Health Sciences

When you can avoid a disease

Coeliac disease has always gripped my interest, therefore I decided to research it further. I found that there were two main types of information available. One was for everyday people wanting to familiarise themselves with the disease, which did not contain much useful and extensive information, and the second was clearly meant for doctors. The contrast in detail between these two sources inspired me to inform others about what coeliac disease really is.

Cellular approach

The disease can be, described as an inflammatory response to a class of proteins called gliadins, a vital component of gluten found predominantly in wheat and other plants in genus Triticum. Gliadin is a protein rich in two types of amino acids: proline and glutamine. This protein becomes partially digested, but the most important detrimental sequences are resistant to proteases as they contain bulky sequences that block the activity of digestive enzymes. These molecules also increase intestinal permeability so absorption is increased and hence cellular passage of gliadin to gut mucosa (inner layer of the intestinal wall) happens.

Intrusion of non-self material triggers both an innate response (macrophages are attracted to the site of invasion) and a cell-mediated response, with the use of T-cells. Some of the fragments that enter the mucosa are captured by dendritic cells, whose function is to process and display a found antigen, this is where the undigested fragments of gliadin are. These in turn stimulate secretion of Interleukin 15 (IL-15), but details of this process remain unclear. Interleukin is a group of proteins which stimulate differentiation and division of T and B lymphocytes, including Natural Killers (NK) – a type of T-cells that are specialized in killing infected cells. One of them NKG2D interacts with a MHC protein MICA (short for MHC class I polypeptide-related sequence A) found on cell surface of enterocytes that acts as a ligand for NKG2D, resulting in enterocyte (cell lining the intestine) killing, and is likely to be one way in which villus atrophy occurs.

As another route of the immune response occurs when gliadin binds to a HLA-DQ2 protein. This is a peptide made of 33 amino acids which has been found in many T-cell antigens, and so is involved in cell-mediated response. Our body is also equipped with tissue transglutaminase (tTG) enzyme, which is capable of alteration of amino acids in the glutamine regions of gliadin by either removal or changing of the amino group from their R groups. The result of these reactions is an altered gliadin that is bound by tTG enzyme, what actually enhances gliadin binding to HLA-DQ2 protein. As the enzyme is a part of this complex. the organism no longer finds the tTG as self. Thus, patients suffering from coeliac disease also have anti-transglutaminase antibodies, which are also often used in testing for the disease. Nonetheless, the question as to whether these antibodies have pathogenic role remains unanswered. The complex is then presented to the T-cells. This usually happens in the mesenteric lymph nodes ( lymph nodes found in proximity to the intestine). This results in the release of gamma-Interferon (IFN-γ), a cytokine, which attracts macrophages to the site.

Fig. 1: Versatile response to gliadin peptides

Fig. 1: A graph

Genetic causes

As noted most of the problems come from incomplete digestion of gluten. Then, these untypical peptides are recognized by immune system so as to become destroyed. In doing so, the immune system damages the intestine lining as well. It seems to be caused completely by digestion errors, but there is also a genetic factor. A part of the major histocompatibility complex II (MHC II; it is a set of molecules found on cell surface of cells that is a vital part of the immune system in vertebrates) called HLA-DQ is basically proteins responsible for distinguishing between self and non-self cells.

There are 8 types of these proteins – from HLA-DQ2 to DQ9. These polypeptide chains are encoded by the genes HLA-DQA1 and HLA-DQB1 that are found to have a loci on 6th chromosome. When a particular allele of previously stated genes, is present, coeliac disease is more likely to develop. These alleles result in a person having HLA-DQ2 or DQ8 which are found in 95% of people suffering from coeliac disease. However, having the genes alone does not guarantee the disease – there are also other environmental factors that might contribute to the development of the disease. It has been noted that a viral infection, that caused a intestine inflammation and increased permeability of the small intestine, could also lead to coeliac disease.

Symptoms and diagnosis

As shown, both interactions give rise to killing enterocytes and thus degradation of villi. Lack of absorption surface results in malabsorption of many vital nutrients such as minerals and fat-soluble vitamins (A, D, E and K) from the food due to decreased absorption surface area in the intestine. Further symptoms may include weight loss and fatigue due to decreased absorption of carbohydrates, iron deficiency anaemia, calcium and vitamin D malabsorption and hence secondary hyperparathyroidism – a condition when your body lacks calcium and phosphates, what triggers release of these minerals from bones so that there are optimal levels of them in your blood, what in turn causes osteoporosis – a disorder in which your bones lose mass and bone mineral density is decreased what leads to increased vulnerability to fractures.

However, the most common symptoms include: pale, loose and greasy stool; pale, voluminous diarrhea, abdominal pain, abdominal distension and mouth ulcers. Sometimes even lactose intolerance might arise. These symptoms are caused by incomplete digestion of food and inflammation of bowel in the sites of villus atrophy. Yet even cases with no noticeable symptoms are possible. There are also known cases when coeliac disease lead to fertility problems, headaches, dermatitis, hair loss and even depression. Coeliac disease leads to increased risk of some tumors, mainly lymphomas and adenocarcinomas (tumor with glandular origin).

Fig. 3: A transverse section through bowel showing villus atrophy

Fig. 2: villus atrophy

Summary

Coeliac disease is a peculiar disease. It is autoimmune and usually has a genetic basis but just as well can be caused by an environmental factor. There is not any other immune disorder where an environmental factor is known. It is manifested by the inflammation of an intestinal wall, villi atrophy and an wide array of other symptoms, mainly gastrointestinal. Even more quaint is the fact, that it can’t be cured but it’s possible to manage all the symptoms by only changing the diet. That is what makes this disease so special, and thus intriguing.