Diabetes Forecast March 2005

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FOR TYPE 2

Research Profile

Mom's Antibodies
A Risk For Type 1?
by Terri Kordella

Åke Lernmark, PhD, suspects that children whose mothers were exposed to certain viruses while pregnant may be at a higher risk for developing type 1.	Åke Lernmark, PhD Occupation Professor, University of Washington School of Medicine Professional Focus Type 1 prevention Outside Interests Skiing, orienteering, gardening, and sailing Research Funding ADA Terry and Louise Gregg Diabetes in Pregnancy Research Award

Type 1 diabetes is an autoimmune disease. The immune system attacks and destroys the beta cells of the pancreas. Beta cells make insulin, and once they are destroyed, they aren't replaced. The result is type 1 diabetes.

The big question is: Why does this happen?

Genetics is thought to play a role, but Åke Lernmark, PhD, professor at the University of Washington's School of Medicine, has another idea. He believes that women who are exposed to certain viruses when they are pregnant may be more likely to have children who develop type 1. Lernmark and his team of researchers are using funds from an American Diabetes Association Terry and Louise Gregg Diabetes in Pregnancy Research Award to test his theory.

Antibodies And Antigens

Your immune system is geared to protect you from a host of foreign invaders or "antigens," such as viruses and bacteria. It monitors your system 24/7. If it senses invader antigens, it releases proteins called antibodies to seek and destroy them. In such cases, your immune system is a real lifesaver.

Lernmark suspects that the immune system is occasionally tricked during pregnancy and makes a serious mistake; it incorrectly views certain substances that naturally occur in the body of the mother-to-be as antigens, and makes antibodies to attack them.

The substances that may trigger a mistaken immune response include GAD, IA-2, and incomplete forms of insulin. GAD and IA-2 are proteins that normally reside in the beta cells, but in certain circumstances—which we'll get to in a moment7mdash;they may leak out into the blood and prompt an immune attack. Insulin normally circulates in the blood to help process glucose, but when the beta cells are damaged, insulin that is still being made leaks out before it's in the proper form, and the body sees it as foreign.

According to Lernmark, the more antibodies created in response to these antigens, the greater the diabetes risk to the child.

"Today we know that if a child has antibodies to all three, that child will definitely develop diabetes within 2 to 5 years," Lernmark says. "We can actually predict diabetes."

Lernmark's team will examine blood samples both from women who gave birth in a hospital in Sweden in the 1970s and from their children. The purpose is to determine if the mothers and children had these antibodies present in their blood when the children were born. Then they will look at the records and see which children later developed diabetes.

The idea to look back in the records came from Lernmark's colleague, Sten Ivarsson, MD, PhD, a pediatrician at the hospital in Sweden where the women gave birth. Early in Ivarsson's career, it was the hospital's practice to test women and their newborns for cytomegalovirus, a virus in the herpes family that can cause hearing impairment and deafness. It can be passed from an infected mother to her child during pregnancy. Over the years, the hospital collected more than 100,000 blood samples.

Ivarsson eventually became head of the pediatric diabetes unit. One day he treated a child for diabetes whose mother he remembered as having been tested for cytomegalovirus years before. Thinking of the blood samples still in storage, he approached Lernmark, and they came up with an idea: Why not go back and look at the samples to see if mother and child had the antibodies when the mother gave birth?

From there, the idea blossomed into the study it is now—"which means that if you're a scientist, you should never throw anything out, because you never know what you'll discover," Lernmark says.

The team has identified about 150 people with type 1 who were part of the original blood sample study. The next step is to look at the samples and see if either mother or child had the antibodies, and see which mothers also had diabetes themselves.

If the mothers had diabetes themselves, that might indicate a genetic risk. It's the mothers who did not have diabetes during pregnancy who hold special interest for Lernmark, because chances are something other than genetic programming triggered their immune systems, something temporary—like a virus.

A Virus

Lernmark believes that when a particular kind of virus strikes a pregnant woman, it may affect the developing immune system of her unborn child and make the child susceptible to the same virus later in life.

"When the mother is hit by the virus during pregnancy, the virus attacks the beta cells, the beta cells get sick and break apart, and GAD, IA-2, and unfinished insulin leak out into the blood," he says. "Antibodies attack because these things should not be in the blood. The virus, antibodies, and antigens leak over into the fetus.

"Meanwhile, the immune system of the child thinks the virus and the mother's antibodies and antigens are okay. The child's immune system sees them as part of the mother, so the child's immune system doesn't react," he explains. "The child is then born with an immunological disability. Years later, the virus comes along and the door is wide open for it. The child has no protection from infection. So, we think the children get hit twice, once from the mother, and once from the virus itself."

According to Lernmark's theory, once the child is infected, his or her own beta cells break apart and leak GAD, IA-2, and unfinished insulin into the blood. Then the immune system kicks in, the way the mother's immune system kicked in when she was pregnant and she was infected with the virus. Only for the child, whose immune system developed abnormally in the womb, the reaction goes one step further. T-cells, which are specialized attack cells in the immune system, recognize not only GAD, IA-2, and insulin, but also the beta cells where these antigens are coming from. Then the T-cells attack the beta cells. No beta cells means no insulin, and no insulin means diabetes.

What virus could be so dastardly? There are a number of suspects, but the Coxsackie family of viruses stands out.

There are some severe forms of Coxsackie virus, but the more common viruses in this family have mild symptoms, says Lernmark. They cause diarrhea, fever, and stomach upset, and they are passed by person-to-person contact either through unwashed hands or droplets in the air from sneezing or coughing. Also, these viruses change much like the flu. Because Coxsackie viruses are so common, their symptoms are so mild, and they change so frequently, there are no vaccines for them.

The next step, then, would be to find out who among the mothers and children were exposed to a Coxsackie virus. Lernmark's team may be able to determine this by looking at the blood samples, because Coxsackie viruses trigger antibodies of their own.

Working Backward

If it turns out that Coxsackie viruses are partly to blame for type 1 diabetes, efforts at preventing diabetes might involve treating or preventing the virus, says Lernmark.

"So far, all we can do is look for GAD, IA-2, and insulin antibodies and tell people they're going to develop diabetes, and we can say that the earlier you're diagnosed, the better off you will be. But we have nothing to offer that will prevent diabetes," says Lernmark. "If we can understand how the disease starts, we'll be in a much better position to treat it.

"We may be able to treat mothers or children when the virus is present and suppress the virus. We may be able to treat them with anti-viral drugs. Or, perhaps we could try and develop a vaccine that would cover many of the viruses, and then treat women before they get pregnant," he adds. "But we have to work our way backwards to the event that starts diabetes before we can try to find a way to stop it."