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HLA-DQ determines the response to exogenous wheat proteins: a model of gluten sensitivity in transgenic knockout mice
The Journal of Immunology. 2002; 169(10): 5595-5600
by Black, KE. et al.
For a link to the full text online, click HERE.
Due to the lack of animal models available to study gluten sensitivity, detailed mechanisms involved in Celiac Disease have been difficult to fully understand. In “HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice", the authors set out to investigate the genetic basis of the immune response to gluten in transgenic mice. In this case, transgenic mice expressing human class II molecules, in the absence of mouse class II molecules, were used to study the mechanism that is specifically involved in the initiation of celiac disease. A protein found to be strongly linked with this initiation mechanism is Gliadin, a protein component of gluten. Susceptibility to celiac disease was also determined to be strongly associated with the HLA class II haplotype DR4/DQ8 encoded by the alleles DQA1/DQB1. These DQA1/DQA2 alleles play a role in the human immune system, specifically presenting peptides to the human CD4 T-cells [7]. Based on this previously determined evidence, the role gluten played in the transgenic mice expressing both of the above mentioned HLA-DQ and human CD4 genes was studied.
The T-cell responses of the transgenic mice to gluten and synthetic peptides of the protein gliadin were assayed. In both cases, the mice were found to produce responses that were very similar to the gluten sensitivity aspect of human celiac disease. These results proved to be extremely significant and suggested that a particular HLA haplotype is required to cause celiac disease.
Although the T-cell response levels were found to match those of human celiac disease, the transgenic mice did fail to develop the same enteropathy observed in the human small intestine following exposure to gluten. For example, in human celiac disease, the small intestine is characterized by shortened villi and gross enlargement/inflammation. There may be a lack of a gene/genes that also contribute to the disease, a lack of an environmental stimulus, or an insufficient gluten exposure time in the transgenic mice. The results discovered here hold the possibility of vaccinations and/or therapies aimed towards gluten intolerance in the future.
The T-cell responses of the transgenic mice to gluten and synthetic peptides of the protein gliadin were assayed. In both cases, the mice were found to produce responses that were very similar to the gluten sensitivity aspect of human celiac disease. These results proved to be extremely significant and suggested that a particular HLA haplotype is required to cause celiac disease.
Although the T-cell response levels were found to match those of human celiac disease, the transgenic mice did fail to develop the same enteropathy observed in the human small intestine following exposure to gluten. For example, in human celiac disease, the small intestine is characterized by shortened villi and gross enlargement/inflammation. There may be a lack of a gene/genes that also contribute to the disease, a lack of an environmental stimulus, or an insufficient gluten exposure time in the transgenic mice. The results discovered here hold the possibility of vaccinations and/or therapies aimed towards gluten intolerance in the future.
