Surprises from celiac disease

http://www.komar.org/faq/celiac_disease/Fasano-Scientific-American-8.2009-1.pdf?hc_location=ufi

Key conceptS

  • Celiac disease (CD) is
    an autoimmune disorder triggered by ingestion of gluten, a major protein in wheat, or of related proteins in other grains.
  • Research into the root causes indicates that
    the disorder develops when a person exposed to gluten also has a genetic susceptibility to CD and an unusually permeable intestinal wall.
  • Surprisingly, essentially the same trio—an environ- mental trigger, a genetic susceptibility and a “leaky gut”—seemstounderlie other autoimmune disor- ders as well. This finding raises the possibility that new treatments for CD may also ameliorate
    other conditions.

—The Editors

My vote for the most important scientif- ic revolution of all time would trace back 10,000 years ago to the Middle

East, when people first noticed that new plants arise from seeds falling to the ground from oth- er plants—a realization that led to the birth of agriculture. Before that observation, the human race had based its diet on fruits, nuts, tubers and occasional meats. People had to move to where their food happened to be, putting them at the mercy of events and making long-term settle- ments impossible.

Once humans uncovered the secret of seeds, they quickly learned to domesticate crops, ulti- mately crossbreeding different grass plants to create such staple grains as wheat, rye and bar- ley, which were nutritious, versatile, storable, and valuable for trade. For the first time, people were able to abandon the nomadic life and build cities. It is no coincidence that the first agricultural ar- eas also became “cradles of civilization.”

This advancement, however, came at a dear price: the emergence of an illness now known as celiac disease (CD), which is triggered by ingest- ing a protein in wheat called gluten or eating similar proteins in rye and barley. Gluten and its relatives had previously been absent from the hu- man diet. But once grains began fueling the

growth of stable communities, the proteins un- doubtedly began killing people (often children) whose bodies reacted abnormally to them. Eat- ing such proteins repeatedly would have eventu- ally rendered sensitive individuals unable to properly absorb nutrients from food. Victims would also have come to suffer from recurrent abdominal pain and diarrhea and to display the emaciated bodies and swollen bellies of starving people. Impaired nutrition and a spectrum of other complications would have made their lives relatively short and miserable.

If these deaths were noticed at the time, the cause would have been a mystery. Over the past 20 years, however, scientists have pieced togeth- er a detailed understanding of CD. They now know that it is an autoimmune disorder, in which the immune system attacks the body’s own tissues. And they know that the disease arises not only from exposure to gluten and its ilk but from a combination of factors, including predisposing genes and abnormalities in the structure of the small intestine.

What is more, CD provides an illuminating example of the way such a triad—an environ- mental trigger, susceptibility genes and a gut ab- normality—may play a role in many autoim- mune disorders. Research into CD has thus suggested new types of treatment not only for the disease itself but also for various other autoim- mune conditions, such as type 1 diabetes, mul- tiple sclerosis and rheumatoid arthritis.

Early Insights

After the advent of agriculture, thousands of years passed before instances of seemingly well- fed but undernourished children were docu- mented. CD acquired a name in the first century A.D., when Aretaeus of Cappadocia, a Greek physician, reported the first scientific descrip- tion, calling it koiliakos, after the Greek word for “abdomen,” koelia. British physician Samuel Gee is credited as the modern father of CD. In a 1887 lecture he described it as “a kind of chron- ic indigestion which is met with in persons of all ages, yet is especially apt to affect children between one and five years old.” He even cor- rectly surmised that “errors in diet may perhaps

be a cause.” As clever as Gee obviously was, the true nature of the disease escaped even him, as was clear from his dietary prescription: he sug- gested feeding these children thinly sliced bread, toasted on both sides.

Identification of gluten as the trigger occurred after World War II, when Dutch pediatrician Willem-Karel Dicke noticed that a war-related shortage of bread in the Netherlands led to a sig- nificant drop in the death rate among children affected by CD—from greater than 35 percent to essentially zero. He also reported that once wheat was again available after the conflict, the mortality rate soared to previous levels. Follow- ing up on Dicke’s observation, other scientists looked at the different components of wheat, discovering that the major protein in that grain, gluten, was the culprit.

Turning to the biological effects of gluten, in- vestigators learned that repeated exposure in

Foods containing wheat, rye or barley trigger an autoimmune reaction (against the body’s own tissues) in people afflicted with celiac disease. the response harms the intestinal lining and impairs the body’s absorption of nutrients. chronic exposure to those foods can also lead to cancer and other ill effects in such individuals.

CD patients causes the villi, fingerlike struc- tures in the small intestine, to become chroni- cally inflamed and damaged, so that they are unable to carry out their normal function of breaking food down and shunting nutrients across the intestinal wall to the bloodstream (for delivery throughout the body). Fortunately, if the disease is diagnosed early enough and pa- tients stay on a gluten-free diet, the architecture of the small intestine almost always returns to normal, or close to it, and gastrointestinal symptoms disappear.

In a susceptible person, gluten causes this in- flammation and intestinal damage by eliciting activity by various cells of the immune system. These cells in turn harm healthy tissue in an attempt to destroy what they perceive to be an infectious agent.

A Diagnostic Discovery

Fuller details of the many mechanisms through which gluten affects immune activity are still being studied, but one insight in particular has already proved useful in the clinic: a hallmark of the aberrant immune response to gluten is production of antibody molecules targeted to an enzyme called tissue transglutaminase. This enzyme leaks out of damaged cells in inflamed areas of the small intestine and attempts to help heal the surrounding tissue.

Discovery that these antibodies are so com- mon in CD added a new tool for diagnosing the disorder and also allowed my team and other re- searchers to assess the incidence of the disease in a new way—by screening people for the presence of this antibody in their blood. Before then, doc- tors had only nonspecific tests, and thus the most reliable way to diagnose the disease was to re- view the patient’s symptoms, confirm the intes- tinal inflammation by taking a biopsy of the gut, and assess whether a gluten-free diet relieved symptoms. (Screening for antibodies against gluten is not decisive, because they can also oc- cur in people who do not have CD.)

For years CD was considered a rare disease outside of Europe. In North America, for exam- ple, classic symptoms were recognized in fewer than one in 10,000 people. In 2003 we pub- lished the results of our study—the largest hunt for people with CD ever conducted in North America, involving more than 13,000 people. Astoundingly, we found that one in 133 appar- ently healthy subjects was affected, meaning the disease was nearly 100 times more common than had been thought. Workers has confirmed similar levels in many coun- tries, with no continent spared.

How did 99 percent of cases escape detection for so long? The classical outward signs—per- sistent indigestion and chronic diarrhea— ap- pear only when large and crucial sections of the intestine are damaged. If a small segment of the intestine is dysfunctional or if inflamma- tion is fairly mild, symptoms may be less dra- matic or atypical.

It is also now clear that CD often manifests in a previously unappreciated spectrum of symptoms driven by local disruptions of nutri- ent absorption from the intestine. Disruption of iron absorption, for example, can cause anemia, and poor folate uptake can lead to a variety of neurological problems. By robbing the body of particular nutrients, CD can thus produce such symptoms as osteoporosis, joint pain, chronic fatigue, short stature, skin lesions, epilepsy, de- mentia, schizophrenia and seizure.

Because CD often presents in an atypical fashion, many cases still go undiagnosed. This new ability to recognize the disease in all its forms at an early stage allows gluten to be re- moved from the diet before more serious com- plications develop.

From Gluten to Immune Dysfunction

Celiac disease provides an enormously valuable model for understanding autoimmune disorders because it is the only example where the addi- tion or removal of a simple environmental com- ponent, gluten, can turn the disease process on and off. (Although environmental factors are suspected of playing a role in other autoimmune diseases, none have been positively identified.)

To see how gluten can have a devastating ef- fect in some people, consider how the body re- sponds to it in most of the population. In those without CD, the body does not react. The nor- mal immune system jumps into action only when it detects significant amounts of foreign proteins in the body, reacting aggressively be- cause the foreigners may signal the arrival of disease-causing microorganisms, such as bacte- ria or viruses.

A major way we encounter foreign proteins

and other substances is through eating, and im- mune soldiers sit under the epithelial cells that line the intestine (enterocytes), ready to pounce and call in reinforcements. One reason our im- mune system typically is not incited by this thrice-daily protein invasion is that before our defenses encounter anything that might trouble them, our gastrointestinal system usually breaks down most ingested proteins into standard ami- no acids—the building blocks from which all proteins are constructed.

Gluten, however, has a peculiar structure: it is unusually rich in the amino acids glutamine and proline. This property renders part of the molecule impervious to our protein-chopping machinery, leaving small protein fragments, or peptides, intact. Even so, in healthy people, most of these peptides are kept within the gas- trointestinal tract and are simply excreted be- fore the immune system even notices them. And any gluten that sneaks across the gastrointesti- nal lining is usually too minimal to excite a sig- nificant response from a normally functioning immune system.

CD patients, on the other hand, have inher- ited a mix of genes that contribute to a height- ened immune sensitivity to gluten. For example, certain gene variants encoding proteins known as histocompatibility leukocyte antigens (HLAs) play a role. Ninety-five percent of people with CD possess either the DQ2 or the DQ8 HLA gene, whereas just 30 to 40 percent of the gen- eral population have one of those versions. This finding and others suggest that HLA DQ2 and DQ8 are not the sole cause of immune hyperac- tivity but that the disease, nonetheless, is nearly impossible to establish without one of them. The reason these HLAs are key becomes obvi- ous from studies of the function of the proteins they specify.

The HLA DQ2 and DQ8 proteins are made by antigen-presenting cells. These immune sen- tinels gobble up foreign organisms and proteins, chop them, fit selected protein fragments into grooves on HLA molecules, and display the re- sulting HLA-protein complexes on the cell sur- face for perusal by immune system cells called helper T lymphocytes. T cells that can recognize and bind to the displayed complexes then call in reinforcements.

In patients with CD, tissue transglutaminase released by intestinal epithelial cells attaches to undigested gluten and modifies the peptides in a way that enables them to bind extremely strongly to DQ2 and DQ8 proteins. In consequence, when antigen-presenting cells under in- testinal epithelial cells take up the complexes of tissue transglutaminase and gluten, the cells join the gluten to the HLAs and dispatch them to the cell surface, where they activate T cells, inducing the T cells to release cytokines and chemokines (chemicals that stimulate further immune activity). These chemicals and en- hancement of immune defenses would be valu- able in the face of a microbial attack, but in this

instance they do no good and harm the intesti- nal cells responsible for absorbing nutrients.

CD patients also tend to have other genetic predispositions, such as a propensity for over- producing the immune stimulant IL-15 and for harboring hyperactive immune cells that prime the immune system to attack the gut in response to gluten.

Guilt by Association

What role might antibodies to tissue transglu- taminase play in this pathological response to gluten? The answer is still incomplete, but scien- tists have some idea of what could happen. When intestinal epithelial cells release tissue transglu- taminase, B cells of the immune system ingest it—alone or complexed to gluten. They then release antibodies targeted to the enzyme. If the antibodies home to tissue transglutaminase sit- ting on or near intestinal epithelial cells, the anti- bodies might damage the cells directly or elicit other destructive processes. But no one yet knows whether they, in fact, cause such harm.

In the past nine years my colleagues and I have learned that unusual intestinal permeabil- ity also appears to participate in CD and other autoimmune diseases. Indeed, a growing body of evidence suggests that virtually the same trio of factors underpins most, and perhaps all, auto- immune diseases: an environmental substance that is presented to the body, a genetically based tendency of the immune system to overreact to the substance and an unusually permeable gut.

Finding the Leak

It is fair to say that the theory that a leaky gut contributes to CD and autoimmunity in general was initially greeted with great skepticism, part- ly because of the way scientists thought of the intestines. When I was a medical student in the 1970s, the small intestine was described as a pipe composed of single layer of cells connected like tiles with an impermeable “grout,” known as tight junctions, between them. The tight junc- tions were thought to keep all but the smallest molecules away from the immune system com- ponents residing in the tissue underlying the tubes. This simple model of the tight junctions as inert, impermeable filler did not inspire legions of researchers to study their structure, and I was among the unenthused.

It was only an unexpected twist of fate, and one of the most disappointing moments of my career, that drew me to study tight junctions. In the late 1980s I was working on a vaccine for

quence, when antigen-presenting cells under in- testinal epithelial cells take up the complexes of tissue transglutaminase and gluten, the cells join the gluten to the HLAs and dispatch them to the cell surface, where they activate T cells, inducing the T cells to release cytokines and chemokines (chemicals that stimulate further immune activity). These chemicals and en- hancement of immune defenses would be valu- able in the face of a microbial attack, but in this

instance they do no good and harm the intesti- nal cells responsible for absorbing nutrients.

CD patients also tend to have other genetic predispositions, such as a propensity for over- producing the immune stimulant IL-15 and for harboring hyperactive immune cells that prime the immune system to attack the gut in response to gluten.

Guilt by Association

What role might antibodies to tissue transglu- taminase play in this pathological response to gluten? The answer is still incomplete, but scien- tists have some idea of what could happen. When intestinal epithelial cells release tissue transglu- taminase, B cells of the immune system ingest it—alone or complexed to gluten. They then release antibodies targeted to the enzyme. If the antibodies home to tissue transglutaminase sit- ting on or near intestinal epithelial cells, the anti- bodies might damage the cells directly or elicit other destructive processes. But no one yet knows whether they, in fact, cause such harm.

In the past nine years my colleagues and I have learned that unusual intestinal permeabil- ity also appears to participate in CD and other autoimmune diseases. Indeed, a growing body of evidence suggests that virtually the same trio of factors underpins most, and perhaps all, auto- immune diseases: an environmental substance that is presented to the body, a genetically based tendency of the immune system to overreact to the substance and an unusually permeable gut.

Finding the Leak

It is fair to say that the theory that a leaky gut contributes to CD and autoimmunity in general was initially greeted with great skepticism, part- ly because of the way scientists thought of the intestines. When I was a medical student in the 1970s, the small intestine was described as a pipe composed of single layer of cells connected like tiles with an impermeable “grout,” known as tight junctions, between them. The tight junc- tions were thought to keep all but the smallest molecules away from the immune system com- ponents residing in the tissue underlying the tubes. This simple model of the tight junctions as inert, impermeable filler did not inspire legions of researchers to study their structure, and I was among the unenthused.

It was only an unexpected twist of fate, and one of the most disappointing moments of my career, that drew me to study tight junctions. In the late 1980s I was working on a vaccine for

expensive than their gluten-containing counter- parts. In addition, sticking perfectly over years to any diet for medical purposes is notoriously challenging. For such reasons, diet therapy is an incomplete solution.

Consequently, several alternative therapeutic strategies have been considered that disrupt at least one element of the three-step process. Al- vine Pharmaceuticals in San Carlos, Calif., has developed oral protein-enzyme therapies that completely break down gluten peptides normally resistant to digestion and has an agent in clinical trials. Other investigators are considering ways to inhibit tissue transglutaminase so that it does not chemically modify undigested gluten frag-

ments into the form where they bind so effective- ly to DQ2 and DQ8 proteins.

No one has yet come up with safe and ethical ways to manipulate the genes that make people susceptible to disease. But researchers are busy developing therapies that might dampen some of the genetically controlled factors that contribute to the immune system’s oversensitivity. For ex- ample, the Australian company Nexpep is work- ing on a vaccine that would expose the immune system to small amounts of strongly immuno- genic forms of gluten, on the theory that repeat- ed small exposures would ultimately induce the immune system to tolerate gluten.

With an eye toward blocking the intestinal

barrier defect, I co-founded Alba Therapeutics to explore the value of a zonulin inhibitor named Larazotide. (I am now a scientific adviser for Alba and hold stock options, but I no longer participate in making decisions for the compa- ny.) Larazotide has now been tested in two hu- man trials examining safety, tolerability and signs of efficacy in celiac patients who ate glu- ten. These were gold-standard trials—random- ized, placebo-controlled tests in which neither the drug deliverers nor the patients know who receives treatment and who receives a sham, un- til the trial is over.

Together the tests showed no excess of side ef- fects in patients given Larazotide rather than the

placebo. More important, the first, smaller study demonstrated that the agent reduced gluten-in- duced intestinal barrier dysfunction, production of inflammatory molecules and gastrointestinal symptoms in celiac patients. And the second, large study, reported at a conference in April, showed that CD patients who received a placebo produced antibodies against tissue transglutami- nase but the treated group did not. As far as I know, this result marks the first time a drug has halted an autoimmune process, interfering spe- cifically with an immune response against a par- ticular molecule made by the body. Other drugs that suppress immune activity act less specifical- ly. Recently Alba received approval from the U.S. Food and Drug Administration to expand stud- ies of Larazotide to other autoimmune disorders, including type 1 diabetes and Crohn’s disease.

These new prospects for therapy do not mean that CD patients can abandon dietary restric- tions anytime soon. Diet could also be used in a new way. Under the leadership of Carlo Catassi, my team at the University of Maryland has be- gun a long-term clinical study to test whether having infants at high risk eat nothing contain- ing gluten until after their first year can delay the onset of CD or, better yet, prevent it entirely. “High risk,” in this case, means infants possess susceptibility genes and their immediate family has a history of the disorder.

We suspect the approach could work because the immune system matures dramatically in the first 12 months of life and because research on susceptible infants has implied that avoiding glu- ten during the first year of life might essentially train that developing immune system to tolerate gluten thereafter, as healthy people do, rather than being overstimulated by it. So far we have enrolled more than 700 potentially genetically susceptible infants in this study, and preliminary findings suggest that delaying gluten exposure re- duces by fourfold the likelihood that CD will de- velop. It will be decades, however, until we know for certain whether this strategy can stop the dis- ease from ever occurring.

Given the apparently shared underpinning of autoimmune disorders in general, researchers who investigate those conditions are eager to learn whether some therapeutic strategies for CD might also ease other autoimmune conditions that currently lack good treatments. And with several different approaches in the pipeline to treat CD, we can begin to hope that this disease, which has followed humanity from the dawn of civilization,is facing its last century on earth. ■

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