetes are now used by many labs in the world.

It is through their studies in these specially bred nonobese diabetic (NOD) mice that Drs. Benoist and Mathis identified the T-cells receptor action as a main culprit. "While many other cells are involved, it appears that the T-cells call the shots on ordering the beta cell destruction and regulating how fast the diabetes progresses," Dr. Mathis says.

"Once the molecular basis of T-cell activation is fully understood, it may be possible to develop specific treatments to regulate the activation of the autoimmune process," says Dr. Benoist. "It may be impossible to prevent autoimmunity, but that might not matter if we can control its harmful consequences." One day it may be possible to inject peptides (small proteins) to slow down or stop the activation of the immune system attack. Or, one day it may be possible to collect T-cells from a patient, modify them using genetic techniques, and transfer them back to the patient in a way that could help. Perhaps the patient would still have an autoimmune attack, but one that does not lead to killing of the beta cells, and could even dampen the killing by other, more aggressive, T-cells. This one day could lead to new drugs to control the autoimmune destruction process.

The researchers also are exploring whether virus or trauma has a role in triggering diabetes. "Possibly there is a link but this is not proven," Dr. Mathis says. In mice they have observed loss in the beta cell function when the animals are stressed or develop a virus. "It seems that the immune system is poised for beta cell destruction, but kept in check. The infection unleashes it," Dr. Benoist says. "The immune system has checks and balances in place that keep it in check most of the time. But some scientists believe that a virus, in susceptible individuals, may trigger an overstimulation of the immune system that can’t be brought back under check, leading it to destroy more than the invading organisms, namely in the case of diabetes, the pancreatic beta cells."

Why do some patients with type 2 diabetes eventually need insulin to manage their blood sugar levels? The Benoist-Mathis team is exploring the notion that the constant stimulation of the beta cells may cause the cells to become tired and die, secondarily activating autoimmunity. As the beta cells break apart in the process of cell death, an overabundance of proteins associated with these cells builds up in the body, triggering an immune system reaction that attacks the still living beta cells, destroying them as well. "The stress of type 2 diabetes on the beta cells could lead to type 1," Dr. Benoist says. "This results in a type 1 and one-half diabetes, or transitional cases of diabetes."

The link with arthritis

"We are very excited to have Diane and Christophe join Joslin’s Research Division. The work of the Benoist/Mathis lab is important not only for understanding diabetes, but also for other diseases," says George King, M.D., Acting Director of Research at Joslin. "They will be taking the lead in the area of autoimmunity in the development of type 1 diabetes and transplant rejection, which are critical areas of development for the control of diabetes." Drs. Benoist and Mathis receive funding from the Juvenile Diabetes Foundation (JDF) for their work on behalf of JDF’s Center for Islet Transplantation at Harvard Medical School.

Coincidentally, their studies of the body’s autoimmune response have shed light on another disease in which the body’s immune system turns against self-tissue — rheumatoid arthritis. Rheumatoid arthritis affects 2.1 million Americans, mostly women.

"By chance, one of the more than 100 strains of mice in which we study diabetes developed arthritis and so we started working on it," Dr. Mathis says.

Earlier this year, the research team and their French colleagues published a paper in the journal Science reporting that they had identified a particular protein that is the target of an autoimmune response in arthritic mice. Joint destruction in rheumatoid arthritis is believed to be caused by an immune system attack against tissue in the joints, although prior to their findings, the antigen that causes the response had not yet been identified. Isao Matsumoto, M.D., of Joslin, a research fellow in the Benoist/Mathis lab, found the problem protein does not reside specifically in the joints, as many researchers had previously thought, but it in an enzyme (protein) called glucose-6-phosphate isomerase (GPI).

To identify the immune system target, the researchers extracted cells from various tissue in normal and arthritic mice. Dr. Matsumoto found that the GPI protein was associated with antibodies in the mice with arthritis. "We then tested our theory in a number of ways. After injecting anti-GPI antibodies in mice that did not have arthritis, the mice did develop the disease," Dr. Benoist says.

Why, if the target is found throughout the body, does this destruction occur in the joints? "We suspect that some unusual physiological feature of joints may be responsible for focusing the autoimmune destruction in that area," Dr. Benoist says. "It is really a puzzle at present, but one which should bring important developments in the future."

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