Celiac Disease: How gluten invades and sets up an auto-immune reaction

Celiac disease: Why your body thinks gluten is a nasty invasive antigen or ‘bug’.

And how – if you keep eating gluten a vicious cycle of damage will ensue.

In this post I will set the scene for future posts on dietary strategies to treat celiac disease. A number of recent studies have shown that just avoiding gluten is not enough for many, and they also need to avoid other foods in order to reduce the gluten antibodies and inflammation in the intestine.

In this post I will explain why and how gluten is a problem for those who have a specific genotype that predisposes them to celiac disease. I won’t be tackling gluten sensitivity in this post.

Celiac disease (CD) is an immune response to gluten proteins that happens in genetically vulnerable people. Gluten is found in wheat and related cereal grains e.g. wheat, rye, barley, triticale. Gluten is a protein – not a carbohydrate – even though it is found in grains.

Protein digestion: we usually break down proteins into single amino acids

Proteins are constructed with very long chains of amino acids. There are 20 standard amino acids; imagine these being 20 different coloured beads and linked like long chains– like those beads that children snap together. Every protein molecule is constructed with a particular sequence of amino acids (i.e. the beads are in a specific pattern or arrangement). These long chains are folded and coiled, and sometimes crosslink to make a specific protein.

When we eat proteins our digestive enzymes (think of these as being chemical scissors) cut the links between the amino acids (pull the beads apart). Each different amino acid requires a different enzyme to disconnect it from its neighbour.

When these are broken down into single amino acids they then go into gut cells (enterocytes) where they are either used or sent on their way out the other side of the cell around the body to other cells. Under genetic instructions the single amino acids are joined into a specific sequence to make them into any tissue, protein or enzyme etc. that the body needs at the time.

Problem: Gluten does not get properly digested into single amino acids

The problem with gluten is that is contains a large number of 2 particular amino acids – glutamine and proline (think of these as green and purple beads), (we call these types of proteins ‘prolamines’). Humans don’t have the enzymes to break proline apart from its neighbour, so instead of breaking the long string of amino acids onto singles, it stops at a peptide, a short chain. Gluten protein breaks down into a number of different peptides that cause problems. [1]

It’s not gluten that is the issue – it is these short strings of amino acids that we can’t digest further. In people with celiac there is a vicious circle of effects, each peptide causing a problem that increases the toxicity of other peptides. This diagram shows a number of different parts of the gluten molecule, that cause problems.[2]

Problem: Gluten peptides pass through the gut cell barrier from one side to the other intact where we react to them as a foreign ‘invader’.

I want you to stop and imagine your gut as being a continuation of the outside of your body, basically one big long tube coiled up inside your body, and think of the cells lining your gut as a skin.(Picture source)

The ‘skin’ of your gut is very wrinkled and folded, in fact if you took the skin of your gut and spread it out it would spread to the size of a tennis court. The large pink sheet below represents the surface area of the gut (the red is lung surface area and the green your skin):

The inside of this tube is called the lumen. It contains huge numbers of bacteria, and of course a constant flow of food and fluid. The cells in your gut secrete acid (in the stomach) and enzymes (in the stomach, pancreas and small intestine) to break down food into simple units that your body can absorb. It is only when a food particle is broken down into the simplest unit (a fatty acid, glucose molecule or amino acid) that it can be transported through the enterocyte into the fluid and bloodstream on the other side. This way we keep out large things like bacteria and viruses from getting underneath the ‘skin’. If large things do get through we have a whole host of ‘fighter’ cells waiting to nab them and deactivate them or digest them so they don’t cause trouble in the body.

You see – gluten and gluten peptides are not really a problem if they stay inside the lumen, they just end up going down the toilet. But this doesn’t happen in people with celiac disease.

Gluten peptides get through in two ways; either through the cell (transcellular) or between the cells (paracellular).

How does gluten get through the gut barrier? Scientists are fairly sure they have worked this out.

First – transcellular transport: how gliadin passes through the cell undigested

In mucous membranes there is one particular antibody called secretory IgA (SIgA). This is a first line defence responsible for keeping toxins and pathogens (bad bacteria etc.) from getting to the gut cells, it is a bit like a bouncer in a nightclub blocking the entrance so undesirables can’t get past. SIgA can also take pathogens to special areas where they can be deactivated by immune cells (sub epithelial dome), like a bouncer escorting an undesirable to the police station to get locked up. SIgA increases in your gut when there is inflammation (as there is with Celiac disease), because it needs to get to work reducing whatever undesirable is causing the inflammation.

In celiac disease something happens that shouldn’t: the SIgA (the protein that should be protecting from invaders) transports the gliadin through the cell and out the other side undamaged. How does it do this? First the gliadin peptide forms a complex with SIgA, which should take it off to get processed as a ‘baddy’ but it doesn’t – there is a doorway in the gut cell than allows the SIgA and gliadin complex to get transported in one side of the cell and out the bottom. Why does this happen when it shouldn’t?

Unfortunately in people with celiac a doorway is available for the IgA to enter with its new buddy gliadin – a doorway that normally shouldn’t be. This doorway results from the person having an iron deficiency (anaemic). People with celiac are often anaemic, as their inflamed gut does not absorb iron properly. In order to try to absorb more iron the gut cells send special iron transporting units (transferrin CD71) up to the surface of the gut cell. For some reason this receptor hooks up with the ‘bouncer’ and the ‘baddy’; the SIgA-gliadin complex, (think of the ‘bouncer’ acting like a Trojan horse that protects and escorts the gliadin) and takes it from one side of the cell to the other. From the outside of the body to the inside. Sneaky! Once on the other side the SIgA releases the gliadin.[3]

Gliadin peptides linked to SIgA, ( secretory IgA) getting taken into cell and passing out the other side via TfR, (transferrin receptor);TG2, (transglutaminase 2) takes peptides and alters them, HLA-DQ2/8 molecule picks it up and presents it to immune cells to set up ‘kill’ response. (Source)

Paracellular pathway: How gluten creates gaps between cells so it can sneak through.

A gut cell needs to be tightly glued to its neighbour in order to prevent any undigested food or pathogens getting through this barrier. Each cell binds to its neighbour with a complex of proteins called a tight junction. This acts like glue, it lets fluid through but no large molecules. The gut cells are able to release a chemical that tells the gates to open. This chemical is called zonulin, and its release is triggered by bad (pathogenic) gut bacteria – this will let the bacteria through below the surface where it can reach the ‘fighter’ (immune) cells and get them into action.

In celiac disease, gliadin proteins interact with the gut cell, (the CXCR3 receptor, which people with celiac have more of than unaffected people), and the gut cell sends out zonulin – which ‘tells’ the tight junction to loosen up, literally opening up a pathway between cells. Now that the gate is open gliadin peptides can bypass the gut cell barrier and make their way down into the area chock full of fighter cells waiting to pounce and quell an assumed infection. [4]

Once through the gut cell barrier, the gluten peptide gets transformed into an even nastier peptide that triggers an immune reaction

One more thing happens in people with celiac disease. Once the gliadin gets through the gut wall it comes into contact with an enzyme called transglutaminase 2 (TG2). TG2 modifies proteins i.e. changes them a little, but it only changes some proteins, gliadin just happens to look like a one of the proteins that TG2 is supposed to change. So it gets on and does the job very efficiently, and changes it into just enough so that it fits into a little pocket on antigen presenting cells.[5]

Bear with me – this is important but a little complicated.

Whenever we have an infection an antigen presenting cell (APC) takes a section of protein (a peptide) from a broken down bacteria, holds it in a little pocket and presents it to fighter cells. The fighter cells then go off and make anti-bodies to this so they can begin the process of spreading throughout the body and killing that specific protein (the invading bacteria). Once the invaders are killed the antibodies disappear, however the dormant fighter cells ‘remember’ this protein so if it invades again it recognises it and can replicate an army of antibodies to go fight very quickly.

People with celiac disease present a bit of protein from gluten as though it is an invading pathogen

People with CD have a particular type of APC specific to their genotype, and the gliadin altered by TG2 fits in perfectly into the little presenting pocket. (The genotype is HLA-DQ2 , specifically HLA-DQ2.5 and HLA-DQ8 which about 30% of the population has. If you don’t have this genotype – you can’t pick up gluten as it doesn’t fit in the APC’s pocket) So as soon as TG2 changes the gliadin protein in a specific way, the APC picks it up (it’s like a key that fits perfectly into a lock) and shows it to the fighter cells. (CD4+ T cells) They then go to work to fight this invader and make numerous antibodies to try to kill it off. (Gliadin antibodies) [6] Below is a diagram of the APC with the gliadin showing it to a T-cell.

People with CD also make anti-bodies against the important transglutaminase enzyme – Why?

The other problem is that not only do people with celiac make antibodies against gliadin, they make antibodies against the enzyme TG2 that transforms the gliadin. (Anti-transglutaminase antibodies) They do this because gliadin is able to bind to TG2, so the body then thinks this combo is a threat, and it then attacks the TG2. This is not great as TG2 has other important roles throughout the entire body. These anti-TG antibodies have been shown to induce apoptosis (suicide) in neuronal (nerve) cells and trophoblasts (cells that form the placenta of an embryo) which explains why there is neurological damage and fertility problems in celiac disease.

The upshot of all these anti-bodies being made to gliadin and TG2 is that inflammation increases in the gut. Think of a time when you have a skin infection – you get red inflamed weeping skin. This happens in your gut. [7]

But wait there’s more…

Still another type of gluten peptide causes trouble for the gut cells

Yet another gluten peptide causes problems, this time though it directly ‘attacks’ the epithelial cell, which sends out stress signals, fighter cells get called in and inflammatory chemicals get sent out to try to stop the ‘attack’.

As long as gluten is eaten, the body reacts as though it is under a never ending attack, and doesn’t give up the fight

If this invader were a bacteria, our body would eventually kill them off and the attack would die down and the anti-bodies and inflammation would disappear. However in celiac disease the attacking agent can’t ever get killed off – it keeps coming and coming, as long as gluten is being eaten. So the body keeps up a never ending fight against an invader that it will never win. The loser is our own epithelium which is in a constant state of inflammation and eventually becomes damaged and non-functional. Also the more inflamed it becomes the more leaky the gut becomes and a never ending stream of pathogens can get through what should be an impenetrable barrier. The more pathogens you let through, the more fighter cells get activated, and anti-bodies can be made to a bigger range of invaders. What’s more the constant damage can eventually lead to cancer. [8]

The ONLY way out of this vicious cycle is to stop the attack from the primary antigen gluten. This means eating a STRICT gluten free diet for the rest of your life.

However for many with celiac disease a gluten free diet is not enough to stop the gut inflammation, and reverse the anti-bodies.

I’ll talk more about this in my next post and how to deal with it.

Sources:

1. Hausch, F., et al., Intestinal digestive resistance of immunodominant gliadin peptides. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2002. 283(4): p. G996-G1003.

2. Fasano, A., Intestinal Permeability and Its Regulation by Zonulin: Diagnostic and Therapeutic Implications. Clinical Gastroenterology and Hepatology, 2012. 10(10): p. 1096-1100.

3. Matysiak-Budnik, T., et al., Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. Journal of Experimental Medicine, 2008. 205(1): p. 143-154.

4. Fasano, A. and C. Catassi, Current approaches to diagnosis and treatment of celiac disease: An evolving spectrum. Gastroenterology, 2001. 120(3): p. 636-651.

5. Klöck, C., T. DiRaimondo, and C. Khosla, Role of transglutaminase 2 in celiac disease pathogenesis. Seminars in Immunopathology, 2012. 34(4): p. 513-522.

6. Koning, F., Celiac disease: quantity matters. Seminars in Immunopathology, 2012. 34(4): p. 541-549.

7. Klöck, C., T.R. DiRaimondo, and C. Khosla, Role of transglutaminase 2 in celiac disease pathogenesis. Seminars in Immunopathology, 2012. 34(4): p. 513-522.

8. Bethune, M.T. and C. Khosla, Parallels between pathogens and gluten peptides in celiac sprue. Plos Pathogens, 2008. 4(2).