SP3.4-TCR-HLA-DQ8-α-1-gliadin complex

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Celiac disease is a disorder that damages the lining of the small intestine when dietary gluten such as wheat barley and rye is consumed. When a person with celiac disease ingests gluten an immune response engages and damages the microvilli of the small intestine. This damage prevents nutrient absorption and causes malnourishment. [1]Celiac disease is typically a predisposed genetic disorder in individuals that express a human leukocyte antigen (HLA) DQ2 and/or HLA-DQ8 molecules. Gluten peptidases bind to these HLA-DQ8 and HLA-DQ2 molecules and cause a T cell mediated response. Specifically, TRBV9*01 is the T-cell responsible for the recognition of the HLA-DQ8-∝-I-gliadin.[2]

Background Information

In patients with celiac disease the antigen is gluten, which consists of a mixture of gliadin and glutenin polypeptides. Proteins, which are usually degraded by gastric, pancreatic, and intestinal enzymes do not usually stimulate an immune response because they are too small too bind to HLA molecules. However, gluten is able to stimulate an immune response because gluten consists of a proline rich peptide and survives through the enzymes in the gastrointestinal tract. The peptide passes through the gastrointestinal lining into the subepithelial space.[3] In the subepithelial space an enzyme called TTG deamidates the gliadin peptide at β57 changing the amino acid from Asp to Ala.[4] This deamidation makes the peptide antigenic, which allows for the identification by HLA-DQ8 and/or HLA-DQ2, the autoantigens of celiac disease. Autoantigens are apart of the immune response defense mechanism of the body and are also known as human leukocyte antigens of the major histocompatibility complex. HLA molecules bind to specific antigens.

HLA-DQ8 and HLA-DQ2 are apart of the class II MHC molecules, whose activity is commonly associated with the development disease. Between 90-95% of patients with celiac disease express HLA-DQ2 and the remaining express HLA-DQ8. Individuals with the disease can express both human leukocyte antigens. [5]

In patients with celiac disease TRBV9*01 is the T-cell responsible for the recognition of the HLA-DQ8-α-I-gliadin. Multiple types of TRBV9*01 T-cells recognize the HLA-DQ8-α-I-gliadin complex. SP3.4 is an example of a TRBV9*01 T-cell that recognizes this complex.[6]

(PDB entry 4gg6)

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Nicole Wypychowski, Jaime Prilusky

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