ER-localized aminopeptidases in ankylosing spondylitis

描述(申请人提供)：强直性脊柱炎(AS)是一种痛苦的、不可治愈的自身免疫性疾病，影响着全球数百万人。虽然环境因素和遗传因素都与该病有关，但AS的病因和发病机制尚不清楚。与MHC-I类等位基因HLA-B27有很强的联系，这意味着抗原处理是一个潜在的因素，最近有证据表明ERAP1(我们和其他人已经证明与抗原处理相关的一种氨基肽酶)的多态性影响发生AS的风险，这一假设得到了加强。我们假设ERAP1基因的多态直接或间接地影响底物的选择和修剪，因此不同的ERAP1等位基因改变了人类白细胞抗原B27上的致关节炎或保护性多肽的水平。我们将使用底物特异性的生化分析来验证这一假设，用培养细胞来测量对抗原处理的影响，并用转基因小鼠来测试体内对疾病的影响。我们还将测试ERAP1基因多态性对其他已被认为影响AS发病机制的途径的影响，包括HLA-B27的组装和稳定性以及细胞因子受体的脱落。本项目的目的是确定ERAP1基因多态性的功能效应，并了解AS的分子发病机制。该项目的长期目标是预测个体AS的风险，并开发预防和治疗AS的方法。我们还将把对AS发病机制的理解应用于其他与MHC I类等位基因相关的自身免疫性疾病。 公共卫生相关性：强直性脊柱炎是一种痛苦、慢性、无法治愈的自身免疫性疾病，影响着全球数百万人。虽然很明显，遗传和环境因素都涉及，但这种疾病的根本原因和机制尚不清楚。在这个项目中，我将利用最近描述的与ERAP1基因的关联来确定导致强直性脊柱炎的机制，最终目标是开发新的技术来预测强直性脊柱炎的风险，并预防和治疗这种疾病。

DESCRIPTION (provided by applicant): Ankylosing spondylitis (AS) is a painful, incurable autoimmune disease that affects millions of people worldwide. Although it is clear that both environmental and genetic factors are involved in the disease, the cause and pathogenesis of AS remain unclear. A strong link with the MHC class I allele HLA-B27 has implicated antigen processing as an underlying factor, and this hypothesis was strengthened by the recent demonstration that polymorphisms in ERAP1 (an aminopeptidase that we and others have shown is associated with antigen processing) affect the risk of developing AS. We hypothesize that ERAP1 polymorphisms either directly or indirectly affect substrate selection and trimming, so that different ERAP1 alleles alter the levels of arthritogenic or protective peptides presented on HLA-B27. We will test this hypothesis using biochemical assays for substrate specificity, cultured cells to measure effects on antigen processing, and transgenic mice to test effects on disease in vivo. We will also test the effects of ERAP1 polymorphisms on other pathways that have been proposed to affect AS pathogenesis, including the assembly and stability of HLA- B27 and shedding of cytokine receptors. The Aims of this project are to determine the functional effects of ERAP1 polymorphisms and to understand the molecular pathogenesis of AS. The long-term goals of this project are to predict the risk of AS in individuals, and to develop methods to prevent and treat AS. We will also apply the understanding of AS pathogenesis to other autoimmune diseases that are linked to MHC class I alleles. PUBLIC HEALTH RELEVANCE: Ankylosing spondylitis is a painful, chronic, incurable autoimmune disease that affects millions of people worldwide. Although it is clear that both genetic and environmental factors are involved, the underlying causes and mechanisms of the disease are not known. In this project I will take advantage of a recently-described association with the gene ERAP1 to identify mechanisms that cause ankylosing spondylitis, with the ultimate goal of developing new techniques to predict the risk of ankylosing spondylitis, and to prevent and treat the disease.