The Autoimmune Epidemic: Bodies Gone Haywire in a World Out of Balance--and the Cutting-Edge Science that Promises Hope (No Series) (27 page)

CAN WE PREDICT WHO WILL DEVELOP TYPE 1 DIABETES?

Nowhere is the ability to predict who will have an autoimmune disease more advanced than in type 1 diabetes research. Here, scientists have been able to identify prediagnostic markers for the disease with staggering accuracy. Type 1 diabetes is an autoimmune disease in which the immune system attacks the healthy beta cells—the cells that produce insulin—in the pancreas. When this happens, the body does not produce adequate insulin, the hormone our body needs to help our cells to absorb glucose. And that means that the body cannot balance its blood sugar. Untreated, type 1 diabetes is quickly fatal. People with type 1 diabetes need to take insulin artificially on a regular basis through injections or pumps. Even so, kidney disease, heart disease, and neuropathy are all common with long-term diabetes.

The disease is particularly troubling to autoimmune-disease researchers because of the rate at which it has been skyrocketing in children in recent years. More than a million Americans suffer from type 1 diabetes, and each year thirty-five thousand children are newly afflicted with the illness. A recent 2006 study—the largest surveillance effort on diabetes in youth conducted in the United States to date—found that 1 in 648 children and young adults under the age of nineteen now has type 1 diabetes—a staggering number. Worldwide studies confirm that even in babies and children aged four and under, rates have been increasing by 6 percent a year.

Knowing that, each year, so many children are being born who will develop type 1 diabetes has been a unique motivator for researchers to identify at-risk children in time to stop the disease in its tracks. Although scientists agree that some combination of genetics, toxins, viral hits, and diet are at play in the development of type 1 diabetes, predicting which children might be most at risk has been, until very recently, a pipe dream.

Older, traditional assays, or tests, determine risk for type 1 diabetes by identifying what are called islet cell antibodies. Islet cell antibodies are produced when the body’s immune system fails to recognize insulin-generating islet cells produced by the pancreas as natural to the body and attacks them as if they were dangerous foreign substances, suddenly decreasing the body’s ability to produce the insulin that helps cells absorb glucose. High levels of islet cell antibodies show that the body is destroying the islet cells in the pancreas.

Tests developed in the mid-1990s found that a combination of two newly recognized autoantibodies—GAD65 and IA-2—could also predict type 1 diabetes over time. However, researchers found that—as with prediagnostic lupus biomarkers—there were some patients who were positive for some of these biochemical markers but still did not develop type 1 diabetes. In 2005, Dr. Massimo Pietropaolo, a native Italian who came to America in 1990 to study as a research fellow in medicine at Harvard Medical School and who now serves as director of the Laboratory of Immunogenetics at the Brehm Center for Type 1 Diabetes Research and Analysis at the University of Michigan, set out to study the effectiveness of combining both the older islet cell antibody test with the two newer biochemical tests to predict who will develop type 1 diabetes.

Pietropaolo, who began the work while an associate professor of pediatrics, medicine, and immunology at the University of Pittsburgh School of Medicine, looked at both levels of islet cell antibodies and newer biochemical markers of autoantibodies in 1,484 first-degree relatives of people with type 1 diabetes. Those who tested positive for GAD65 and IA-2 autoantibodies had a 14 percent risk of developing type 1 diabetes after 10 years. However, those who displayed those two autoantibodies along with islet cell antibodies had an 80 percent risk of developing the disease after just 6.7 years. The surprise, says Pietropaolo, was that “by using these older assays in combination with the newer tests, we were able to more accurately predict type 1 diabetes in the family members of those with type 1 diabetes.” His results delivered the highest level of accuracy ever achieved in not only predicting type 1 diabetes, but any autoimmune disease.

In addition, family members who tested positive for a fourth newly recognized biomarker developed type 1 diabetes more quickly than others. Pietropaolo, whose work is funded by the National Institutes of Health, suspects that having this new biomarker may predict a more rapidly developing form of the disease in first-degree relatives of patients with type 1 diabetes. In 2005, Pietropaolo began more in-depth studies, looking at all these prediagnostic biomarkers to predict who will develop type 1 diabetes and when. Results have been exciting. “We can now predict with accuracy type 1 diabetes in first-degree relatives of type 1 diabetic patients,” he says. “This allows us to consider novel intervention strategies in an effort to delay or even prevent overt disease in those individuals who are at greatest risk of developing type 1 diabetes.”

In other autoimmune diseases, the race has only recently begun to recognize antibodies that confirm diagnosis after symptoms have already occurred—and researchers remain years away from using such newly understood blood biomarkers to predict who may or may not develop disease. In multiple sclerosis—a disease that has traditionally been difficult to diagnose conclusively—recognizing what protein patterns signal that the body is at work against itself is just evolving, as researchers struggle to find a distinct pattern of proteins and antibodies that is highly indicative of disease. In an array of recent studies over the past two years, researchers have found a distinct fingerprint of individual proteins that can differentiate people with MS from healthy people. This suggests that, over time, scientists may be able to develop a blood test that could help them to identify the earliest changes that represent MS and aid in speeding up diagnosis as well as treatment. Other breakthroughs in MS diagnostics include a recent Yale study in which investigators isolated several newly recognized antibodies that were shown to interact with a form of myelin found in MS and state-of-the-art eye exams that use four different tests to find abnormalities in the retina and damage to optic-nerve fibers, often the spot where MS damage first occurs.

Other researchers, including Douglas Kerr at Hopkins, are looking at elevated levels of specific proteins not in the blood, but in the spinal fluid of MS patients, to help confirm diagnosis. Kerr has found that levels of a particular protein, interleukin-6, or IL-6, are dramatically elevated in the spinal fluid of patients with transverse myelitis. Interleukin-6 is a pro-inflammatory cytokine, a messenger that cells of the immune system use to communicate with one another. One of the cell types injured by high levels of the protein IL-6 includes oligodendrocytes, which help to produce the protective myelin sheath around nerve cells. Kerr’s team found that the level of IL-6 proteins directly correlated with the severity of paralysis in patients.

Additional proteins and antibodies related to multiple sclerosis are being isolated in labs across the country—raising the question as to whether or not, one day soon, a map of blood biomarkers may emerge that predicts disease years in advance in multiple sclerosis, just as in lupus and type 1 diabetes.

As newer technologies are developed, researchers are on the cusp of being able to measure increasingly complex combinations of unique proteins and antibodies at one time. Such measurements may provide clinicians with the ability to study large groups of people to see how predictive these patterns of biomarkers are in determining who develops a disease and how long it takes for symptoms to appear. As we improve our ability to see what biomarkers of disease predict actual disease, researchers can begin to look at patient-specific therapies and develop prevention trials.

THE GENETIC LINK

Genetic testing provides yet another key to identifying who is most likely to be afflicted by these diseases. Researchers believe that our genes determine roughly 30 percent of one’s risk of developing autoimmunity, with the remaining risk being attributable to environmental factors. All of the twenty thousand genes that scientists (at latest count) believe we are born with are encoded in our DNA from the moment of conception. Our cells read these genes in order to build proteins in our bodies. Proteins carry out the various cellular processes that make our bodily systems function. What genes we have determine what protein sequences we create and what enzymes we produce—which, in turn, determine how our cells will behave in an array of challenging circumstances. Small defects in genes—and in protein codes—can make a whopping difference in how the cells in our bodies act. By understanding which genes precipitate a specific disease we can better understand the process by which disease is kick-started. But it’s a complex task: not only do we have an estimated twenty thousand genes, but each of these genes can have multiple, complex, individual variations. One gene might have only the slightest modification in terms of the proteins it expresses, but that small difference will lead to dramatic changes in the way our body functions.

As with all gene research, efforts to decipher how specific genes influence our susceptibility to an array of autoimmune diseases is stepping up around the country. In two related 2006 studies, researchers at the University of Texas Southwestern Medical Center recently found defective genes in mice that contribute to triggering lupus. One of the two studies determined that a defective version of a gene known as
Ly108
rendered mice susceptible to lupus. The defective version of the gene impairs one of the most basic steps in the development of immune-system cells. When it is functioning normally, the body destroys any immune-system cells that, by mistake, have started to produce antibodies against the body. But in mice with a defective
Ly108
gene, those rogue self-attacking cells escape detection, allowing them to attack the body’s healthy cells, resulting in the disease. If researchers are able to demonstrate that the same genetic defect found in the mouse model also creates susceptibility in human lupus, it might open ways to block the disease by developing new drugs that block the activation of a defective
Ly108
gene.

In a separate lupus study from UT Southwestern, researchers describe the role of a mutated gene called
Tlr7,
which interacts with
Ly108
in triggering lupus by causing another component of the immune system to malfunction. The gene turns out to affect the body’s ability to alert the immune system to an invading germ. The research team, led by Dr. Edward Wakeland, professor of immunology and director of UT Southwestern’s Center for Immunology, discovered that mice that died of lupus in their study carried twice the normal amount of the mutated receptor gene
Tlr7
. Interestingly, for lupus to occur, the lupus-causing versions of
Tlr7
and
Ly108
both have to be present. If you put both genes together, you create a fatal form of lupus—the mouse dies.

Although these genes are in mice and not humans, chances are that they will shed light on the genetics of lupus in people. Already, genes that have been linked in mice to type 1 diabetes and rheumatoid arthritis have turned out to influence the same diseases in humans. Ultimately, understanding how small differences in our genetic expressions can lead to disease may help doctors to tailor lupus treatments to individual patients, since the cause of each individual patient’s disease may differ, and the genes that work together to help precipitate disease in one person may be different from those that lead to genetic susceptibility in another.

At the Oklahoma Medical Research Foundation, John Harley has played an instrumental role in identifying a pair of genes in humans that may be responsible for genetic susceptibility to lupus. His lab has also created the Lupus Multiplex Repository and Registry, the world’s largest collection of blood and tissue samples from families in which more than one member suffers from lupus, in order to help researchers investigate more genetic links to lupus in people—and to see which combination of genes is most likely to result in disease. Likewise, a 2007 genome study searching for MS genes pinpointed two gene variants as heritable risk factors for multiple sclerosis.

Already, the technology we have to look at how genetic codes influence disease is opening up new avenues of scientific questioning. For example, researchers have shown that mutations of several genes are strongly associated with Crohn’s disease. Surprisingly, one type of mutation appears actually to be protective—helping to prevent people from acquiring Crohn’s or ulcerative colitis, both types of inflammatory bowel disease. Lupus researchers are likewise discovering that there are certain strains of mice that—even if exposed to high levels of what are traditionally thought to be lupus-causing agents—still don’t develop disease. The idea that a gene might be protective against disease—meaning that those with a specific gene don’t get the disease—is a twist on the traditional thinking of the genetics of disease, opening up inquiry into what we might think of as the genetics of health.

THE GENDER EQUATION

One clear-cut genetic difference that weighs in heavily on who will have autoimmune disease is the most obvious of all—gender. Women account for nearly 80 percent of the 23.5 million Americans with autoimmune disease. Women also tend to have higher antibody levels than males and mount more robust immune responses to antigens. Hormonal shifts in pregnancy, menopause, and aging are associated with fluctuations in the course of autoimmune disease. Think back to Jan Pankey, who started taking birth-control pills and developed full-fledged antiphospholipid antibody syndrome shortly after starting their use. Birth-control pills didn’t cause Jan’s sudden plunge into autoimmunity, but increased hormonal levels no doubt helped to fill her barrel so that when she met up with those chemically noxious smoke clouds crossing into Montana something in her immune system just snapped. Indeed, research shows that many women who develop lupus do so a few months after giving birth to a child—a time when hormone levels undergo swift and dramatic changes.