Gluten triggers a t-cell mediated immune response from the body. T cells stands for Thymus- dependent because these cells are produced from stem cells in the thymus and then are stored in the thymus, spleen and lymph nodes, from which they are then sent out to other organs. T cells have receptors sensitive to antigens, related to immunoglobulins (antibody proteins), on the surface of specific other cells, and must come into close contact with the afflicted cell. B cells, which are made in the bone marrow, instead respond to infections by sending out antibodies through the circulatory and lymphatic systems. They also have receptors for antigens, however they are surface antibodies. Due to these differences T cells form part of a human's cell-mediated immunity, while B cells are part of a person's humoral immunity.
T cells proceed to either directly attack the cell 'wearing' the antigen, or they direct the body's immune response towards the infected cell. In particular, T cytotoxic cells respond to antigens on major histocompatibility complex molecules, because MHC molecules receptors are sensitive to foreign antigens. In human beings the MHC molecules are known as human leukocyte antigens, and their expression plays a large role in the development of Celiac Disease. (Quote from the physio text book!)
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Gluten breaks down into two other main proteins in the body known as the prolamins, glutenin and gliadin, (Darewicz, 2008, Koning, 2005). These, in turn, are predominantly made of the amino acids glutamine and proline. Enzymes within the gastrointestinal tract are unable to act on proline and glutamine, and thus, large fragments of gluten are permitted to pass through the digestive system, (Koning, 2005). In a person without Celiac Disease, this is a normal process and those fragments would be excreted out; however, in a Celiac sufferer this seems to be the exact reason why gluten causes an allergic reaction. The fragments of gluten, or gluten peptides, are modified by the enzyme tissue transglutaminase, tTG, and subsequently are able to bind to human leukocyte antigens, specifically, HLA-DQ2 and HLA-DQ8 proteins, (Alessio, 2009).
HLA is located on chromosome 6, which is the location of the major histocompatibility complex in humans, (Louka, 2002). Depending on a person's genetic code, they may or may not code for specific HLA proteins. The HLA molecules linked to the gluten response in Celiac Disease are the HLA DQ2 or DQ8 complex. As mentioned before, the T cytotoxic cells respond to the antigens present on the surface of HLA molecules. Therefore, once tTg has modified glutamine and proline, the receptors on the surface of HLA DQ2 and DQ8 are able to grab onto the modified peptides, and in effect, wave the peptide flag to alert the T cytotoxic cells of the immune system, (Alessio, 2009). The T cytotoxic cells then either release cytokines and chemokines, or â€œproduce specific IgA autoantibodiesâ€Â, (Alessio, 2009, Darwicz, 2008). (Explain how this causes damage) Therefore, a person who suffers from celiac is hyper reactive to the presence of gluten peptides, because they are readily catalyzed into a form to which the human leukocyte antigen can use to enlist an immune response through the T cytotoxic cells of the immune system, which in turn damages the small intestinal lining.(citation needed here) ******LOOK UP IN PHYSIO TEXTBOOK T CELL RESPONSE*************
The sequence of the immune system response to gluten in Celiac disease, though mainly understood, does not explain a person's genetic predisposition to have the disease. This is complicated by the fact that Celiac â€œinheritance does not follow a Mendelian segregation patternâ€Â, (Koning, 2005). There are a variety of other genes that seem to influence the expression of Celiac; however, their influence is conservative when compared to the influence of the expression of certain other predominantly noticed genes in Celiac genomes. (Koning, 2005). Therefore, even though scientists are now able to identify specific base pairs coding for everything from sickle cell anemia to alcoholic predisposition, because Celiac is the result of one to many activated genes, researchers have been unable to identify the exact codons that code for an immune reaction against gluten. Research has thus focused on several different genetic factors in an attempt to explain the inheritance and expression of Celiac Disease.
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The presence of the specific HLA proteins, DQ2 or DQ8, is one of the studied genetic factors linked to Celiac. HLA-DQ2 and HLA DQ-8, located on chromosome 6p21.3, are not coded for in everyone's DNA, (Koning, 2005). While only a minority of people expressing DQ2 actually develop Celiac Disease, (Koning, 2005), 95% of people who have Celiac also code for one of these two proteins, (Holtmeier, 2006). If a person with Celiac does not code for DQ2, which is the minority of people with Celiac Disease, he or she will almost invariably code for DQ8, (Santin, 2007). Also, an homologous carrier of HLA-DQ2 is much more likely to develop Celiac disease than is a heterozygous carrier of HLA-DQ2/DQx, because the latter, as a heterozygous carrier, would introduce more possible variations into the expression of the gene, (Koning, 2005). Finally, the HLA complex contains over a 1,000 alleles, making it very large and elaborate, (Louka, 2002). Therefore, while DQ2 and DQ8 have been definitely linked to Celiac expression, there could be a variety of other HLA genes associated with it, yet to be understood. In addition, while HLA and Celiac Disease are definitely linked, it is not the sole genetic factor influencing the expression of Celiac disease.
HLA-DQ2 and DQ8 can only account for between 30%-40% of Celiac onset, therefore, additional research has focused on chromosomal regions coding for a Celiac Disease immune system response, (Koning, 2005, Holopainen, 1998). In particular, the CD28/CTLA4 region on chromosome 2q33, associated with the T cell immune response, has been studied and linked to a variety of autoimmune diseases, thus making it a likely candidate for causes of Celiac Disease, (Holopainen, 1998, Kristiansen, 2000). Also, the T cytotoxic cell immune reaction towards gluten is a series of events, a cascade, which leads to visible tissue damage in the small intestines of people with Celiac. In particular, the interaction of the OX40 receptors, on CD-4 T cells, and OX40's ligand OX40L, are associated with tumor necrosis. This means that the body utilizes these cells against cancerous mutations, but they were also found in biopsies of inner lamina of Celiac patient's small intestines. This indicates that the genes which code for OX40 receptors and their ligands, may also play a role in the expression of Celiac, (Stuber, 2000). In addition, chromosome 11which codes for six genes, CD3E, CD3D, CD3G, IL10RA, THY1 and IL18, has also been tested for their link to Celiac Disease, (Brophy, 2010). Overall, the HLA complex may be responsible for roughly 30% to 40% of the development of Celiac, while the other above mentioned loci contribute, probably, no more than 4%, leaving a substantial amount of other unknown variables, (Brophy, 2010).
Celiac disease is, seemingly, on the rise in the United States, while in Europe it has been prevalent for quite a while, (Alessio, 2009) This is misleading and it is probably due to the fact that so many people with the disease, in the United States, are subclinical, and thus show no outward symptoms. Though the prevalence of refined grains may contribute to the heightened sensitivity noticed in people, as well as genetically modified grains; Aretaeus of Cappadocia, in the first century AD, was the first to document celiac like symptoms, (Alessio, 2009). Alessio further claims that because neolithic man was primarily a hunter-gatherer, depending on where he lived geographically, (Diamond, Jared), his diet probably lacked gluten. The discovery of agriculture not only allowed people to stay in one area and accumulate a food surplus, but also exposed people's immune systems to a new type of protein, gluten, and some immune systems reacted negatively. It was not until World War II that Willem Karel Dicke, of the Netherlands, realized that gluten was the likely source of the symptoms, which had then been observed for centuries, particularly in children. The Netherlands had experienced a bread shortage during World War II, which Dicke realized correlated with an almost complete drop in child mortality rate. His theory was soon corroborated by other scientists, and thus developed the modern day understanding of Celiac Disease, (Alessio, 2009).