Zonulin, haptoglobin 2 and autoimmunity
Kofi
Scientists Pinpoint Critical Molecule To Celiac Disease, Possibly Other
Autoimmune Disorders
ScienceDaily (Sep. 7, 2009) � It was nine years ago that University of
Maryland School of Medicine researchers discovered that a mysterious
human protein called zonulin played a critical role in celiac disease
and other autoimmune disorders, such as multiple sclerosis and diabetes.
Now, scientists have solved the mystery of zonulin's identity, putting a
face to the name, in a sense. Scientists led by Alessio Fasano, M.D.,
have identified zonulin as a molecule in the human body called
haptoglobin 2 precursor.
Pinpointing the precise molecule that makes up the mysterious protein
will enable a more detailed and thorough study of zonulin and its
relationship to a series of inflammatory disorders. The discovery was
reported in a new study by Dr. Fasano, published the week of September
7, 2009 in the online version of the Proceedings of the National Academy
of Sciences. Dr. Fasano is a professor of pediatrics, medicine and
physiology and director of the Mucosal Biology Research Center and the
Center for Celiac Research at the University of Maryland School of
Medicine.
Haptoglobin is a molecule that has been known to scientists for many
years. It was identified as a marker of inflammation in the body.
Haptoglobin 1 is the original form of the haptoglobin molecule, and
scientists believe it evolved 800 million years ago. Haptoglobin 2 is a
permutation found only in humans. It's believed the mutation occurred in
India about 2 million years ago, spreading gradually among increasing
numbers of people throughout the world.
Dr. Fasano's study revealed that zonulin is the precursor molecule for
haptoglobin 2 � that is, it is an immature molecule that matures into
haptoglobin 2. It was previously believed that such precursor molecules
served no purpose in the body other than to mature into the molecules
they were destined to become. But Dr. Fasano's study identifies
precursor haptoglobin 2 as the first precursor molecule that serves
another function entirely � opening a gateway in the gut, or intestines,
to let gluten in. People with celiac disease suffer from a sensitivity
to gluten.
"While apes, monkeys and chimpanzees do not have haptoglobin 2, 80
percent of human beings have it," says Dr. Fasano. "Apes, monkeys and
chimpanzees rarely develop autoimmune disorders. Human beings suffer
from more than 70 different kinds of such conditions. We believe the
presence of this pre-haptoglobin 2 is responsible for this difference
between species."
"This molecule could be a critical missing piece of the puzzle to lead
to a treatment for celiac disease, other autoimmune disorders and
allergies and even cancer, all of which are related to an exaggerated
production of zonulin/pre-haptoglobin 2 and to the loss of the
protective barrier of cells lining the gut and other areas of the body,
like the blood brain barrier," says Dr. Fasano.
"The only current treatment for celiac disease is cutting gluten from
the diet, but we have confidence Dr. Fasano's work will someday bring
further relief to these patients. Zonulin, with its functions in health
and disease as outlined in Dr. Fasano's paper, could be the molecule of
the century," says E. Albert Reece, M.D., Ph.D., M.B.A., dean of the
School of Medicine, vice president for medical affairs of the University
of Maryland and John Z. and Akiko K. Bowers Distinguished Professor. Dr.
Fasano, as a physician scientist, fulfills two of the core missions of
the University of Maryland School of Medicine: making basic science
discoveries that can impact human health, and finding ways to translate
those discoveries into treatments and diagnostic tools."
People who suffer from celiac disease have a sensitivity to gluten, a
protein found in wheat, and suffer gastrointestinal distress and other
serious symptoms when they eat it. In celiac patients, gluten generates
an exaggerated release of zonulin that makes the gut more permeable to
large molecules, including gluten. The permeable gut allows these
molecules, such as gluten, access to the rest of the body. This triggers
an autoimmune response in which a celiac patient's immune system
identifies gluten as an intruder and responds with an attack targeting
the intestine instead of the intruder. An inappropriately high level of
production of zonulin also seems responsible for the passage through the
intestine of intruders other than zonulin, including those related to
conditions such as diabetes, multiple sclerosis and even allergies.
Recently, other groups have reported elevated production of zonulin
affecting the permeability of the blood brain barrier of patients
suffering from brain cancer.
"We hope pre-haptoglobin 2 will be a door to a better understanding of
not just celiac disease, but of several other devastating conditions
that continue to affect the quality of life of millions of individuals,"
says Dr. Fasano. "This is quite a remarkable molecule that was just
flying under the radar. We would have never have thought it would be the
key. Now that we have identified this molecule, we are able to replicate
it in the lab to use for research purposes. We hope to learn much more
about it and its potential for treating and diagnosing celiac disease
and other autoimmune conditions. This molecule has opened innumerable
doors for our research."
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Adapted from materials provided by University of Maryland Medical
Center, via EurekAlert!, a service of AAAS.