ERAP2 blocking peptide

HLA-B*40:02 is one of a few major histocompatibility complex class I (MHC-I) molecules associated with ankylosing spondylitis (AS) independently of HLA-B*27. The endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme that process MHC-I ligands and preferentially trims N-terminal basic residues, is also a risk factor for this disease. Like HLA-B*27 and other AS-associated MHC-I molecules, HLA-B*40:02 binds a relatively high percentage of peptides with ERAP2-susceptible residues. In this study, the effects of ERAP2 depletion on the HLA-B*40:02 peptidome were analyzed. ERAP2 protein expression was knocked out by CRISPR in the transfectant cell line C1R-B*40:02, and the differences between the peptidomes from the wild-type and ERAP2-KO cells were determined by label-free quantitative comparisons. The qualitative changes dependent on ERAP2 affected about 5% of the peptidome, but quantitative changes in peptide amounts were much more substantial, reflecting a significant influence of this enzyme on the generation/destruction balance of HLA-B*40:02 ligands. As in HLA-B*27, a major effect was on the frequencies of N-terminal residues. In this position, basic and small residues were increased, and aliphatic/aromatic ones decreased in the ERAP2 knockout. Other peptide positions were also affected. Because most of the non-B*27 MHC-I molecules associated with AS risk bind a relatively high percentage of peptides with N-terminal basic residues, we hypothesize that the non-epistatic association of ERAP2 with AS might be related to the processing of peptides with these residues, thus affecting the peptidomes of AS-associated MHC-I molecules.

Objectives: To determine the association between ERAP2 rs2549782 and rs17408150 polymorphisms and pre-eclampsia among Iranian women. Methods: A retrospective case-control study comparing 319 women with pre-eclampsia and 291 normotensive pregnant Iranian women between January and August 2016. Pre-eclampsia was diagnosed by the International Society for the Study of Hypertension in Pregnancy's criteria. Demographic data were collected by oral interview. Genotyping was done by allele-specific PCR. Data were analyzed using SPSS v. 16. Results: The frequency of the rs2549782TT genotype was 31.0% and 27.5% among cases and controls, respectively (P=0.006). There was no difference in the frequency of the T allele between groups (P> 0.05). Regarding the rs17408150 polymorphism, a high portion of women with pre-eclampsia was homozygous for the AA genotype (P<0.001). The frequency of the A allele was 32.5% and 25.05% among cases and controls, respectively (P=0.004). The combined haplotype of the rs2549782A and rs17408150G alleles was associated with increased risk of pre-eclampsia (P=0.031). Conclusion: ERAP2 gene polymorphisms were associated with the risk of pre-eclampsia in an Iranian population. The results provide further evidence of the role of ERAP2 in the pathophysiology of this disease.