The Autoimmune Epidemic: Bodies Gone Haywire in a World Out of Balance--and the Cutting-Edge Science that Promises Hope (No Series) (19 page)

Harley ruefully recalls the day they decided to push ahead with their research. “Judi came to me with what she’d found and said, ‘We should study EBV further.’ I said, ‘Judi, you had better hope and pray EBV is not involved here, because it has been claimed to cause everything and been proven to cause very little. No one in the entire medical community will believe us, we will be treated like scientific pariahs, and it will take us the rest of our careers to prove we’re right.’” The suggestion that Epstein-Barr virus might have a hand in autoimmunity, would, Harley knew, “be irritating to our colleagues because our predecessors had looked at it and found very little there. Resuscitating it before the medical community was going to be even worse than if it had never been looked at before.”

The next step was to test their prediction that Epstein-Barr played a role in lupus. Harley told James that they would immunize some of the animals in the lab with EBV peptides that looked like the Sm B self-protein, and that if these Epstein-Barr protein pieces produced lupus in them he would shut down several other projects in order to test whether that association could also be found in humans. Sure enough, the lab animals got a lupuslike disease. James was astounded to find that she could “take one piece of the structure of EBV and cause lupus by immunizing the animals with it.”

Harley and James quickly published their findings and applied for a grant from the National Institutes of Health seeking research funding. They were so gung ho, in fact, that, in a story well known to colleagues, Harley was once racing a grant application to Federal Express when his old Ford Pinto burst into flames. Firefighters were still extinguishing the fire when Harley bummed a ride to FedEx to send the grant proposal. The front of the car, meanwhile, “melted like icing.”

As he’d predicted, fellow scientists were not supportive. He and James were, Harley says, “body-slammed.” Nevertheless, true to his word, Harley closed down some other areas of research and he and James went to work. In order to see if the same association was found in humans, they decided to study children and teens—an easier population to study than adults because children have a lower rate of EBV infection, which makes testing for association with lupus easier and more straightforward. The research team took blood samples from healthy children and teens and found that roughly 70 percent of these children had EBV DNA present in their bloodstreams. But when they examined lupus patients from the same age group, they saw that virtually every one of them tested positive for Epstein-Barr exposure. Ninety-nine percent of the same children who had lupus were also positive for Epstein-Barr—a statistically significant higher percentage than in their control group.

Harley and James’s results, published in 1997, provided striking evidence that Epstein-Barr plays a role in triggering lupus—and that the same relationship that exists between Epstein-Barr and autoimmune disease in lab animals also exists in humans. “For most patients with lupus, Epstein-Barr is a necessary condition for autoimmune disease,” submits Harley. Although EBV works in connection with many, many other factors, says Harley, “without the Epstein-Barr connection I think most patients would not be affected with lupus.”

In lupus research, Harley is what social psychologists might refer to as a “change agent”—someone so far out on the cutting edge of a new line of thought that by the time early adopters of that new concept sign on to it as well, they nevertheless lope far behind. Since 1997, Harley and James have published numerous other studies in top medical journals that continue to affirm their conclusions about Epstein-Barr. And in the fall of 2006, Harley was given the first ever Excellence in Scientific Mentoring Award by the American College of Rheumatology for his achievements in helping young researchers, like Judi James, to make their mark resolving cutting-edge research questions such as this one.

Meanwhile, the wider scientific community has come on board as multiple studies at other institutions around the world have supported Harley and James’s original findings. One recent study supporting the link between Epstein-Barr and lupus shows that African Americans who test positive for Epstein-Barr are five to six times more likely to have lupus. Not surprisingly, genes play a specific role in the connection between Epstein-Barr and lupus as well.

African-American and white patients who have lupus and Epstein-Barr are more likely to possess a genetic variation in the way their T cells control the immune response. Having this genetic variation significantly increases the risk of developing lupus if one has been exposed to Epstein-Barr.

Still, few diagnosing physicians think to ask about recent viruses when struggling to detect whether or not a patient has autoimmunity. In a sense, this is hardly surprising, because there is often a significant time lag between viral exposure and the onset of autoimmune illness. It can take days, weeks, months, and even years to develop autoantibodies against one’s own body tissue after having been exposed to a virus. In a clinical setting, cause and effect are difficult, if not impossible, to ascertain.

Just think of LaShekia Chatman. For years after coming down with and being diagnosed with Epstein-Barr, LaShekia suffered from the symptoms of—and nearly died from—undiagnosed lupus. For decades, scientists had dismissed not only the chemical-autoimmune link but the viral-autoimmune connection as well. As it would turn out, both featured in LaShekia’s autoimmune story. And that scientific blindness played a subtle part in why, for seven years, no physician suspected that LaShekia had lupus—even though her history so clearly pointed to both a viral and chemical overload.

What Harley and James were able to do by first isolating that “smoking gun”—that Sm B protein sequence targeted by lupus patients’ antibodies—was to demonstrate, on the smallest cellular level, that the body can be tricked into attacking itself. Their research was a dramatic example of molecular mimicry at work between a protein in a virus and a protein in the body. They had, in a manner of speaking, been able to travel back in time and show that the autoimmune reaction in lupus patients was a slow-brew reaction to an Epstein-Barr exposure that had occurred months, years, or even decades before. As Harley puts it, “I do not know of a human model of molecular mimicry as convincing as this.”

Today, a bevy of other researchers is on the hunt for similar links between viruses and autoimmune disease in the hopes of better understanding the mystery of how an infectious agent might interact with other factors to induce autoimmunity. One 2006 study reported in the
Archives of Neurology
, published by the American Medical Association, shows that young adults who have high levels of antibodies against the Epstein-Barr virus are significantly more likely to develop multiple sclerosis fifteen to twenty years down the road. Harvard School of Public Health and Kaiser Permanente researchers were able to determine this correlation by examining records of more than 100,000 patients who joined health plans between 1965 and 1974, when they were in their early thirties. All participants had undergone multiple examinations and all of them had had their blood samples stored. In the late 1990s, Kaiser researchers went back and scoured the medical lab records of forty-two of these women and men whose earlier blood samples had been kept and who later went on to develop MS. A control group of patients who did not develop MS—three times the size of the group with the disease—was also studied. Scientists looked at all the participants’ preserved blood samples to determine what their levels of antibodies against the Epstein-Barr virus had been fifteen years earlier.

Measuring those antibodies yielded marked results. Those with the highest levels of antibodies against Epstein-Barr were twice as likely to develop multiple sclerosis fifteen to twenty years later. Researchers concluded that mounting evidence relating “Epstein-Barr virus infection to other autoimmune diseases, particularly lupus, suggests that Epstein-Barr virus may have a broad role in predisposing to autoimmunity.” Likewise, National Institutes of Health researchers recently found that patients with multiple sclerosis carry a larger than normal number of antibodies against Epstein-Barr. One particularly provocative study out of the Hospital for Sick Children in Toronto shows an association between pediatric multiple sclerosis and the Epstein-Barr virus, indicating that exposure to the virus in childhood may be an important environmental trigger for developing MS early on.

Epstein-Barr is hardly the only viral infection that has been under the microscope in recent years in autoimmune-disease research labs. Scientists can now show the precise process by which proteins in streptococcal bacteria mimic cells in the heart, resulting in the autoimmune reaction known commonly as rheumatic heart disease. Other scientists are examining the relationship between the measles virus and multiple sclerosis, suggesting that viral outbreaks of measles might contribute to some localized epidemics of multiple sclerosis. And for many years, one of the more unsettling questions in the field of viral autoimmune-disease research has been whether individuals exposed to common viruses while in their mothers’ wombs, or as newborns, are more likely to develop type 1 juvenile-onset diabetes.

In type 1 diabetes, an autoimmune disease also known as insulin-dependent diabetes mellitus, or IDDM, the pancreas undergoes an attack by the body’s own immune system and becomes incapable of making insulin. Investigations into whether viruses might be implicated in type 1 diabetes go back decades. But it has only been with the help of more recent and sophisticated lab techniques that scientists have been capable of pinpointing how certain viruses, called enteroviruses, second only to the common cold as the most common cause of viral infections, incite some cases of type 1 diabetes. Enteroviruses, those ordinary viral infections that keep young children home from day care or school with cold and flulike symptoms and sometimes fever and muscle aches, cause an estimated 10 to 15 million infections a year in the United States. The most serious of these, the family of polio enteroviruses, have been eradicated in the United States as a result of aggressive vaccine campaigns. But researchers today are concerned about a more common and seemingly innocuous type of virus within the family of sixty-one nonpolio enteroviruses known as the coxsackie B viruses.

In the mid 1990s, researchers in Sweden examined stored blood samples from mothers who had delivered babies in Swedish hospitals, in hopes of better pinning down the relationship between coxsackie B viruses and childhood diabetes. They compared blood samples of 57 mothers of diabetic children with those of 203 mothers of nondiabetic children. Coxsackie B antigens turned out to be significantly more prevalent in mothers whose children later developed diabetes. The researchers concluded that enteroviral infection during pregnancy put the baby at risk for developing childhood-onset diabetes, particularly for developing the disease before the age of three.

Other studies tie mumps infection to the onset of diabetes. Although childhood immunization programs begun in the late 1950s have all but eradicated mumps, a recent resurgence of mumps outbreaks in the United States coupled with today’s skyrocketing rates of childhood diabetes seems likely to resurrect this inquiry again in the near future.

It all sounds quite grim. One viral infection and you end up with a lifelong, debilitating autoimmune disease? Well, not exactly. Remember the barrel effect? While researchers and physicians are concerned by rising rates of children with autoimmunity—especially type 1 diabetes—most researchers agree that the causes of autoimmune disease in children, as in adults, are exceedingly multifaceted. The disease erupts in a given person at a given time due to a barrel effect, and viruses play just one part in filling that barrel. In the past, our understanding of what factors coalesce over a patient’s lifetime and cause the barrel to suddenly spill over has been sorely lacking. Today, as more and more lab evidence pours in, clues, if not answers, are beginning to emerge.

Still, the profound link between viruses and autoimmune disease has not yet trickled down to the majority of medical practitioners. Few doctors know to address the potential role that a recent viral attack may play in developing autoimmunity when they are struggling to diagnose a patient who may have autoimmune disease.

It may also help to think of our growing understanding of the association between common viruses and autoimmune disease in the context of what is happening today in medical research in general. For centuries, scientists failed to recognize that pathogens played a role in a whole range of what were deemed to be noninfectious diseases. Up until the late twentieth century, health professionals believed that cancers and such chronic diseases as peptic ulcers were probably caused by a combination of genetics, diet, stress, and other lifestyle factors. But researchers now know that most peptic ulcers are caused by an infection with the bacterium
Helicobacter pylori
and can be treated with antibiotics. Treating patients surgically, it turns out, has been completely unnecessary. Infection with human papillomavirus, the cause of genital warts, is now known to be the major cause of cervical cancer. Epstein-Barr virus, in addition to being a culprit in lupus and multiple sclerosis, is now fingered in certain cancers such as Burkitt’s lymphoma and nasopharyngeal carcinoma. Hepatitis B is thought to be associated with an increased risk of some liver cancers. Even some psychiatric conditions, such as schizophrenia and certain types of obsessive-compulsive disorder, are believed to be directly or indirectly the result of infections. And scientists are now finding tentative links between viral infections and obesity as well.

A recent report from the American Society of Microbiology highlights how widely this “new germ theory” applies to some thirty viral and bacterial microorganisms for which there exists strong evidence of an association to chronic disease.