While again this was written for a celiac aware audience, it does get into
the various proteins in the grains that celiacs find toxic. Fits in with
the recent discussion of grains versus the "gluten" grains. Don.
"Genetics and What's New in Research"
-------------------------------------
a talk by Martin F. Kagnoff, MD
summarized by Jim Lyles
Dr. Martin F. Kagnoff is the director of the Laboratory of Mucosal
Immunology at the University of California at San Diego, and
well-known for his research in celiac disease, particularly with
respect to genetic factors. He gave a talk at the 1995 CSA/USA
conference on October 5, 1995, in San Francisco, California. What
follows are some highlights of Dr. Kagnoff's talk.
Celiac Disease (CD) is associated with small bowel damage, which
occurs when a celiac eats gluten containing foods. "Gluten" is
something of a misnomer. Gluten really refers to the disease-
activating proteins in wheat, and we know there are similar, related,
but somewhat different proteins in other grains that activate CD as
well. However, gluten-free (GF) has come to mean free of the grains
which are toxic to celiacs.
Nutrients are not absorbed properly in an untreated celiac, due to the
damage in the small bowel. This results in a wide spectrum of
different symptoms.
When a celiac consumes gluten, the damage to the small intestine may
be slight or it may be extensive. It depends on how sensitive that
individual is to gluten, and on how much gluten is consumed. However,
it is not just the small intestine that is sensitive to gluten; the
entire digestive tract including the large bowel is sensitive. In a
study done several years ago, wheat was placed at the very bottom of
the small intestine, where celiac damage does not usually occur. This
caused the type of damage that is characteristic of CD. More
recently, Mike Marsh has inserted gluten into the rectum to help in
diagnosing CD. He has found that inflammation and changes in the
rectal lining occur in celiacs exposed to gluten in this fashion.
Dr. Kagnoff showed slides with the two extremes: normal, healthy
villi with small crypts and completely flattened villi with elongated
crypts. He said that there are many in-between situations, where the
villi are only partly gone or partly damaged. A healthy small
intestine has many folds, with villi on the folds, and microvilli on
the villi. Altogether, this provides a surface area equivalent to two
regulation-size tennis courts; this is about 600 times as large as the
surface area inside piece of tubing the same size and length as the
small intestine. As the villi are damaged and the microvilli
disappear in active CD, the absorptive surface is greatly reduced.
The severity of the symptoms varies depending on the amount of
absorptive surface that has been lost.
Another point to consider is: What do you absorb in your small
intestine, and where? One of the common symptoms of untreated CD is
iron deficiency. Some celiacs had iron deficiency for years, but were
not diagnosed until other symptoms began to show up as well. Dr.
Kagnoff has a set of twins as patients that were diagnosed with iron
deficiency at age seven, are short in stature, and wasn't until they
were over 40 that they developed symptoms such as bloating and
diarrhea which finally led to a diagnosis of CD. The reason this can
happen is that iron is absorbed in the very top portion of the small
bowel. If the villi damage is not severe and limited to that area,
then other nutrients are absorbed further down in the intestine and
only iron is malabsorbed. Another common problem with untreated
celiacs is iron malabsorption coupled with calcium malabsorption.
After malabsorbing calcium for years these people are susceptible to
bone fractures, but really don't have that full-blown "picture" of CD
which is the underlying cause of these fractures.
As the small bowel lining becomes more damaged and abnormal, one
starts to malabsorb fat-soluble vitamins such as D, E, A, and K. As
the disease progresses, water soluble vitamins start malabsorbing as
well. However, if the damage is limited to the first foot or so of
the small intestine, full-blown malabsorption may never occur as the
remaining 20 feet or so if small intestine will continue to absorb
nutrients normally. However, in these cases iron absorption will be a
continual problem as iron is only absorbed in the earliest portion of
the small intestine.
In CD genes, environmental factors, and the immune system all play a
role. Dr. Kagnoff touched on all three of these factors.
Environmental Factors
---------------------
We all know that ingesting certain grains activates CD: wheat, rye,
barley, and if taken in large enough quantities, oats. There is some
debate in some groups as to whether or not oats are toxic to celiacs.
We know that rice, corn, and sorghum are fine, as long as they are not
contaminated by one of the toxic grains. When you look at the plant
ancestry, you find that wheat, rye, and barley all come from a common
ancestor. If you go up one more level, you find a point where oats
also shares a common ancestor. These grains all have a high content
of some alcohol-soluble proteins that are called prolamins. (The
content is somewhat lower in oats.) These prolamins have a very high
content of glutamine and proline, which are two amino acids.
When we talk about a gluten-free (GF) diet, what we are really talking
about are these alcohol-soluble proteins, which are named as follows:
Grain Proteins
----- --------
wheat gliadins
barley hordeins
rye secalins
oats avenins
Note that we are not talking about a single protein. A variety of
wheat may have 40 different gliadins encoded on multiple genes within
the wheat. Some of the chromosome specialists years ago tried to
engineer wheat that would lack the gliadins that active CD; but there
were so many different genes encoding gliadins, on different
chromosomes, that they soon realized it was an almost impossible feat.
Within the wheat gliadins, there have been studies to determine which
part(s) of the gliadin activate CD. Gliadins (and the corresponding
proteins of the other three toxic grains) are proteins made up of many
different building blocks that are called amino acids. We've found
that only a small part of these proteins is needed to activate CD,
about 12-15 of these amino acids; these are called gliadin peptides.
Studies are being conducted all around the world, and some sort of
consensus is being reached as to which peptide sequence activates a
celiac response.
One particular wheat gliadin (alpha-gliadin) has been studied in more
detail. Don Kasarda, of the USDA research facility, and his group
purified this protein, and others at the facility isolated the
nucleotide and peptide sequences for alpha-gliadin. Other groups
around the world have also worked with this single protein. What
they've found is this protein has 266 amino acids, with over 60
glutamines and over 30 prolines. This is very unusual; most proteins
have a fairly random scattering of amino acids.
Tests with celiacs using alpha-gliadin have been conducted to isolate
the actual amino acid sequence that triggers a celiac-type response.
Groups in Norway and England have isolated the same sequence, which
MAY be the part of alpha-gliadin that activates the disease.
Genetic Factors
---------------
Is CD a genetic disease? The answer is probably "yes"; susceptibility
to CD is certainly genetic. Certain genetic factors are required;
without them you don't get CD. However, even with them you might not
get the disease, so CD is not entirely genetic.
Within families of celiacs, depending on which studies you read, the
incidence among other family members is between 2% and 15%. This is a
relatively small number, but still far greater than the incidence in
the population at large. What really points to a very strong genetic
association is the incidence in monozygotic (identical) twins: Where
one twin has CD, at least 70% of the time the other also has CD. The
fact that this incidence is not 100% is another indication that there
are other factors besides genetics involved in CD.
Susceptibility to CD is associated with HLA genes encoded on the sixth
chromosome. The HLA genes are among the most diverse set of genes
encoded in humans or other mammals. They determine and govern why we
are different from one another in terms of our immune system and how
it reacts and responds.
Celiacs nearly always have one of two HLA genes: DQ2 or DQ8. These
genes are relatively common among Caucasians of European descent,
occurring in about 25% of the population. These genes are not found
in Japan or Africa among the blacks; consequently CD is virtually
unheard of in these areas of the world. Most people with these HLA
genes don't get CD, so there is still more to this puzzle than we
currently know. About 95% of the celiac population carry the DQ2
gene, another 5% carry the DQ8 gene, and far less than 1% would carry
anything else.
If a celiac and a sibling share the same HLA genes, there is a 20-40%
chance that the sibling will develop CD also.
There are some studies going on which are trying to induce something
similar to CD in animals. Dr. Kagnoff's group has just submitted one
for publication in which they cloned DQ2 and other HLA genes and put
them into mice. They are beginning to look at how the mice respond to
gliadin.
The Immune System
-----------------
In CD, two types of T-cells come into play. The first type is
intraepithelial T-lymphocytes, which exist between the epithelial
cells. In active CD, one of the striking features is an increase in
the number and density of these intraepithelial T-lymphocytes. These
T-cells were thought to be responsible for the villi damage, but
recent studies suggest that these cells actually help in the growth
and development of epithelial cells. The increase in these T-cells
during active CD may be an attempt to maintain the normalcy of the
epithelial lining. In fact, when the gene responsible for these cells
is deleted from mice, the epithelial lining is totally abnormal.
The T-cells in the lamina propria are the ones responsible for the
villi damage, by reacting to the presence of gliadin. During this
reaction the T-cells release cytokines, and it is the cytokines which
appear to cause the damage to the villi.
Diagnostic Tests
----------------
CD can present with a broad array of symptoms. Often the symptoms are
very subtle and appear to be far removed from the small intestine.
This makes diagnosing CD difficult in many cases.
The blood tests can be useful for screening. Three of the four
antibody tests can be highly sensitive, but only when there is fairly
marked damage to the villi. These tests generally do not come back
positive when the damage is mild. Also, we have to take into account
how often these tests give a false positive. For a while the
endomysial antibody was felt to be nearly 100% specific, i.e., no
false positives. In recent years that number has fallen off some, as
there have been some false positives detected. The bottom line is:
These tests are good as a screening device and to monitor compliance
with the GF diet, but they cannot be used in place of the small bowel
biopsy for diagnosing CD. Dr. Kagnoff does not believe these tests
would be useful in screening the population at large; they are most
useful in screening those in whom there is some suspicion of CD due to
the symptoms.
Next we need to look at HLA Class II DQ gene typing tests. These can
be useful in eliminating the possibility of CD, as CD is virtually
unheard of unless you have one of the two DQ markers we discussed
earlier. Of course, the converse is not true: The vast majority of
those which DO have one of these markers also don't have CD, so all
you can say in that case is that CD remains a possibility.
The HLA typing tests are also useful in determining for the siblings
of a celiac if CD can be eliminated as a potential future concern.
At this point Dr. Kagnoff answered some questions from the floor:
Q: What is the risk of small bowel lymphoma?
A: There is good (but not definitive) evidence that the increase in
lymphoma is related to not being on a strict GF diet. For celiacs
on a strict GF diet, the risk of small bowel lymphoma is not
significantly greater than it is for non-celiacs. The question
is, how much gluten is okay? Dr. Kagnoff has detected
inflammation in biopsies of individuals who only eat a small
amount of gluten. We know from other malignancies that ongoing
inflammation is associated with increased risk.
On the other hand, the overall risk is still very small, even in
studies where people with active CD have eaten gluten for 30, 40,
or 50 years. The risk is real, but the risk of an earthquake in
California is probably higher. However, I still recommend that
celiacs maintain as GF a diet as they can.
Q: What is the risk of colon cancer in celiacs?
A: There is no evidence that there is an increase risk of colon
cancer in celiacs. The increase in risk, which is small, refers
to cancers in the mouth, esophagus, oral pharynx, lymphoma of the
small bowel, and cancer of the small intestine (which is very
rare, even in celiacs). There is no increased risk elsewhere.
Q: What is the possibility of developing a GF grain of wheat?
A: Very unlikely. By the time you eliminated all of the
gliadin-related genes from wheat, I'm not sure there would be much
left.
Q: Are you born with CD, or can it "develop" at any age?
A: First it must be triggered by some event in the environment, such
as a certain kind of flu, stress, etc. Then, once it is
triggered, you continue to have the disease for the rest of your
life.
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