If you read our post on Monday, you will already know about the difficulties of living with Coeliac Disease. But what about the science behind it?
Coeliac Disease (CD) is a disease related to dysfunction of the immune system when it comes into contact with gluten. It comes in varying severities, meaning that whilst most patients can control the disease by living a gluten-free lifestyle (as Claire told us on Monday, it really is a huge change in your life), some unlucky sufferers have to resort to much more radical therapies. These include immunosuppresive drugs and others agents targeted to receptors in the gut (more about this later) – both of which come with their own milieu of side effects. There has also been some interesting research done on stimulating intestinal stem cells to regenerate damaged intestinal tissue lost during severe forms of the disease- if this interests you we’ve previously written about regenerative medicine and personalised therapies.
Sufferers have also been shown to have changes in their intestinal flora – if you’ve seen all those adverts for probiotics you’ll know we have a natural collection of bacteria that live in our gut that are beneficial to our health. In CD patients the normal constitution of this flora is disrupted, throwing it out of balance with the rest of the body.
What actually causes CD?
The gut is naturally a harsh environment, and cells have a very high turnover rate (renewing every 3-5 days). Renewal of these cells is driven by intestinal stem cells: they divide and differentiate, and the newly formed cells migrate outwards over time. These cells are eventually shed and lost themselves as yet more new cells are made from the pool of intestinal stem cells.
The main genetic risk for CD comes from variants in the Human Leukocyte Antigen (HLA) genes, primary HLA versions HLA-DQ2 and HLA-DQ8. HLA genes code for proteins that form heterodimers which present small peptide sequences to the immune system to help it recognise infections. HLA-DQ2 or HLA-DQ8 molecules are found in almost all CD patients (although it’s important to note that 1/3 of the population carries the DQ2 gene, and not all of them have CD, highlighting the role of other genes and environmental factors in CD). The HLA-containing region of the genome codes for proteins involved in all aspects of your immune system, and so it makes sense that dietary gluten can induce both innate and adaptive immune responses (these are different arms of your immune system that are triggered by different stimuli and have different roles in helping to fight disease).
The DQ2 and DQ8 proteins are expressed on the surface of antigen presenting cells where in CD patients they will bind deaminated gluten peptides (a modification that happens within the lining of the gut due to the action of a protein called transglutaminase II). This then elicits a T cell response, another type of immune cell that is involved in a number of other processes, one of which is releasing proteins called cytokines. These cytokines are involved in a number of different processes in the body, doing so by interacting with other immune cells. One of the main problems with these cytokines in CD patients is that they cause inflammation of the intestinal tissue that results in degradation of the protective protein matrix surrounding these cells, as well as causing other cells (intestinal epithelial lymphocytes and natural killer cells) to become more effective at destroying the tissue. Chronic inflammation also leads to activation of a transcription factor called NF-kB, which in turn reinforces this immune response, leading to further damage and impairment of regeneration of the intestinal epithelium.
But that’s not all. When the gluten peptides are deaminated, they can also cause oxidative stress (which can cause a huge amount of damage to cells), rearrangement of the cellular cytoskeleton, deregulation of epithelial homeostasis, and impairment of tight junction assembly – these are the junctions which form between cells and act as a seal, stopping molecules that need to be regulated by the body from moving through the epithelium and into the blood. Without this junction, the epithelium becomes “leaky” allowing more gluten peptides through, making the situation even worse! Zonulin, a receptor in the gut barrier, is also upregulated in CD patients which causes further dysregulation of tight junctions leading to an even leakier gut. The body just can’t catch a break!
This is just some of the science behind the development of coeliac disease- in actual fact there are even more complex processes going on in the body of CD sufferers! All in all, severe CD initiates a vicious cycle that results in a huge amount of damage to the intestine due to a total overreaction of the body against a harmless protein.
So next time a friend comes to your house and has to bring their own gluten free pizza, or you have to go to certain cafes to accommodate their dietary needs, think about the internal war they’re fighting every time they eat gluten. Be thankful. Be tolerant. And most of all, be positive like our guest blogger Claire!
If you enjoyed this post you may also like:
Pascual, V. (2014). Inflammatory bowel disease and celiac disease: Overlaps and differences World Journal of Gastroenterology, 20 (17) DOI: 10.3748/wjg.v20.i17.4846
Piscaglia AC (2014). Intestinal stem cells and celiac disease. World journal of stem cells, 6 (2), 213-229 PMID: 24772248
Guandalini S, & Assiri A (2014). Celiac disease: a review. JAMA pediatrics, 168 (3), 272-8 PMID: 24395055