Unraveling the role of HLA-B51/ERAP1 in Behcet's eye disease

摘要/项目摘要 具有ERAP1单倍型Hap10的HL A-B*51具有目前已知的最强的白塞病(BD)和白塞氏眼病(BED)风险，但这种关系对免疫表型、克隆性和功能的影响完全未知。本应用程序的主要目标是确定这些后果。这符合我们的长期目标，即发现、理解和纠正导致白塞氏眼病(BED)的免疫途径中的异常。 基于我们的初步研究，我们提出的中心假设是ERAP1 Hap10通过激活驱动疾病的克隆性CD8T和NKT效应细胞群来形成HLA-B*51+BED中的免疫反应。我们遵循的基本原理是，阐明HLA-B51/ERAP1 Hap10的生物学后果将促进对受影响携带者BED的机制理解，从而实现有针对性的治疗设计。 我们将在两个具体目标上验证我们的中心假设：1)通过确定与HLA-B*51+/ERAP1 Hap10床位相关的免疫表型，结合使用我们开发的计算工具进行大规模流式细胞仪分析，获得我们自己和我们的国际合作者的独特患者队列。2)采用单细胞转录法和T细胞克隆方法鉴定卧床患者的克隆性效应反应和功能。 满足这项建议的目标将产生知识，为设计有针对性的卧床疗法提供科学依据，卧床是最具破坏性的非感染性葡萄膜炎形式之一，在世界大部分地区发病率很高。我们期望通过交叉研究其他与人类白细胞抗原-I/ERAP相关的疾病，包括人类白细胞抗原-B27相关的葡萄膜炎和脊柱炎、鸟枪病的脉络膜病、牛皮癣相关疾病和炎症性肠病(IBD)，产生更多的积极影响。

ABSTRACT / PROJECT SUMMARY HLA-B*51 in epistasis with the ERAP1 haplotype Hap10 confers the strongest currently known risk for Behcet’s Disease (BD) and Behcet’s Eye Disease (BED), but the consequences of this relationship for immune-phenotype, clonality, and function, are entirely unknown. The main objective of this application is to identify these consequences. This is in line with our long-term goal to find, comprehend, and correct aberrancies in immune pathways that drive Behcet’s Eye Disease (BED). Based on our preliminary studies we propose as our central hypothesis that ERAP1 Hap10 shapes immune responses in HLA-B*51+ BED through the activation of clonal CD8 T and NKT effector cell populations that drive the disease. We follow the rationale that elucidation of the biological consequences of HLA-B51/ERAP1 Hap10 will promote a mechanistic understanding of BED in affected carriers, and therefore enable targeted therapy design. We will test our central hypothesis in two specific aims: 1) Through the determination of immune phenotypes linked to HLA-B*51+/ERAP1 Hap10 BED, combining access to unique patient cohorts of our own and those of our international collaborators with large-scale flow cytometric analyses using computational tools we have developed. 2) Through the identification of clonal effector responses and function in BED patients using single cell-transcriptomics and methods of T cell cloning we have established. Meeting the objective of this proposal will generate knowledge providing scientific rationale for the design of targeted therapies for BED, which is one of the most devastating forms of non-infectious uveitis with significant prevalence in large parts of the world. We expect additional positive impact by cross-fertilizing research of other HLA-I/ERAP-related diseases including HLA-B27-associated uveitis and spondylitis, Birdshot’s choroidopathy, psoriasis-associated conditions, and inflammatory bowel disease (IBD).