Contrary to popular belief, especially here in Boulder, Colorado (the capital of the Gluten-free diet fad), gluten is not the spawn of Satan (recent paper published on gluten and article here). In fact, for the average person, the opposite may be true, as gluten-free foods contain extra sugar, fats, or eggs to compensate for lack of texture gluten provides. The addition of these extra ingredients can adversely affect your health.

But enough of that! Simply put, gluten is a protein composite made mostly of gliadin and glutenin proteins, and is most commonly found in wheats and grains. Unfortunately, some unlucky (usually genetically predisposed) individuals have allergic reactions to the gliadin in the gluten, and are thereafter no longer able to enjoy gliadin containing foods like bread, pasta, cookies, or cereal (sucks to be you… just kidding☺).

People who have allergic reactions to gliadin (commonly associated with gluten) have Celiac Disease. It is a disease characterized by digestive problems, severe skin rash, muscle/bone/joint pain, among other abnormal symptoms that are quite unpleasant. The disease reportedly affects about 1% of the population, about 3 million people in the U.S.. However, it is hard to say, with any certainty, how common the disease actually is because it is thought that many people who have the disease are undiagnosed or misdiagnosed.

A Short History of Celiac Disease

Celiac disease (note: no ‘s’ at the end of celiac) likely appeared around 9000 BCE, when humans began cultivating grains in the fertile crescent of western Asia, though the first documented report of the disease did not appear until 100 AD. The ancient Greek doctor Aretaeus of Cappadocia described one of his patients as atrophied, pale, and feeble due to incomplete digestion resulting in diarrhea (yikes). He hypothesized that the patient’s lack of necessary stomach-heat required for digestion, in addition to a reduced ability to distribute digested products through the body, was causing the intense, watery expulsion of you-know-what from his large intestine. Obviously this explanation is wrong, but it is interesting to note that celiac disease is derived from the term koiliakos (from koelia, meaning abdomen) that Aretaeus used to describe the condition.

English pediatrician Samuel Gee gave us the modern definition of celiac disease in 1887, but it wasn't until the Dutch famine of 1944 that the disease was better understood. Pediatrician Dr. Willem Karel Dicke bridged the gap between celiac disease and the consumption of wheat containing foods when he observed the improved condition of celiac patients while wheat products were scarce. In fact, the mortality rate of celiac disease patients dropped from 35% to virtually 0%. And, as you might have suspected, the mortality rate returned to previous levels in the years following the famine, thus showing that wheat likely contained the causative agent implicated in celiac disease.

Breaking Down Gluten

As previously mentioned, gluten is a composite protein mostly containing glutenin and gliadin, the latter of which can (if you’re a gluten intolerant individual) cause negatives affects in the body. Gliadin is most commonly associated with gluten (hence the gluten-free diet), but it is also found in gluten-free foods. (Hold up!) Thus, individuals with gluten intolerance must be conscientious of foods that are gluten-free but NOT gliadin-free. The take home message: Gliadin, not necessarily gluten, is the allergen and things that are labeled as “gluten-free” might not be safe for individuals with Celiac disease. That said, we will be using gliadin and gluten interchangeably for all intents and purposes for the rest of this post.

Please, tell me more!

In the average Joe, gluten is processed like most other proteins…initially at least. Proteases in your small intestine chop proteins into small pieces that your body then absorbs and uses as building blocks for muscles and other proteins in your body; simple enough. However, gluten is a little different because it is very difficult to break down, and subsequently harder to absorb. Therefore, gluten usually just passes right through the gut. For those who are gluten intolerant, the pieces of broken-down gluten protein, now called peptides, interact with another protein found in the lining of the small intestine called Tissue Transglutaminase (TG2 for short), istead of passing through.

TG2 is typically not involved in gluten processing, but, when activated, can alter the chemical properties of gluten.

The activation of TG2 would require another couple of paragraphs, so for the sake of simplicity and our sanity, we will say that through a series of interactions and cascades, the TG2 is activated in response to any physical or chemical damage (so cut back on those red-hot cheetos!). For the nerdy and/or interested folk, a paper exploring TG2 activation can be found here. But, when TG2 is activated when gliadin is present, we run into some problems.

Sound The Alarm!

Tg2 is found in all individuals and usually maintains an inactive state. The protein becomes activated only when the body needs to restore and repair damaged tissue. When the protein is activated, it can interact with gluten proteins. As is the case with gluten intolerant individuals, TG2 deamidates (changes) certain parts of the gluten protein. OK, but so what? Well, these deamidated gluten peptides act like Joey-roos who want to snuggle up in the pouch of a momma-roo protein called MHC-II (yup kangaroo reference).

Now buckle up and hold on… it’s time for some science!

MHC-II (major histocompatibility complex II) protein is a vital part of the immune system, and plays a major role in organ transplants, as well as driving immune responses to dangerous bacteria/viruses/fungi. It is only found in specific immune system cells called antigen presenting cells (APC). APCs sample all the proteins found in the body and essentially directs the MHC-II to present potentially dangerous molecules in our bodies to other immune system cells. These other immune system cells then decide if the molecule in questions is truly dangerous or not. In most individuals, it’s thought that the gluten peptides are simply ignored by the MHC-II proteins and no presentation occurs. However, in gluten intolerant folk, a specific type of MHC-II decides that the deamidated gluten is potentially dangerous and sounds an alarm by binding (grabbing hold of the molecule) and presenting it to the immune system cells.

MHC-II in all individuals is encoded for by genes HLA-DR, HLA-DQ, and HLA-DP. Gluten-intolerant individuals have a specific type of HLA-DQ, called HLA-DQ2, which is able to bind the altered gluten protein (while all the other types cannot), and mistakenly tell the body that it is dangerous. Individuals who have this variant form (also known as an allele) of HLA-DQ are considered to be genetically predisposed to having celiac disease. So in plain English: Before you are even born, the combination of genes you receive from your parents will determine your susceptibility to diseases, including celiac disease (thanks dad). However, that’s not to say if you have this certain allele, you definitely will get celiac disease; it just means you have a higher chance than others who don’t have the allele.

Preparing for attack

In your blood, there are small immune cells called T-cells and B-cells that roam throughout your body looking for trouble. When we mentioned "other immune system cells" earlier, we were referring to the T-cells. While meandering through the body, T-cells interact with the MHC-II found on the APCs (mentioned above). The cells engage in a sort of “meet and greet” throughout the body and exchange information about potential threats. If the MHC-II is bound to a potential threat (such as the altered gluten in intolerant people), the T-cell and APCs can activate each other. The APCs release proteins that recruit effector cells to the area, while the T-cells go off and activate B-cells (we'll get to B-cells in a sec).

What does all that mumbo-jumbo mean?

T-Cells circulate through the body and “talk” with other cells. When MHC-IIs on the APCs have a little threat particle bound in the pocket, the T-cells investigate to determine whether the particle is a real threat or not. Usually, T-Cells will identify proteins produced within the body or proteins required for nutrition as safe, so no big deal. In this case, the T-Cell would “shrug its shoulders” and move along to survey other MHC-II molecules. However, if the T-Cell does not recognize the protein as safe, it tells the APC to send out signals to recruit effector cells to move into the area. The effector cells are the army of the body, and once they receive an order, they immediately take action.

One of these effector cells is called a neutrophil, which, upon reaching the vicinity of the APC, explodes! The neutrophils contains antimicrobial (anti-bad guy) products that (when the cell explodes) aids in the destruction of threats. In addition to destroying the bad guy (in this case, gluten peptides), the debris acts as a kill-all mechanism, subsequently damaging our own good cells as well as the bad. Neutrophil explosion might seem like a bad thing, but it’s one of the body’s natural defense mechanisms and is very effective in almost all cases of infection. It just so happens that in gluten intolerance,these events take place in the small intestine and the damage sustained during the explosions is extensive in both ways, inevitably causing more harm than good.

From Intolerance to Autoimmunity (Say what!?)

The small intestine is the most important organ for nutrition absorption. It is lined with villi (little sea anemone-looking things) that help absorb nutrients, allowing the body to utilize the food we eat. When neutrophils explode in the small intestine, the debris can damage the villi, leading to diarrhea and insufficient absorption of nutrients characteristic of gluten-intolerance.

Once the alarm sounds and the neutrophils reach the APC and explode, both the gluten proteins and the villi in the small intestine are damaged. (some good, a lot of bad!) When the villi are damaged, the extracellular TG2 bound to gluten proteins are exposed and often broken down. The small pieces of TG2 (along with the gluten) are picked up by APCs. Unfortunately, the gluten-associated and broken down TG2 proteins are no longer recognized as docile and can be bound by MHC proteins discussed earlier, and presented on the APCs to the rest of the immune system. (Oh no!)

Now remember, TG2 is a protein produced and stored in your own body (It’s one of the good guys).

The TG2 in your small intestine, has been “flagged” and marked as an antigen, and your body begins to attack and produce antibodies to it. As we mentioned earlier, activated T-cells can activate B-cells. When B-cells are activated, they can become plasma cells, which produce and secrete antibodies- a form of highly specific long-term protection against antigens that you encounter over the course of your life. Antibodies are exactly the reason why (almost all) individuals only get chicken pox once as a child and then never contract the disease again — you are protected in the long term by antibodies that can identify a problem molecule before it becomes a full-blown problem a second time. However, when the antibodies are specific to molecules produced and held in your own body, this can cause complications (self-destruction, eepp!).

Celiac Disease (finally)

Did you ever think you were going to make it to this part? Pat yourself on the back for sticking to your guns and hanging in there!

When your body begins producing antibodies specific to the TG2 in your own body, you officially have Celiac Disease; it is an autoimmune disease characterized by self-specific antibodies, (also called autoantibodies ) caused by adverse reactions to gluten — not that you are simply allergic to gluten. And what a sad story it is 😟 . Once an individual has autoantibodies, he/she is said to have broken tolerance. The individual is likely to produce more autoantibodies to other self-made proteins, leading to other diseases. That’s why people with Celiac Disease often end up having other autoimmune diseases in the future, like Hashimoto’s Disease, Graves’ Disease, Type I diabetes, Lupus, to name just a few. (What a trainwreck right?)

Wait, there’s still more?

The gluten-specific antibodies (not the autoantibodies) can actually undergo slight changes within the body in processes called hypermutation and class switching which actually make them more efficient in every sense. We won’t worry too much about these processes, but essentially once they undergo these changes, gluten-specific antibodies can bind cells called mast cells within the lining of the small intestine. Kind of like neutrophils, these mast cells explode and cause damage to surrounding areas. However, they only explode when they come in contact with specific molecules (gluten in this case).

Need a bit of clarification to solidify things a bit? We thought so!

Most individuals have some sort of allergy to pollen, dust, or other non-threating particles in the air, and this is exactly what’s going on in the body — a gluten allergy. For example, many people in Colorado are allergic to pollen. The body produces antibodies to the pollen which bind mast cells, and whenever pollen is inhaled, the pollen binds the antibody which signals the mast cells to explode, causing runny noses and sneezes and sometimes shortness of breath (that was a long sentence… here’s a picture to help visualize it).

The same thing happens in Celiac patients, but with gluten. The effect is similar to that of the neutrophil explosions, except mast cells are already in the area, and the response is quicker and more violent. Each subsequent exposure to gluten leads to a more efficient (read: more dangerous) response. That’s why eating gluten after an initial exposure can actually be quite harmful!

I thought this post would never end:

Fortunately, individuals with Celiac Disease are able to live normal lives and get plenty of nutrition so long as they avoid gluten-containing foods. Re-exposure to gluten can cause very severe reactions, so it’s definitely good that more and more companies are labelling their gluten free products. That said, it’s also kind of ridiculous that being “gluten free” is becoming synonymous with “being healthy.”

Hopefully, you’ve learned something about Celiac Disease and won’t give in to the gluten free diet fad, unless of course you are truly gluten intolerant or have Celiac disease. Here's some recent good news; there are scientists working on pills that, like lactaid pills, that introduce enzymes to the gut that will allow intolerant individuals to eat gluten (and drink beer, hoorah!) for a short period of time. These pills are still in trials, but will hopefully be available for purchase at your local grocery stores.

As an aside, we hear of many individuals reporting that they feel better when they go gluten-free, but we believe (no proof, just a hunch) that the gluten-containing foods they’ve cut out of their diets were probably full of sugar as well (omg sugar is, like, totally bad... might even be the real spawn of Satan). Some examples of these foods include brownies, cakes, cookies, pies, and other Pinterest delights, which are all chock-full of sugar. That said, what we want to say is… please look into scientific reports/articles/etc before you jump straight into a potentially-more-harmful-than-healthy diet!

Shoot us an email at cellgoobers@gmail.com if there’s anything you’d like to see us cover in our blog, or if you see any glaring mistakes or have questions!