The gastrointestinal tract specializes in digestion and nutrient absorption via its mucosal surface. Through this large mucosal surface, interactions between the host and its environment, including food antigens and microbes, occur. Therefore, it is imperative that the gut discriminates between innocuous food components, and potential threats such as infections. On some occasions, this fine-tuned discrimination fails, leading to chronic inflammation. Celiac disease (CeD) is an autoimmune enteropathy triggered by gluten, the name given to a family of storage proteins (prolamins) that are naturally found in wheat, barley, and rye. To develop CeD, an individual must carry the susceptibility genes, the HLA-DQ2 and/or HLA-DQ8 alleles and consume gluten. However, this is not sufficient to cause disease, indicating that environmental co-factors are at play. Individuals homozygous for the HLA-DQ2 allele are at high risk to developing CeD in infancy. Currently, there is no existing transgenic animal model that addresses early life exposure to gluten, co-factors, and their effects on CeD development. Therefore, the overall goal of my thesis is to characterize a mouse model transgenic for the HLA-DQ2 allele with exposure to gluten in early life.
I first studied the physiological and immunological responses to gluten at the time of solid food introduction using DR3-DQ2 transgenic mice. I determined that after sensitization to gluten before weaning, mice developed moderate enteropathy and some developed both anti-tissue transglutaminase 2 and anti-gliadin antibodies. I then evaluated the recovery of gluten immunopathology after gluten was removed for an extended period. After 6 months on gluten-free food, enteropathy and intestinal anti-gliadin and anti-TG2 antibody levels improved. These findings show pre-weaning sensitization of DR3-DQ2 transgenic mice reproduces key features of CeD, which can be used in future studies to assess environmental triggers and mechanisms that are of importance during early life. / Thesis / Master of Science in Medical Sciences (MSMS) / Celiac disease is the destruction of the upper gut lining by an immune reaction caused by gluten in people with genetic risk. Celiac patients cannot absorb nutrients well and have many complications. While it can occur at any age, its onset in children is associated with the HLA-DQ2 gene. Because not every child with the HLA-DQ2 gene will develop celiac disease, additional factors are suspected. Understanding these factors could help prevent disease, as the only treatment – a life-long gluten-free diet – is not always effective. Thus, an animal model that mimics early life disease onset would be useful. Therefore, I characterized signs of celiac disease in young mice with the HLA-DQ2 gene. I determined that gluten and a microbial toxin given in early life induces inflammation and positive celiac blood tests. This model constitutes a useful tool to test the role of environmental factors in celiac disease in early life.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27857 |
| Date | January 2022 |
| Creators | Godbout, Julie K. |
| Contributors | Verdú, Elena F., Medical Sciences (Division of Physiology/Pharmacology) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
Page generated in 0.0017 seconds