This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.

Below is a copy of my final presentation in both Powerpoint and Keynote format:

File Size: 2142 kb
File Type: ppt
Download File

File Size: 2055 kb
File Type: key
Download File


 The goal of this experiment was to determine the mechanism of the toxic immune response associated with celiac disease.  I began by exploring information on the gene HLA-DQA1 and its association with celiac disease.  The finding that HLA-DQA1 functions critically in the immune system strengthened the previously completed data available on the gene and its predicted involvement in celiac disease.  I also found 4 homologous organisms: chimpanzee, domestic dog, rat, and mouse.  The homologous genes in these organisms demonstrate that HLA-DQA1 is well conserved in other mammals.  I was able to create phylogenetic trees demonstrating the relatedness of these homologs, showing they would all be good options for an HLA-DQA1 model system.  

Further investigation of HLA- DQA1 protein domains and gene ontology allowed me to narrow down its cellular role, functioning in the membrane to present peptides to T-cells.  I found that HLA-DQA1 contains an MHC class II alpha domain functioning in cell-cell interaction; and an Immunoglobulin C-1 set domain functioning in cell-cell recognition, cell surface reception, and the immune system.  These protein domains were found to be conserved across the homologs, specifically 71.8% in the mouse.  However, the cellular function of HLA-DQA1 did not lead me to discover the exact mechanism that initiates the toxic immune response associated with celiac disease.

A PubChem search led me to the protein gliadin, a simple protein derived from the gluten of wheat, rye, and barley.  Gliadin has been found to be the known toxic factor associated with celiac disease, although its mechanism in how it functions at the molecular level remains unknown.  One strong mechanism that has been proposed involves the binding of the gliadin peptide to the HLA-DQA1/DQB1 heterodimer.  This heterodimer is then proposed to present the gliadin peptide to T-cells, which ultimiately mediate the inflammatory, toxic immune response.  This is the mechanism that I chose to investigate as I moved forward in my HLA-DQA1 research.

Then, I analyzed the HLA-DQA1 expression levels using previously completed microarray data.  Previous data displayed here, shows high HLA-DQA1 expression in WT peripheral blood samples and low/zero HLA-DQA1 expression in celiac disease peripheral blood samples.  I wanted to look further into the expression levels of HLA-DQA1 and its relation to gliadin levels.   I could not find any direct information on this relationship, but based on this previous data I would predict that increased gliadin levels would decrease the HLA-DQA1 expression.  Going off of this HLA-DQA1 microarray data, I then looked into the phenotypes that were associated with the different expression levels.  I was unable to find any published data on the phenotypic damage of the small intestine and its relationship with either gliadin levels or HLA-DQA1 expression levels.  However, once again based on previously completed microarray data I would predict that the damage to the small intestine would increase with increased levels of gliadin, corresponding to low/zero HLA-DQA1 expression levels.  

Lastly, I looked into the predicted protein interaction web of HLA-DQA1.  I found three primary interacting proteins that confirmed the role HLA-DQA1 plays in the presentation of peptides to T-cells and its role in the immune system.  Based on the main goal of this experiment, I first wanted to research how gliadin is affecting HLA-DQA1.  I did not find any published research on this relationship, but believe that further research should be applied here.  I would predict that research would show gliadin either binding directly to HLA-DQA1 or one of its primary interacting proteins shown in the interaction web.  

In conclusion, the data that I have found in my research on HLA-DQA1 and celiac disease shows that further research needs to be done on the molecular mechanisms of proteins involved, specifically the relationship between gliadin and HLA-DQA1.  

Future Directions

  1. MUDPIT- Multidimensional Protein Identification Technology: Take intestinal tissue samples from WT and celiac disease patients, observe specific protein identifications from each sample.  I predict that the HLA-DQA1 protein should be found at high levels in the WT tissue samples, while at very low levels/zero in celiac disease tissue samples.
  2. Microarray primary interacting proteins of HLA-DQA1: Look at expression levels of these proteins in  WT patient tissue samples versus celiac disease patient tissue samples- are these proteins expressed in similar patterns as HLA-DQA1?