Endoplasmic reticulum aminopeptidases, ERAP1 and ERAP2, are zinc-dependent multifunctional homologues, implicated in the trimming of antigenic peptides in order to allow their loading on HLA-I molecules [1, 2, 3]. One of these molecules, ERAP1, is also involved in numerous physiological functions, including blood pressure regulation, neoangiogenesis, shedding of proinflammatory cytokine receptors (TNFRI, IL-6R, IL-1RII). It can be secreted by activated macrophages, inducing an increase in their phagocytic activity [4, 6, 7, 9, 10]. Recent Genome Wide Association Studies (GWAS) have identified several SNPs (Single Nucleotide Polymorphisms) strongly associated with various diseases some such as ankylosing spondylitis, Behçet's disease and psoriasis known to be immune-mediated, but also preeclampsia and hypertension [5, 6, 7]. The loss of both aminopeptidases seems to be the most often associated event connected with the lack of expression of HLA-I molecules on the cell surface, suggesting that this phenomenon may contribute to the evasion of immune surveillance by specific tumors [15]. Thus, an altered functionality of both ERAP molecules is likely to be at the base of a peptide repertoire that predisposes to an abnormal or inefficient immune response. We will focus our work on the ERAPs, studying their expression in cell lines and primary cells (monocytes and macrophages), evaluating if they are secreted by which cells, exploring the role of their genetic variants and eventually correlating these variants with protein expression. The study and identification of factors related to gene modulation of the ERAPs will provide important background information for possible manipulation of these proteins that may lead to new therapeutic strategies, not only for IMDs (Immuno-mediated diseases) but also for other diseases, such as hypertension, pre-eclampsia, viral infections and neoplastic diseases.
It is well described that an altered functionality of the ERAPs can lead to a peptide repertoire predisposing to an abnormal or inefficient immune response. However, there is an important knowledge gap as we do not know all the possible roles that the two proteins have and how they carry them out. Having a comprehensive analysis of these two ERAPs to identify their possible physiological roles and to understand the mechanisms by which they act could be the key to delineate new therapeutic strategies, not only for immuno-mediated diseases, but also for hypertension, viral infections and neoplasms. Until now, most of the work has been carried out only on ERAP1. However, understanding the functions that ERAP2 and of their different isoforms should help to clarify its role as immunomodulator but also other aspects of its biology.
References
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