HLA-peptide repertoire in autoimmunity

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DESCRIPTION (provided by applicant): Ankylosing Spondylitis (AS) is a chronic inflammatory joint disease of the axial skeleton. It causes joint inflammation of the spine and pelvis, ultimatey leading to fusion of the spine. The disease affects people worldwide and is highly heritable, with >90% of the risk of developing the disease determined genetically. The human MHC class I molecule HLA-B27 is strongly associated with AS, but the molecular basis of the association of HLA-B27 with AS remains unclear. Recently, the ER-resident aminopeptidase ERAAP (ERAP1 in human) was shown to be also strongly associated with AS. ERAAP is a crucial component for generating peptide-HLA class I complexes. Multiple genome-wide association studies have identified several polymorphisms in the ERAAP gene that increase the risk of AS as much as 26%. How these polymorphisms affect the biological function of ERAAP or what role they might play in onset of the disease is not known. Here we test the hypothesis that ERAAP-polymorphisms alter the peptide-repertoire presented by HLA-B27 resulting in T cell responses involved in the onset of AS. This exploratory grant proposal will analyze human ERAAP function in living cells under physiological conditions, as well as assess the effect of ERAAP polymorphism on immune responses in HLA-B27 transgenic mice. We expect the completion of these aims to provide new insights into changes that occur in the HLA-B27 peptide repertoire in AS as well as provide key tools for future studies of this potentially debilitating disease.