The Autoimmune Epidemic: Bodies Gone Haywire in a World Out of Balance--and the Cutting-Edge Science that Promises Hope (No Series) (11 page)

Once a T cell’s antigen receptor finds an antigen has entered the body that it recognizes as foreign, the T cell forms what is known as an immunological synapse—think of it as a telephone call from the T cell to the dendritic cell—querying dendritic cells for additional information about the antigen and its source in the body. Is the antigen a deadly danger or simply, say, a harmless food protein? (In the case of food allergies, this might be a food protein that the body decides to mount an attack against as if it’s a deadly foreign invader, as happens when a peanut is eaten by a person who has an allergic response to peanut protein.)

This interrogation may last hours. If, finally, the antigen is deemed a threat, the T cell starts multiplying, producing a posse in a rapid cellular population explosion. These T-cell police progeny are capable of killing invaders outright as well as marshaling other cells to destroy them.

In the case of autoimmune disease, however, T cells begin to function erratically. In a healthy immune system, regulatory T cells are able to make sure that other T cells never attack our own tissue. Part of their job is to ensure that T cells recognize our own body tissue as ourselves and never mistakenly attack “self.” But in autoimmunity, T cells lose their “tolerance” to self. These self-reactive T cells stimulate other immune cells to produce autoantibodies that attach to the perfectly fine, healthy cells within our body—in any organ or tissue—and cause cells to die.

Environmental toxins appear to mess with normal internal signaling pathways, making it difficult for our immune cells to recognize what is foreign and what is self—a bit like a covert enemy force sending up smokescreens and spreading disinformation. Mouse studies show that even subtle signaling imbalances can predispose animals to produce antibodies against the self. In patients with lupus, for instance, certain signaling molecules that relay messages between cells and rally the production of antibodies have been shown to be present in abnormal amounts.

Gilbert and Pumford wanted to find out whether TCE might stimulate the production of an autoimmune response and, if so, see what cells might be involved. As is standard in this sort of research, they used a machine known as a flow cytometer to examine the surface of cells from the mouse, taken from immune-system organs such as the lymph nodes and the spleen. The flow cytometer uses a laser to light up cells if the cells express certain markers that should not, in normal circumstances, be present on the T cells. If, however, the cells light up, this could be considered as a “bingo” moment; a T cell that should recognize the mouse’s tissue as self and tolerate it has, instead, become activated to possibly destroy the mouse’s own tissue.

In Gilbert and Pumford’s experiment, the T cells from mice exposed to TCE lit up all over the place. Yet no cells lit up in the group of control mice that had not been given TCE-laced water. Specifically, the flow cytometer told Gilbert that in the mice exposed to TCE, a T-cell activation molecule, CD44, was acting differently than it would have if there had been no autogen. CD44 molecules are usually activated when the body is fighting, say, a very bad viral infection. But in this case CD44 was signaling that, even in the absence of a viral infection, T cells had been activated—and they were most likely activated against self. Chances were that what Gilbert and Pumford were staring at was the mouse’s own immune system, or T cells, being activated—and going on to destroy the mouse’s own tissue and cells.

“It was a very robust effect,” says Gilbert. “The more TCE we gave them, the more cell activation we got.” Gilbert and Pumford were stunned. They were staring at not only an increase in the percentage of cells expressing CD44, but these CD44 cells were also producing a multitude of other inflammatory molecules known as cytokines, which are found in overabundance in patients with lupus and many other autoimmune diseases.

And so, they wondered, what would happen if they exposed mice to a lower dose of TCE over a longer period of time—a chronic exposure equal to exactly what a person might have in a tannery or airplane manufacturing company, an amount corresponding to limits already approved of as safe by the EPA for industrial workers?

This time around, even at these low doses, Gilbert and Pumford saw an increase in the percentage of cells that expressed CD44. But they also saw something else: after being exposed to TCE at lower doses over a longer period of time, the mice’s T cells began to destroy their own liver tissue, causing a disease known as autoimmune hepatitis.

“It was a big moment,” Gilbert recalls. In 2000, Gilbert and Pumford and colleagues published two back-to-back groundbreaking studies: they were among the first immunologists and toxicologists to show that low-dose exposure to environmental toxicants could be a potent stimulator of an autoimmune response.

While there have long been epidemiological studies telling us that people who work around certain chemicals are more likely to have autoimmune disease, those studies are complicated by the fact that people who might have been exposed to TCE are probably also exposed to other chemicals at the same time. This has made it simple for chemical manufacturers to cast such epidemiological studies as spurious; there is no way to tease out, much less prove, cause and effect based on occupational studies. Because the silent exposures that lead to disease are so often chronic, and happen slowly over time rather than in one fell swoop, it is difficult, if not impossible, to tie any single compound—or combination of contaminants—back to disease long after the fact.

“To suddenly see in the lab that occupational levels of TCE cause mice to come down with autoimmune disease was a huge jump,” says Gilbert. In the world of autoimmune-disease research, what had been a mere hypothesis—that toxicants can promote autoimmune disease—had become proven fact in their Arkansas lab.

DIFFERENT AUTOGEN THRESHOLDS IN US ALL

Still, Gilbert and Pumford were admittedly working with mice known to already possess autoimmunity genes. They could only theorize as to how their findings might apply to the general population of humans.

Yet, like mice, many people possess a predisposing genetic susceptibility to autoimmune disease. The number of genes involved in each autoimmune disease are manifold; investigators are still uncovering new lupus genes every year. But the rough guesstimate is that about one in four—an estimated 20 to 25 percent of the general population—carry some combination of genes that make them more susceptible to one or more autoimmune diseases. For example, one in four people carries a gene variant that makes him or her more likely to develop rheumatoid arthritis, MS, and other autoimmune diseases.

For those who carry such subsets of genes, low doses of environmental toxicants are clearly a bigger deal than they might be for someone else. As the sixteenth-century Swiss-born physician and alchemist Paracelsus put it, the dose makes the poison. The quantity of a substance to which we’re exposed is as important as the nature of the substance itself. Yet the dose at which a substance becomes dangerous differs for each individual, given his or her genetic makeup. For some, a minute exposure to a toxin may, for a period of time at least, be a manageable hit for the immune system—but at high or continuous enough doses, it will kill pretty much anyone. Even those who have no genetic susceptibility to autoimmunity will find that their immune systems flail in the face of a high enough dose of a toxic compound. They may not get autoimmune disease, but another disease—perhaps cancer, perhaps something else—will set in.

But for those with a genetic vulnerability to autoimmunity, even a small dose may trigger disease, creating a cellular mayhem in which the body begins to destroy its own blood, tissue, nerves, and organs. And this is what concerns researchers the most. For those 25 percent of people around the world who do have a genetic predisposition to autoimmunity, it may not take very much exposure to cause cells to miscommunicate.

For one in four people, the answer to the question of how much of a chemical has to exist in a person’s body for it to wreak immune system havoc may indeed be very, very little. Twin studies show that autoimmune disease is roughly 30 percent genetic and 70 percent environmental. While two identical twins might hold the same genetic code for a certain autoimmune disease, either one of them will be struck with disease only if they meet up with the right environmental hit. As one researcher put it, while genetics may load the gun, it’s environment that pulls the trigger. Or think of it this way: if genes are the icy mountain road, chemicals are the truck driving ninety miles an hour in a blizzard.

THE BARREL EFFECT

For patients who do possess the genetic variants predisposing them to autoimmune disease, reaching that threshold at which disease can more easily strike involves a number of factors. You might liken it to the “barrel effect.” You can fill a barrel to the absolute rim, and even while water hovers about the edge, not a drop will spill. But add one more minuscule drop of liquid and the water will begin to cascade over the sides.

Think back, for a moment, to Jan Pankey. What factors might have caused her immune cells to destroy the fatty proteins that her blood needs to clot? How did this happen so suddenly, seemingly overnight, and without warning? Jan’s more obvious risk factors were clear enough. For starters, Jan was, like three-quarters of those afflicted with autoimmunity, female. Now, pour in Jan’s personal genetic makeup: by the sheer fact that she has an autoimmune disease, Jan no doubt possesses a genetic vulnerability to autoimmunity. Add in the fact that Jan had recently increased her estrogen levels by going on birth-control pills, which may have toyed slightly with her endocrine system. A little more in the barrel. Mix in whatever industrial load of contaminants Jan might have stored up in her bloodstream and tissue over the course of her forty-nine years—which we can only guess at, based on the high amount of contaminants found in other women of her age—and which may already have been slightly, if unobtrusively, tinkering with the messages her cells are sending to one another. The water in the barrel rises just a tad farther. We might also wonder about whatever viruses Jan has been exposed to in her lifetime, which, as we will see in ensuing chapters, can also increase one’s chances of developing autoimmune disease. Now imagine that the barrel is full to the brim with this mix of genes, hormones, and environmental and viral hits.

For some, the final drop that spills the barrel may be an infiltrating virus that taxes the immune system just one degree too much, setting an autoimmune response in motion (as has been the case in my own life); for others, it might be an unexpected environmental hit that pushes the immune system into overload and chaos. Given Jan’s risk factors, Jan was hovering at that threshold. She was at that brim.

When Jan and David drove into those smoky Montana fires, they were steering into a chemical path of burning trees and nearly two dozen homes and other freestanding structures—a superintensified kind of air pollution made up of what are known in the scientific world as “microparticles.” These air particles almost certainly carried not only forest debris but the chemical burn-off from possessions packed inside these homes—everything from flame retardants in the burning clothing, mattresses, and furniture to hundreds of additional toxins with which our household goods are laced during the manufacturing process. It certainly contained dioxin—since burning trash and trees are the largest source of dioxin in our atmosphere—as well as other known endocrine-mimicking chemicals.

Even though they themselves are physicians, Jan and David had no way of knowing, as they drove through those billowing smoke clouds, that in recent years environmental health researchers have documented the relationship between many such inhaled particles and the onset and exacerbation of autoimmune disease.

Indeed, in the same summer of Jan’s ordeal, University of Montana chemistry professors and scientists were busy setting up sampling machines that sucked in that dense Missoula wildfire air and pumped it through tubing that collected the smallest particulates—the kind that are so tiny they find their way deep into people’s lungs. In the process of looking at these particles, which are about one-thirtieth the diameter of a single strand of human hair, chemists found hundreds of chemical compounds in that smoke. These included a complex soup of pollutants including dioxin, mercury, and the same compounds found in diesel exhaust. Moreover, the sheer volume of particles was in and of itself shocking: the particulate matter in the air that wildfire season was ten times greater than the standard set as safe by the Environmental Protection Agency.

Five months after Jan’s ordeal, three EPA researchers would publish a study on how twenty-four hours of breathing such densely polluted air particles can lead to dramatic, negative changes in our blood, including shifts in clotting factor. Eighteen months later, work would be published directly linking fatal blood clots with exposure to the airborne particulate matter in forest fires.

And in 2006, a shocking study based on hospital data from thirty-four cities over a fourteen-year span would show that people with autoimmune inflammatory diseases such as rheumatoid arthritis (RA) and lupus are at a substantially increased risk of death when they are exposed to particulate air pollution, or soot, for a substantial period of time. Individuals with rheumatoid arthritis or lupus who breathe in heavy particles of air pollution for a year or more face a 22-percent increase in their risk of dying from their autoimmune disease. An obvious question might be, Why don’t we see headlines about those with autoimmunity being at such a heightened risk of dying in bigger, more polluted cities? The answer is very likely this: since, unlike cancer, there is no autoimmune-disease registry and no way to track these diseases or those who have them, no one—but a few researchers—has really been looking or taking any note.