Ankylosing Spondylitis (AS) is a disease with strong genetic basis. that primarily affects the spine, causing chronic pain and discomfort.
The gene conferring the higher risk is HLA-B27, present in over 85% of patients.
Other genes have been found to contribute to the disease among which the aminopeptidases of the ER (ERAP1 and ERAP2). Their role is to influence the peptide repertoire, in particular that of the HLA-B27 molecules.
Understanding how qualitative and quantitative variations of the two ERAPs influence HLA-B27 expression and its peptide repertoire is therefore likely to give insights into the disease pathogenesis.
This project is aimed to investigate these aspects with the following tasks:
. Correlation of the ERAP1/ERAP2 transcript and protein levels with the magnitude of HLA-B27-restricted CD8+ T cell responses to viral and self peptides.
. Analysis of the relative ERAP1 and ERAP2 expression in polarized M1 and M2 macrophages in dependence of SNPs variations
Quantitative trait loci variations in gene expression (eQTL) is an important albeit disregarded aspect in pathology. This is due to several reasons among which the difficulties to identify the causes of such behavior which can go from epigenetic controls to tissue and cell specific variations. In this context, our identification of a SNP that simultaneously regulates the expression of two contiguous genes is a relevant finding. Te fact that the two genes are two amino peptidases of the ER which shape the antigenic repertoire of the HLA molecules, makes particularly interesting this aspect. Moreover, the consequences of this modulation on specific disease such as Ankylosing Spondylitis appears as particularly attractive since both ERAP genes have been found associated with the disease. In particular ERAP1 works epistatically with the HLA-B27, which is the HLA allele that contributes more to the genetic basis of Ankylosing Spondylitis. This disease is in the spotlight since many decades but its pathogenesis has not been completely elucidated. Therefore, to understand how this quantitative variations influence the HLA-B27 repertoire is particularly interesting. Moreover, there is a most relevant missing point that is the influence of the ERAPs polymorphisms on the functional activity of T cells restricted for HLA-B27. We have here the opportunity to explore how these quantitative variations affect the effector T cell response against self and viral peptides by correlating it with the ERAPs quantitative variations. In addition, it must be considered that ERAP2 has been found involved in other pathologies which are not defined as Immune Mediated Diseases (IMD) such as pre-eclampsia suggesting more than one role for this enzyme which could be performed by soluble molecules. We intend to explore also this aspect by asking which macrophage type, M1 or M2, secrete ERAP2 which, once released in the microenvironment, might play pleiotropic functions.