Anne McCullom loved sandwiches and pasta. “Those were my favorite foods,” the 34-year-old Indiana resident says, almost wistfully. It’s been seven years since she ate traditional spaghetti or a ham and cheese on rye.
McCullom, 34, is one of roughly 1 in 133 people worldwide living with celiac disease. When she ate anything containing gluten — a protein found in wheat, rye, and other grains — her immune system sniffed out the molecule and charged into alert mode. Immune cells tracked the “threat” to the cells lining her small intestine, where gluten was leaking out. The immune cells attacked, damaging cells critical to proper nutrient absorption. For McCullom, an insurance risk analyst, digestive distress was almost immediate: vomiting and diarrhea. Fatigue was near constant.
Since a blood test and an endoscopy performed in 2009 finally confirmed celiac disease, McCullom hasn’t eaten gluten — at least not on purpose. Her energy levels have soared in recent years, and she’s taken up running. But recently, she’s been struggling with intense pain that has slowed her pace, and she worries she may be dealing with a second autoimmune disease. McCullom’s cousin in Boulder, Colorado, Beth Hayden, has rheumatoid arthritis, a painful autoimmune disease that targets joints. Hayden’s joints swell up and become especially painful when she eats — you guessed it — foods containing gluten.
To many researchers in the field of autoimmunity, such family connections and dual diagnoses come as no surprise. Increasingly, medical researchers are identifying heritable connections among seemingly diverse autoimmune diseases, including celiac, juvenile idiopathic arthritis, ulcerative colitis, and others.
If your sister or parent has celiac, your risk goes up, to about 1 in 22. If you have celiac disease itself, you are 3 to 10 times more likely than the general population to develop other autoimmune diseases, which include psoriasis, type 1 diabetes, Crohn’s disease, and multiple sclerosis.
“In the broadest sense, if you have one autoimmune disease, your risk of having another is higher,” says Soumya Raychaudhuri, an associate professor and physician at Harvard Medical School and Brigham and Women’s Hospital in Massachusetts.
What seems like a patently unfair double-whammy to those with autoimmune diseases today may, in the long run, benefit others who are likely to develop them in the future. That’s because the genetic connections among the diseases are leading to a better understanding of their shared biology.
“One of the things that has been astonishing is that in many instances, the same genes — and in some cases, the same alleles of the same genes — seem to play roles in multiple diseases,” Raychaudhuri says.
“If you have common genetic factors that increase or enhance the risk of these diseases, it means if you can intervene in one disease, you may be able to intervene in another,” says Hakon Hakonarson, director of the Center for Applied Genomics at the Children’s Hospital of Philadelphia (CHOP).
In 2003, Alessio Fasano, who now directs the Center for Celiac Research at Massachusetts General Hospital in Boston, showed that celiac disease was far more prevalent than previously understood. He and his colleagues used blood tests and biopsies of the small intestine to determine that close to 1 percent of adults and children in the United States had the disease.
Fasano and other medical researchers around the world were also beginning to illuminate the complicated set of cellular interactions involved in celiac disease.
Broadly put, in autoimmune diseases, a person’s body begins mounting an attack against the wrong enemy — its own tissues. Type 1 diabetes is an autoimmune disease in which the immune system attacks pancreatic cells involved in regulating blood sugar. In multiple sclerosis, the targets are nerve cells of the brain and spinal cord; in psoriasis, skin cells.
In celiac, immune cells fight ferociously against a crumb of bread, damaging the small intestine in the process. Gluten, normally innocuous, leaks out of the small intestines of people with celiac disease, triggering a sequence of cellular activity more appropriate for fighting off a deadly salmonella infection.
Celiac disease is not to be confused with gluten intolerance or other phrases used lightly by people seeking to eat healthily, says Alice Bast, president and CEO of the National Foundation for Celiac Awareness. “Celiac disease is a serious genetic autoimmune disease,” Bast says.
She repeats, with emphasis: “Serious. Genetic. Autoimmune.”
For years, Bast struggled with undiagnosed celiac disease, with periods of unrelenting diarrhea — “I knew where every bathroom was, everywhere” — and harmful consequences to her reproductive system: three miscarriages and a stillborn baby born at full term, followed by a baby (now healthy) born at six months, weighing only three pounds. “I was one very sick person,” says Bast, now 54.
The long-term consequences of celiac, especially if it is untreated, can be very significant. People with celiac disease bear a significantly higher-than-average risk of non-Hodgkin lymphoma (two to four times higher than average) and cancer of the small intestine (30-fold increased risk).
More common is the malabsorption of nutrients, caused by damage to cells lining the small intestine. Anemia and osteoporosis, delayed puberty, even malnutrition can ensue, especially in children.
“So many of these kids with celiac have been cramping and having pain for years, even,” says CHOP’s Hakonarson. “They don’t grow well … there are multiple stigma.”
For McCullom, whose symptoms began appearing after the birth of her first child, fatigue, presumably from lack of proper nutrition, was crippling. “I’d catch my eyes closing while I was driving,” she says. “I’d roll down the windows, drink coffee, and then more coffee.”
Today, a gluten-free diet (GFD) is the only treatment for celiac disease. McCullom and others say it works well (most of the time), but it’s a burden that can hit the waist as well as the wallet.
“If I want to eat a bagel, my gluten-free bagel is going to have at least two times the calories and carbs as yours,” says McCullom. At first, she ate the gluten-free version of everything she loved. “I gained 15 pounds and realized I just couldn’t do that.”
Her food costs more, too. The other day at the grocery store, McCullom searched desperately for a can of tomato soup that didn’t contain gluten — she was craving grilled cheese and tomato soup, and she had the gluten-free bread covered already. But most of the tomato soups looked risky: The one she eventually purchased cost more than $4 for a single serving; others were less than $1.
And gluten hides, too, in products where you might least expect the molecule: lipstick and pharmaceuticals, for example, and candy. “I ate a Twizzler at work one day in the late afternoon,” McCullom says. Helping her son with his homework an hour or two later, she was suddenly overcome with nausea. She didn’t make it to the bathroom.
Today, such episodes are rare for her, and they usually follow trips to a restaurant with friends or work colleagues and clients. “I choose to take the risk,” McCullom says. “I can’t be a hermit.”
There are treatments for other autoimmune diseases, but none that cure and few that are broadly effective. McCullom’s cousin Hayden, a writer and marketing consultant, takes Rituxan (rituximab), an anti-cancer drug that targets immune system cells involved in the inflammation process and can slow or prevent joint damage. People with multiple sclerosis can take a variety of therapeutics that slow disease progression in some but not others, and that can carry serious side effects. Diabetes is managed, not cured, with insulin, healthy diets, careful blood sugar monitoring, and exercise.
In The Pipeline
ALV003, a mixture of two enzymes designed to break down gluten. During a small phase 2 trial, researchers gave a daily gluten challenge (two grams of gluten) to 41 people with celiac disease; 20 were given a placebo drug, and 21 were given ALV003 daily. Researchers took small intestine biopsies from the patients after six weeks, to evaluate damage. Patients on the placebo had measurable injury to cells lining part of the small intestine; those given the drug had none. Alvine Pharmaceuticals, Inc., in San Carlos, California, makes ALV003, which is taken orally as a liquid.
Larazotide acetate, a drug that works to effectively seal up cellular leaks that let gluten escape the gut, triggering immune system attack. In a phase 2 trial, patients given the drug reported significant improvement: Fewer gastrointestinal issues and headaches, and less fatigue, diarrhea, and stomach pain. Alba Therapeutics in Baltimore makes larazotide acetate, which is designed to be given as a capsule.
Nexvax2, a drug designed to build tolerance to gluten. As with allergy shots or desensitization, the idea of Nexvax2 is to induce immune tolerance to gluten, thereby preventing damage to the intestine. The drug is in early clinical trials to evaluate safety and tolerability.
BL-7010, in development by the Israeli company BiolineRX. BL-7010 targets a part of the gluten molecule itself, sequestering the trigger for the disease and preventing it from leaving the small intestine. Tested successfully in animals, this drug is in early clinical testing in humans.
At least half a dozen other pharmaceutical companies around the world are developing drugs that target a biological pathway involved in celiac disease. These companies include Calypso Biotech; Celimmune, LLC; Cour Pharmaceuticals; Dr. Falk Pharma; Biomedal, and more.
For more information, visit beyondceliac.org.
One of the challenges to understanding and treating autoimmune diseases is the fact that they trigger such varied symptoms in different people. A decade or two ago, many of these diseases probably weren’t diagnosed reliably, and even today, diagnosis can take years: Celiac may present with symptoms of Crohn’s disease or lactose intolerance — even depression. Lupus can look like a rash or a kidney problem.
Several tests, including the tissue transglutaminase antibodies (tTG-IgA) screening blood test, can help confirm celiac disease or lead to an endoscopic biopsy, a procedure that allows your doctor to get a clear picture of what’s going on inside your small intestine.
Increasingly powerful genetic tools are helping to sort through the complexities, but studies often raise more questions than they answer. About 95 percent of people with celiac disease have the HLA-DQ2 allele (an allele is a variant of a gene), for example, and the others have HLA-DQ8. However, many more people have those alleles and never exhibit symptoms, are never diagnosed with the disorder, or don’t get sick until adulthood. So while HLA typing, which is done through a blood test, cheek swab, or saliva sample, can be used to rule out celiac (the disease just doesn’t occur in people without one of these two HLA types), the presence of these alleles does not guarantee that a person will develop celiac.
Mass General’s Fasano has funding from the National Institutes of Health to try to sort out some of the reasons that people develop celiac, including the roles of antibiotic history and bacterial colonies in our guts (see “We are What We Eat,” on this page).
“For all these autoimmune diseases, we suspect you have to be genetically predisposed, and you have to be exposed to something in the environment — a trigger,” Fasano says. “Celiac disease is the only autoimmune disease for which we know the trigger — gluten. That makes it not only fascinating but unique. ”
In Fasano’s view of autoimmune diseases, genetic predisposition and an environmental trigger are not enough; you also need a biological connection that links the two. In celiac disease, he points to the gaps that form between the normally tightly packed cells lining a person’s small intestine. Those gaps let gluten (the trigger) through, where it stimulates an intense immune response (associated with genetic predisposition).
If you close the gaps, could you stop the disease? That’s one approach that pharmaceutical researchers are testing today, and Fasano finds reason to hope that the treatment might help in autoimmune disease beyond celiac (see “In the Pipeline,” page 63).
Beyond the trigger, the broader environment clearly matters as well, Fasano says. “You are born with the potential to develop this disease. If you do or do not may depend on your lifestyle or the environment around you.”
Celiac and other autoimmune diseases are rising in prevalence, and although some of that increase is due to better diagnosis of the diseases, some is likely also tied to our changing environment, which includes what we eat, Fasano says.
“In celiac, we see this increase mostly in developed countries,” Fasano says. Genetics probably cannot explain that.
Hakonarson agrees. “The most alarming disease where we are seeing the biggest changes is IBD [inflammatory bowel disease], which includes Crohn’s disease and ulcerative colitis. Those are growing very rapidly in very early onset, in children less than 5 years of age. There is clearly an environmental component that brings it on. Maybe the microbiome, altered in our gut by the food we eat.”
So, to understand better the connections among celiac and other autoimmune diseases, it’s necessary to dip into the field of immunology. Raychaudhuri breaks it down for a non-expert by starting with human leukocyte antigens (HLAs), which are “tremendously diverse” components of our immune systems.
These proteins are designed to help cells sense and alert other cells (like so-called killer T cells) to the presence of enemies, “foreign” proteins that might cause disease. It makes sense for a population of people to have very diverse HLAs, he says. They help us fight off diverse and constantly evolving pathogens, such as disease-causing bacteria and parasites, and they can help a population survive an epidemic.
“Imagine a superbug comes through and could wipe us all out,” Raychaudhuri says. “With HLA diversity, you have survivors.”
And you can also have victims. Since the 1970s, researchers have recognized that people with certain types of HLA alleles carry a higher risk of autoimmune diseases.
In recent years, researchers have found specific alleles associated tightly with specific autoimmune diseases. In the case of celiac, for example, remember those HLA-DQ2 and DQ8 alleles.
With today’s sophisticated tools for genetic research, Raychaudhuri and other scientists can go much deeper than HLA alleles. Some conduct “genome-wide association studies,” for example, searching HLA alleles and much more of the genome to find genetic linkages that might help explain who is vulnerable to celiac and why they are also at higher risk of other immune dysfunction. That would potentially be helpful in broadening treatment options. Could drugs used against rheumatoid arthritis help with celiac, too? Or could a gluten-free diet help ease the effects of other autoimmune diseases?
The research is uncovering many connections:
1. Alleles that explain about half of celiac disease heritability
2. Single nucleotide polymorphisms or SNPs (variability in the genome) that help explain the shared incidence of celiac disease and rheumatoid arthritis
3. Strong genetic overlap between the pediatric autoimmune diseases Crohn’s and ulcerative colitis; and similarly strong overlap between common variable immunodeficiency disorder and juvenile idiopathic arthritis
But many questions remain unanswered. Despite scrutiny, it’s still not clear if gluten or the “leaky” small intestinal cells of celiac disease play similar roles in other autoimmune diseases. Research is turning up some trends, though: Some people with rheumatoid arthritis, for example, do report improved symptoms when they shun gluten.
It works for Hayden, 41. “If I ate two pieces of pizza, I wouldn’t be able to walk tomorrow,” she says. So she doesn’t.
We Are What We Eat
They affect our risk of colon cancer. Our propensity for obesity. The ways we age.
The bacteria and other microbes living in our gastrointestinal system appear related to our health and well-being in many ways, according to a growing body of research. So, the idea that the “microbiota” of our guts may be connected to our broader immune systems, including the development of autoimmune diseases such as celiac, might come as little surprise.
In the lungs, outside air meets and connects with our internal tissues, bringing in oxygen, dust motes, and, sometimes, airborne bacteria. But it’s the gut that serves as the locale for the biggest interchange betweenthe outside world and our inner selves, says Alessio Fasano, director of the Center for Celiac Research at Massachusetts General Hospital.
In the small intestine, tiny villi, finger-like projections that are a half to one millimeter long, increase the surface area through which our bodies can absorb nutrients — and much more — from the food we eat.
“The GI [gastrointestinal] tract is our largest interface with the environment by far,” Fasano says. “You have about 3,000 square feet of villi. That’s the size of a tennis court.”
In the diverse communities of bacteria living on that convoluted tennis court, Fasano and his colleagues hope to find clues to a conundrum: About one-third of the general population has genes associated with celiac disease, but many of those people will never develop symptoms. Learning why that is — including the role of microbes in our guts — could lead to earlier intervention in the disease or new treatments.
In a pilot study a few years ago, Fasano and his colleagues followed about 45 infants from birth to 24 months. Some were at genetic risk for celiac disease, others weren’t, and the scientists found significant differences in the makeup of the bacterial communities colonizing their GI tracts. With funding from the National Institutes of Health, the scientists are now beginning a much larger, longer trial.
“We will follow from birth to five years about 500 people at risk for celiac disease,” Fasano says. “And we will see which one goes the wrong direction and which one continues to stay healthy. The intent is to learn and then predict microbiota associated with celiac disease progression … and intervene.”
He and his colleagues plan to examine genetic factors as well as environmental ones, including: the method of delivery (cesarean section versus vaginal, which confers very different communities of microorganisms on infants), use of antibiotics, breast and formula feeding, and timing of food introduction.
“Environment matters. For example, if you are born by C-section, you have a five-fold higher chance of developing celiac disease than if you were born by vaginal delivery,” Fasano says.
He and his colleagues in the U.S. (Boston) and Italy (Rome and Ancona) are now enrolling infants who have a first-degree relative with celiac disease in the Celiac Disease Genomic Environmental Microbiome and Metabolomic Study.
To the researchers involved in dissecting the genetic, environmental, and immunological dances of autoimmune disease, the hope for improved treatments lies in the details. At nearly every step in celiac disease — from the way our bodies break down gluten to the way it leaks into the blood and triggers a cascade of immune response — there are opportunities for intervention.
“One of the real promises of genetics in autoimmune disease and elsewhere is that as we find genes mediating risk,” Raychaudhuri says, “targeting those genes will help us come up with effective therapies.”
It’s happened many times before, he and others say. For example, this kind of progress is occurring in childhood cancer, according to Hakonarson. Researchers identified rare genetic variants that predisposed kids to neuroblastoma. Similar or identical mutations are also present in other forms of cancer, like non-small cell lung cancer. And suddenly, a drug used for one form of cancer can be used to treat others. “That’s the beauty of these studies finding shared variants,” Hakonarson says.
“My prediction for five years from today,” says Fasano, “is that through models like celiac disease, we will be able to tackle the interim mechanisms that bridge the trigger and the genetics in autoimmune disease. If we understand how that happens, there is a chance we can arrest disease progress.”
We might also improve diagnosis, Hakonarson says. The relatively blurry lines between some autoimmune diseases may simply become irrelevant. In five years, he predicts, “we will be diagnosing and treating you based on the genetic variants you have. We may not even call it celiac disease or IBD anymore.”