HLA-peptide repertoire in autoimmunity

描述(申请人提供)：强直性脊柱炎(AS)是一种慢性炎症性关节疾病的轴骨。它会引起脊柱和骨盆的关节炎症，最终导致脊柱融合。这种疾病影响着世界各地的人们，具有高度的遗传性，90%的患病风险是由基因决定的。人类MHC-I类分子HLA-B27与AS密切相关，但其与AS关联的分子基础尚不清楚。最近，内质网驻留的氨基肽酶ERAAP(人类的ERAP1)也被证明与AS密切相关。ERAAP是产生多肽-人类白细胞抗原I类复合体的关键成分。多基因组关联研究已经发现ERAAP基因中的几个多态性会增加高达26%的风险。这些多态如何影响ERAAP的生物学功能，以及它们在疾病发生中可能发挥的作用尚不清楚。在这里，我们检验了ERAAP基因的多态改变了人类白细胞抗原B27所呈现的多肽谱系，从而导致T细胞反应参与AS发病的假说。这项探索性的拨款计划将分析人类ERAAP在生理条件下在活细胞中的功能，以及评估ERAAP基因多态性对HLA-B27转基因小鼠免疫反应的影响。我们希望这些目标的完成将为人类白细胞抗原-B27多肽谱的变化提供新的见解，并为这种潜在的衰弱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.