ER-Localized Aminopeptidases in Ankylosing Spondylitis

强直性脊柱炎中的内质网定位氨肽酶

• 批准号: 8670551
• 负责人: Andrea na Amalfitano
• 金额: $ 28.96万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670551
• 关键词: Affect; Age of Onset; Alleles; Aminopeptidase; Animal Model; Ankylosing spondylitis; Antigen Presentation; Autoimmune Diseases; Binding; Biochemical; Biological; Biological Assay; Cell Culture Techniques; Chronic; Clinical; Collaborations; Cultured Cells; Cytokine Receptors; Cytotoxic T-Lymphocytes; Diagnosis; Disease; Disease Progression; Environmental Risk Factor; Epitopes; Frequencies; Genes; Genetic; Genetic Polymorphism; Genomics; Goals; HLA-B27 Antigen; Histocompatibility Antigens Class I; Human; Immune response; Individual; Knockout Mice; Knowledge; Lead; Link; MHC Class I Genes; Measures; Methods; Molecular; Molecular Target; Mus; Nature; Onset of illness; Pain; Pathogenesis; Pathway interactions; Peptides; Predisposition; Prevention; Research; Risk; Role; Substrate Specificity; Symptoms; System; Techniques; Testing; Transgenic Mice; Transgenic Organisms; Variant; antigen processing; clinically significant; experience; genetic association; high risk; in vivo; mouse model; novel; novel strategies; outcome forecast; preference; prevent

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.

描述（由申请人提供）：强直性脊柱炎（AS）是一种痛苦的、无法治愈的自身免疫性疾病，影响着全世界数百万人。虽然环境因素和遗传因素都与该疾病有关，但AS的病因和发病机制尚不清楚。与MHC I类等位基因HLA-B27的紧密联系暗示抗原加工是一个潜在的因素，最近的研究表明，ERAP1（一种氨基肽酶，我们和其他人已经证明与抗原加工相关）的多态性会影响患as的风险，这一假设得到了加强。我们假设ERAP1多态性直接或间接影响底物选择和修剪，因此不同的ERAP1等位基因改变了HLA-B27上的关节炎或保护肽的水平。我们将使用生化分析来测试底物特异性，培养细胞来测量对抗原处理的影响，以及转基因小鼠来测试对体内疾病的影响来测试这一假设。我们还将测试ERAP1多态性对其他已提出的影响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。该项目的目的是确定ERAP1多态性的功能影响，并了解AS的分子发病机制。该项目的长期目标是预测个体患AS的风险，并制定预防和治疗AS的方法。我们还将把对AS发病机制的理解应用于与MHC I类等位基因相关的其他自身免疫性疾病。

项目成果

ERAP1 functions override the intrinsic selection of specific antigens as immunodominant peptides, thereby altering the potency of antigen-specific cytolytic and effector memory T-cell responses.

ERAP1 的功能超越了作为免疫显性肽的特定抗原的内在选择，从而改变了抗原特异性溶细胞和效应记忆 T 细胞反应的效力。

• DOI: 10.1093/intimm/dxu078
• 发表时间: 2014
• 期刊: International immunology
• 影响因子: 4.4
• 作者: Rastall,DavidPW;Aldhamen,YasserA;Seregin,SergeyS;Godbehere,Sarah;Amalfitano,Andrea
• 通讯作者: Amalfitano,Andrea

ERAP1 deficient mice have reduced Type 1 regulatory T cells and develop skeletal and intestinal features of Ankylosing Spondylitis.

• DOI: 10.1038/s41598-018-30159-5
• 发表时间: 2018-08-20
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Pepelyayeva Y;Rastall DPW;Aldhamen YA;O'Connell P;Raehtz S;Alyaqoub FS;Blake MK;Raedy AM;Angarita AM;Abbas AM;Pereira-Hicks CN;Roosa SG;McCabe L;Amalfitano A
• 通讯作者: Amalfitano A

Autoimmune disease-associated variants of extracellular endoplasmic reticulum aminopeptidase 1 induce altered innate immune responses by human immune cells.

• DOI: 10.1159/000368899
• 发表时间: 2015
• 期刊: Journal of innate immunity
• 影响因子: 5.3
• 作者: Aldhamen YA;Pepelyayeva Y;Rastall DP;Seregin SS;Zervoudi E;Koumantou D;Aylsworth CF;Quiroga D;Godbehere S;Georgiadis D;Stratikos E;Amalfitano A
• 通讯作者: Amalfitano A

Endoplasmic reticulum aminopeptidase-1 functions regulate key aspects of the innate immune response.

• DOI: 10.1371/journal.pone.0069539
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Aldhamen YA;Seregin SS;Rastall DP;Aylsworth CF;Pepelyayeva Y;Busuito CJ;Godbehere-Roosa S;Kim S;Amalfitano A
• 通讯作者: Amalfitano A

Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens.

• DOI: 10.3109/08916934.2013.819855
• 发表时间: 2013-12
• 期刊: Autoimmunity
• 影响因子: 3.5
• 作者: Seregin SS;Rastall DP;Evnouchidou I;Aylsworth CF;Quiroga D;Kamal RP;Godbehere-Roosa S;Blum CF;York IA;Stratikos E;Amalfitano A
• 通讯作者: Amalfitano A