WHY THE CURSE OF CELIAC DISEASE IS A BLESSING TOO:

WHY THE CURSE OF CELIAC DISEASE IS A BLESSING TOO:

We have a remedy (stop eating gluten) // We know the cause (a faulty gene,
faulty antibodies) // And now the disease is providing a window into how
autoimmunity occurs.
Celiac Disease: Eating Away at You
By Cathryn Delude // Photo Illustrations by Hugh Kretschmer // Winter 2010

In medical school in Naples, in the late 1970s, Alessio Fasano learned a thing
or two about human intestines. More than twenty feet long, with an interior
surface a bit bigger than a tennis court (about 3,000 square feet if you include
the shaggy, finger-shaped villi that grab nutrients from digested food and
drink), the intestines are lined with epithelial cells that were thought to be
sealed permanently by groutlike junctions. Tiny nutrients are absorbed through
the cells, but the "grout" was credited with creating an impermeable barrier
preventing larger, harmful material from entering the gut. Then, in the late
1980s, when Fasano was working on a cholera vaccine, he began to wonder how
large molecules, such as the cholera toxin, got past the intestinal wall and
into the bloodstream, and learned that the space between cells was not sealed
after all. His suspicions were confirmed in 1988, when a Japanese research group
discovered that the "tight" junctions are actually perfectly fitted doors that
open and close under special circumstances.
Fasano, who now directs the Mucosal Biology Research Center and the Center for
Celiac Research at the University of Maryland School of Medicine, hypothesized
that the cholera bacterium, Vibrio cholerae, had evolved a key to that door, and
he proved the notion in 1991. Using Latin for tight junction, the key was named
"zonula occludens toxin," or Zot. "Vibrio uses Zot to make the intestine
permeable," he says, "and intestinal permeability allows access to the things
that can harm us."
In 2000, Fasano discovered that the body produces its own key, a molecule he
called zonulin. Scientists are still trying to determine zonulin's normal
function, but they do know that bacteria and inflammatory molecules can
stimulate its production to make the intestines "leak." It turns out that
certain undigested portions of gluten, the storage protein of wheat, barley and
rye, may have the same effect.
This accumulating understanding of how, when and under what circumstances the
intestines can be breached ultimately led Fasano to an innovative and somewhat
controversial theory about autoimmunity—in which the body mistakenly turns on
itself—and about one of its clearest examples, celiac disease, in which the
autoimmune response is triggered by gluten. He had become interested in celiac
disease after searching the scientific literature for references to intestinal
permeability and finding that it occurs in many autoimmune diseases—from type 1
diabetes and multiple sclerosis to rheumatoid arthritis and inflammatory bowel
diseases, including celiac. That people with autoimmune diseases also have
elevated levels of zonulin in their gut could partially explain this leakiness,
Fasano reasoned.
In autoimmunity the human immune system, rather than protecting the body from
dangerous microbes, goes on the attack against the body's own cells. Part of the
cause is genetic, but to develop an autoimmune disorder, people also need to be
exposed to an environmental trigger, such as bacteria or food. Somehow the
interaction of genes and trigger generates autoantibodies, which recruit the
immune system to destroy a particular type of cell—the insulin-producing
pancreatic beta cells in diabetes, for example, or neurons in multiple sclerosis
or intestinal epithelial cells in celiac disease.
For an autoimmune disease to take hold requires all three legs of the triad:
predisposing genes, the appropriate environmental trigger and the autoantibodies
that subvert the immune system's normal, protective function. For most
autoimmune diseases, the triggers and even the genes remain unknown, but in the
case of celiac disease, all three legs of the triad have been identified.
Scientists have found some of the genes and the autoantibodies, and they know
that gluten in the diet triggers symptoms. Celiac disease is also the only
autoimmune disorder for which there's a cure—removing the trigger. Stop eating
gluten, and the autoimmune response will end, returning the intestines to
normal.
It would be ideal, of course, if all autoimmune disorders were as easily curable
as celiac disease, which afflicts an estimated one in 133 people. But while
researchers attempt to find other genes, triggers and autoantibodies associated
with other diseases, Fasano wonders whether there might be a simpler approach.
What if some of these diseases also depend on intestinal permeability for
getting the environmental trigger into the body? If that was the case, a drug
that could prevent the tight junction door from opening might reverse the
progress of these diseases, even if their triggers remain unknown.
"It's a nice hypothesis," says Detlef Schuppan, a gastroenterologist at Beth
Israel Deaconess Medical Center in Boston. Yet despite encouraging results from
trials of a drug that attempts to close off the tight junctions in the
intestines, the hypothesis remains unproved. Still, that idea, along with other
strategies for removing one or another leg of the triad, is being put to the
test. "With celiac disease," says Joseph A. Murray, a gastroenterology
researcher at the Mayo Clinic in Rochester, Minn., "we now have a window into
how autoimmunity occurs"—and a way to test new therapeutic strategies.
The human intestine, the body's largest interface with a world full of hazardous
microorganisms and toxins, is the most common avenue for infectious organisms
invading the body. To counter such attacks, the lamina propria, a moist mucosal
layer beneath the epithelial lining, teems with immune cells. But the intestine
also hosts beneficial micro¬organisms that aid digestion, as well as essential
particles from our diet. So the immune system needs an elaborate mechanism to
distinguish between what is benign and what is dangerous and should be attacked.
"The immune system in the gut is meant to be tolerant," says Murray. "It's
mostly welcoming, though in a cautious way. But if it encounters a danger
signal, it puts up its guard, and everything that comes in at that time is
considered suspect."
Macrophages and dendritic cells survey the intestinal periphery, asking at each
encounter: "Are you part of me, or are you not? And if you're not, are you
friend or foe?" They find the answers posted on a cell's surface, attached to
histo¬compatibility leukocyte antigen (HLA) molecules. These molecules display
to the rest of the immune system bits of a cell's proteins that serve as name
tags, or antigens, that can generate an "anti" response, such as inflammation or
antibody production.
The immune system learns to recognize the antigens from the body's own cells as
"self" and also to tolerate the many "nonself" tags on beneficial intestinal
microbes and food particles. But in some people, the immune cells misread the
antigens attached to HLA, mistaking, say, pollen for a cold virus or gluten for
a toxin. Then they send out a faulty danger signal that makes their body's own
cells look suspicious, summoning other immune cells to attack the body's tissue.
That loss of tolerance happens in celiac disease, but only in people whose genes
produce a specific subtype of HLA molecule. Some 85% to 95% of celiac patients
have HLA DQ2; the rest have HLA DQ8. But even among those who have one or both
subtypes, only some get sick—and only if they eat gluten.
Suppose someone eats a piece of toast. Digestive enzymes home in on particular
sequences along the gluten protein's amino acid chain and cleave them so that
the gut can absorb the component amino acids and send those nutrients to the
bloodstream. But gluten is such a relative newcomer to the digestive
system—humans began cultivating grain just 10,000 years ago—that the body hasn't
evolved enzymes that can break apart an unusual cluster of glutamine and proline
amino acids. Some of the undigested protein fragments, or peptides, are
excreted, but others may linger in the small intestine. As Fasano showed, gluten
peptides stimulate the release of zonulin, the protein that opens the doors in
the intestine's tight junctions and allows gluten to squeeze through into the
immune-cell-rich mucosal underlayer. And some gluten is absorbed directly into
the epithelial cells, which release the peptides into the same underlayer, where
the immune cells await.
No one knows exactly what happens during the first encounter between gluten
peptides and the immune system, but scientists think that in most people,
macrophages, B cells and dendritic cells gobble up the intruders, completing
what the digestive enzymes couldn't do on their own. In someone with celiac
disease, however, inflammation and possibly gluten itself cause intestinal cells
to secrete an enzyme called tissue transglutaminase 2 (TTG). In 1997, Schuppan
and his team discovered that the combination of TTG and gluten peptides induces
certain B cells to produce antibodies to the gluten peptides and TTG—the
autoantibody in celiac's immune triad. Finding autoantibodies to TTG in the
blood has become a reliable way to diagnose active celiac disease.
The TTG enzyme, it turns out, is crucial to celiac's pathology because it reacts
with gluten, transforming it into a "super antigen" that has a magnified effect
on other immune cells. Even that result wouldn't ordinarily be a problem, says
Murray: "Our gut is used to seeing all kinds of strange things." But this
excessively immunogenic form of gluten fits perfectly into the two forms of HLA
molecules (DQ2 and DQ8) that predispose people to celiac disease. It doesn't fit
any other variety of HLA.
Only when the gluten antigen is displayed on these two HLA molecules can it
activate T cells (Th1 and Th2), which then alert other white blood cells
belonging to something called the adaptive immune system, which responds to what
it considers specific threats. "This sets off a cyclone of activities that feeds
on itself and creates a lot of damage," says Murray.
Swirling within that maelstrom are cytokines that induce inflammation (which
makes the lining of the gut even more porous), destroy intestinal cells, remodel
intestinal connective tissue and, in advanced stages, decapitate the intestinal
villi. Without the villi, even someone who eats a healthy diet won't be able to
absorb nutrients effectively and could suffer nutrient deficiencies and
malnourishment.
This intestinal turmoil can cause symptoms beyond celiac's typical diarrhea,
bloating and gas, including anemia, bone loss, neurological problems,
inflammatory arthritis, hepatitis and even intestinal malignancies and
lymphomas. With the ability to screen people for the disease and a growing
understanding of celiac disease's range of symptoms has come the realization
that it is not nearly as rare in the United States as researchers once believed.
Approximately 1% of the U.S. population is now thought to have celiac disease,
about the same prevalence as in Europe and elsewhere. It is about twice as
common as rheumatoid arthritis and much more prevalent than multiple sclerosis.
Celiac patients also have an unusually high incidence of other autoimmune
diseases, probably because those disorders involve some of the same genes.
Still, while celiac disease can't happen without HLA DQ2 or DQ8, just 3% to 5%
of people who carry the genes for those molecules go on to develop the disease.
The amazing thing about celiac disease is that except in rare refractory cases,
without gluten, TTG no longer oozes out of intestinal cells, the autoantibody
disappears from the bloodstream, the epithelial cells close up their tight
junctions and rebuild their nutrient-absorbing villi, and symptoms fade away.
This has prompted Fasano to suggest that "if we could stop zonulin from opening
the door to the intestine, maybe we could stop celiac's immune response even
when gluten is present."
Alba Therapeutics, a company Fasano co-founded in 2004 to develop a zonulin
inhibitor, is now testing such a drug, called larazotide, in a Phase II clinical
trial. (Fasano has left the company but still serves on its scientific advisory
board and owns stock options.) "The implication is that if it works in celiac
disease, maybe it would work in other autoimmune diseases that also have
intestinal permeability," he says.
In fact, Fasano first used larazotide in preclinical studies of type 1 diabetes
in rats. His team reported that the intestines of rats that would later develop
diabetes started to leak within five to six weeks of weaning. In addition, the
rats had increased levels of zonulin. Then, two weeks before the onset of
diabetes, the animals developed antibodies to islets that contain
insulin-producing beta cells, whose loss causes the disease. But giving rats the
zonulin inhibitor limited the production of those antibodies, thereby reducing
the incidence of diabetes by 70%.
Alba Therapeutics subsequently received approval to test larazotide in people
with celiac disease, and the company reported preliminary results of its human
trial at a conference in April. Patients taking the inhibitor who ate small
amounts of gluten had fewer celiac symptoms and lower levels of auto¬antibodies
than those on a placebo who also got gluten. "This is the first time a drug has
blocked the autoimmune process by blocking a specific mechanism," Fasano says.
(Past efforts had always involved suppressing the body's overall immune response
or using a general anti-inflammatory.)
But Schuppan of Boston's Beth Israel Deaconess Medical Center notes that
patients on the zonulin inhibitor still showed some intestinal permeability,
based on an established measure of sugar absorption. What's more, he adds, "just
closing off the tight junctions is not a magic bullet," because some gluten is
also absorbed into the epithelial cells and thence into the lamina propria.
Still, even though the trial didn't really prove its primary objective—that
larazotide closes up the intestines' tight junctions—the drug did seem to
protect patients from the ill effects of gluten. "So it looks like the drug
works, but maybe in a different way than hypothesized," says Peter Green,
director of the Celiac Disease Center at Columbia University College of
Physicians and Surgeons in New York City.
Another possibility is that larazotide really does affect the tight junctions
but that the clinical test used to measure intestinal permeability, which looks
at sugar absorption, is too crude to detect the drug's impact, suggests Daniel
Leffler, director of clinical research for the Celiac Center at Beth Israel
Deaconess Medical Center, who was an investigator in the larazotide trial. "We
all believe that various things can affect leakiness," he says, "but a lot of us
don't believe a sugar-based test is specific enough to measure that effect."
Schuppan suspects that the ideal treatment would involve vaccines and related
immunotherapies that work the way allergy shots do for hay fever victims: by
introducing a series of tiny doses of an antigen that teach the immune system to
tolerate that antigen. "To do that, you need to know exactly which parts of
gluten are toxic," says Robert Anderson, an investigator at the Walter and Eliza
Hall Institute of Medical Research in Parkville, Australia. "Then you can target
the parts of the immune reaction that cause the disease."
Anderson thinks he has identified those parts—three specific peptides—and the
vaccine he has developed, now in early clinical trials, focuses on the role of
the DQ2 version of the HLA molecule. When these immunogenic gluten peptides
enter the body by subcutaneous injection rather than through the gut as they
normally do, the immune system could learn to tolerate them. In theory the
antigen-presenting cells will still display the peptides on the HLA DQ2
molecule, but instead of causing activation, the T cells will become
"regulatory" and not trigger an inflammatory cascade. Anderson believes the same
principle should apply to other autoimmune diseases in which antigens presented
on HLA molecules also activate a T cell response. "Diseases like type 1
diabetes, multiple sclerosis, rheumatoid arthritis and autoimmune thyroid
disease use the same T cells, but the T cells choose to react differently, so
they affect different tissues," he says. "Celiac disease has the advantage of
being the first human autoimmune disease for which the critical
T-cell-activating peptides have been discovered."
The beauty of inducing tolerance is that it targets only the parts of the immune
system that cause the disease, rather than affecting the whole system the way
many current immunotherapy drugs do, which leave people vulnerable to infections
and other serious complications. Similarly, larazotide, despite uncertainty
about how it works, also has a good safety record.
That's what's so exciting about knowing so much about the pathology of a
disease, as researchers do with celiac disease. As researchers learn how to
prevent or treat autoimmunity in celiac disease, they may be able to apply those
lessons and to devise better therapies for less well understood autoimmune
diseases that are much less easily controlled.

Now for an absolute awesome quote!

"I think the one "value-added" idea that we have here is that oxalate may be
something that keeps the autoimmune reaction going by provoking continued
inflammation in tissues that have been injured by infection or something else.
That is why I suspect LOD [low oxalate diet] may dial down the autoimmune process when someone
still has a leaky gut.

The immune system is designed to calm down after enough of the antigen has
disappeared from sight. Cell necrosis (when cells explode) can get the whole
thing going again. Oxalate can induce that sort of cell death and seems to keep
things from healing that otherwise would."

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and a testimonial in someone probably suffering from autism

"Susan, I think this is what has happened with Daniel. He was on a strict GF
diet and still had issues. Once we got LOD in the works for him.Â
Everything calmed down. Today he's doing GREAT!"

Interesting read Jdp, thank you. But how important would you say going oxalate free is compared to what else we are doing, controlling excess insuline, dht, aromatase activity, calcium, follicle inflammation etc.

Not sure about aromatase but low oxalate diet covers all that you mentioned and others.

jdp710 - Very interesting stuff.

is the only remedy for celiac disease restriction of diet?

Yes, although some things such as enzymes help.

A good link with info of how to make practice of low oxalate diet.

http://lowoxalate.info/index.html