The molecular basis of Celiac disease

Question 1

Which peptides do HLA-DQ2 and DQ8 prefer?

Answer 1

Peptides that contain amino acids with a negative charge (E or D). Gluten doesn’t have a negatively charged peptide.

Question 2

How can it be that gluten binds to HLA-DQ2 and DQ8 in CD patients?

Answer 2

The autoantigen against Tissue transglutaminase (tG2) can modify Glutamine into Glutamic acid so it perfectly binds HLA-DQ2 / HLA-DQ8.

Question 3

When is tissue transglutaminase produced?

Answer 3

When there is tissue damage, which is caused by T-cells binding to gluten. The tTG will be produced for tissue repair but will also amplify the immune response by deamidation of glutamine into glutamic acid so it has better HLA binding.

Question 4

Why do not all HLA-DQ2/DQ8 positive people have CD?

Answer 4

Only people with a specific TCR (which contains an Arginine) can bind gluten.

Question 5

What could possibly initiate CD?

Answer 5

Molecular mimicry or cross-reactivity between microbial antigens and gluten epitopes.