HLA-peptide repertoire in autoimmunity

描述（由申请人提供）：强直性脊柱炎（AS）是中轴骨骼的慢性炎症性关节疾病。它会引起脊柱和骨盆的关节炎症，最终导致脊柱融合。该疾病影响世界各地的人们，并且具有高度遗传性，其中>90%的发展该疾病的风险由遗传决定。人类MHC I类分子HLA-B27与AS密切相关，但HLA-B27与AS相关的分子基础尚不清楚。最近，ER驻留氨肽酶ERAAP（ERAP 1在人类）也被证明与AS密切相关。ERAAP是产生肽-HLA I类复合物的关键组分。多个全基因组关联研究已经确定ERAAP基因中的几个多态性使AS的风险增加多达26%。这些多态性如何影响ERAAP的生物学功能或它们在疾病发作中可能发挥的作用尚不清楚。在这里，我们测试的假设，ERAAP多态性改变的肽库提出的HLA-B27导致T细胞反应参与AS的发病。这项探索性的资助计划将分析人类ERAAP在生理条件下活细胞中的功能，以及评估ERAAP多态性对HLA-B27转基因小鼠免疫反应的影响。我们期望这些目标的完成为AS中HLA-B27肽库的变化提供新的见解，并为这种潜在的衰弱性疾病的未来研究提供关键工具。

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.