Cathepsins in Antigen Presentation and Lung Immunity

组织蛋白酶在抗原呈递和肺免疫中的作用

• 批准号: 7174809
• 负责人: MANUELA CERNADAS
• 金额: $ 38.93万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174809
• 关键词: Address; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Asthma; Attention; B-Lymphocytes; CD1 Antigens; Cathepsin L; Cathepsins; Class; Complex; Cysteine Protease; Data; Defect; Dendritic Cells; Development; Endopeptidases; Enzyme Inhibition; Enzymes; Epitopes; Event; Exhibits; Genetic; Glycolipids; Graft Rejection; Histocompatibility Antigens Class II; Host Defense; Immune response; Immunity; Infection; Inflammatory; Inflammatory Response; Lung; Lung Inflammation; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Natural Immunity; Numbers; Ovalbumin; Peptide Hydrolases; Peptides; Play; Pneumonia; Principal Investigator; Process; Proteolysis; Pulmonary Tuberculosis; Regulation; Role; Sarcoidosis; Surface Antigens; T-Cell Activation; T-Lymphocyte; Testing; Tissues; alpha-galactosylceramide; antigen processing; base; cytokine; in vivo; invariant chain; mouse model; polypeptide; programs; trafficking

The immune response within the lung is critically dependent on antigen presentation by the major histocompatibility complex (MHC)class II and CD1 molecules. These antigen presentation pathways are critical effector mechanisms in asthma and host defense against infection. Endosomal cysteine proteases, including cathepsin S, play important roles in trafficking of both MHC class II and CDld. Antigen presenting cells (APC) devoid of cathepsin activity do not degrade class II-associated invariant chain (Ii) resulting in accumulation of endosomal class II-Ii complexes. Interestingly, APC from cathepsin S-deficient mice also exhibit abnormal endosomal trafficking of CD ld molecules, resulting in defective selection of NK1.1 +T cells. These data implicate an interaction between the MHC class II and CD l d antigen presentation pathways, and suggest that cysteine proteases regulate components of both innate and adaptive immunity. The central hypothesis of the proposed studies is that regulation ofcathepsin activity, particularly cathepsins S, L, and F, will control MHC class II- and CDl-restricted antigen presentation, T cell activation, and lung inflannnation. To study this hypothesis three specific aims are advanced. The first aim addresses the hypothesis that different cysteine proteases control Ii proteolysis and MHC class II function in different APC. This hypothesis will be tested by analyzing Ii processing and class II-dependent antigen presentation in cathepsin-deficient APC, derived from a variety of tissues including the lung. The second aim will focus on examining the molecular basis for class II-CDld interactions in cathepsin-deficient APC. We will address whether there is a direct class II-CD l d molecular association, or whether these interactions are solely the result of a generalized endosomal trafficking defect. The third aim is based on the premise that alteration of cathepsin activity can modulate lung immunity via effects on class II and CDld function. These studies will use a mouse model of asthma, based on ovalbumin-induced pulmonary inflammation (Th2-type), and a mouse model of mycobacterium tuberculosis pulmonary infection (Thl-type). Together, these studies will probe the basic mechanisms by which cysteine proteases regulate immunity, and will determine whether inhibition of these enzymes can effect MHC class II- and CDl-dependent inflammatory responses within the lung.

肺内的免疫应答严重依赖于由主要免疫原性抗原呈递。 组织相容性复合物（MHC）II类和CD 1分子。这些抗原呈递途径是至关重要的 哮喘和宿主防御感染的效应机制。内体半胱氨酸蛋白酶，包括 组织蛋白酶S在MHC II类和CD 1d运输中起重要作用。抗原呈递细胞（APC） 缺乏组织蛋白酶活性不降解II类相关不变链（Ii），导致 内体II-Ii类复合物。有趣的是，来自组织蛋白酶S缺陷小鼠的APC也表现出异常的 CDld分子的内体运输，导致NK1.1 +T细胞的选择缺陷。这些数据表明 MHC II类和CD 1 d抗原呈递途径之间的相互作用，并表明半胱氨酸 蛋白酶调节先天免疫和适应性免疫的组分。提出的中心假设 研究表明，组织蛋白酶活性的调节，特别是组织蛋白酶S、L和F， II和CD 1限制性抗原呈递、T细胞活化和肺部炎症。研究这个 假设提出了三个具体目标。第一个目标是解决不同的半胱氨酸蛋白酶 在不同APC中控制Ii蛋白水解和MHC II类功能。这一假设将通过分析Ii来检验 来源于多种组织的组织蛋白酶缺陷型APC中的加工和II类依赖性抗原呈递 包括肺部第二个目标将集中于研究在细胞中II类-CDld相互作用的分子基础。 组织蛋白酶缺陷型APC。我们将讨论是否存在直接的II类-CD Id分子关联，或者是否存在 这些相互作用仅仅是普遍的内体运输缺陷的结果。第三个目标是基于 前提是组织蛋白酶活性的改变可以通过影响II类和CD 1d功能来调节肺免疫。 这些研究将使用基于卵清蛋白诱导的肺部炎症（Th 2型）的哮喘小鼠模型， 和结核分枝杆菌肺部感染（Th 1型）的小鼠模型。这些研究将 探索半胱氨酸蛋白酶调节免疫的基本机制，并将确定是否抑制 这些酶的活性可以影响肺内的MHC II类和CD 1依赖性炎症反应。

项目成果

PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis.

• DOI: 10.1371/journal.pone.0033067
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Chang HH;Tai TS;Lu B;Iannaccone C;Cernadas M;Weinblatt M;Shadick N;Miaw SC;Ho IC
• 通讯作者: Ho IC

PU.1 regulates cathepsin S expression in professional APCs.

PU.1 调节专业 APC 中组织蛋白酶 S 的表达。

• DOI: 10.4049/jimmunol.176.1.275
• 发表时间: 2006
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Wang,Ying;Baron,RebeccaM;Zhu,Guangli;Joo,Myungsoo;Christman,JohnW;Silverman,EricS;Perrella,MarkA;Riese,RichardJ;Cernadas,Manuela
• 通讯作者: Cernadas,Manuela