PhD defence: Targeting ERAPs in autoimmune uveitis: The function and regulation of ERAP2 in birdshot uveitis

We worked on understanding the role of endoplasmic reticulum aminopeptidase 2 (ERAP2) in context of autoimmune uveitis (ocular inflammation). ERAP2 trims peptides before these peptides are loaded on HLA Class I molecules. ERAP2 is associated to many autoimmune diseases of which Birdshot uveitis (BU) is one of them. This rare form of uveitis is the only autoimmune disease where all patients carry at least one HLA-A*29 allele. Therefore BU is an interesting disease to use as a model to study autoimmunity and to study antigen processing by ERAP2 and antigen presentation via HLA-A*29.

In order to study the role of ERAP2 in antigen presentation, our group developed our own patient-derived cell lines (EBV-LCLs) to identify thousands of HLA-A*29 bound peptides. Using CRISPR-Cas9 to knockout ERAP2 in these LCLs we were able to distinguish a shift in peptide abundance depending on the presence of ERAP2. As a result we were able to determine a preferable peptide motif which ERAP2 uses to trim peptides. In addition, we found that ERAP2 is involved in facilitating the presense of HLA-A*29 exclusive peptides. Finally, we looked into a long debated protein called S-antigen to validate if this protein can cause an inflammatory response via HLA-A*29.
Apart from the function of ERAP2 we also assessed the regulation of the ERAP2 gene. Here we studied the function of single nucleotide polymorphisms related to ERAP2 expression. We found that some SNPs are involved in creating a chromatin loop structure that might influence the expression of ERAP2.
With our work we were determined to validate and translate genetic associations (which are often found, but not explained) towards a more clear understanding how in this case the ERAP2 association with (ocular) autoimmunity influences inflammation.