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Cysteine Proteases in MHC Class II Antigen Presentation

MHC II 类抗原呈递中的半胱氨酸蛋白酶

基本信息

批准号：
7162129
负责人：
Harold A Chapman
金额：
$ 32.32万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-01-01 至 2007-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7162129
关键词：
Affect Allergens Antibody Formation Antigen Presentation Antigen-Presenting Cells Antigens Asthma Autoimmunity B-Cell Development B-Lymphocytes Biological Assay CD4 Positive T Lymphocytes Cathepsins Cell Communication Cell physiology Cysteine Protease Cysteine Proteinase Inhibitors Dendritic Cells Development Disease Effectiveness Endopeptidases Gene Expression Goals Histocompatibility Antigens Class II Human IL4 gene IgE Immune Immune System Diseases Immune response Immunity Learning Lung Lung diseases MHC Class II Genes Messenger RNA Molecular Molecular Chaperones Mus Myelogenous Peptide Hydrolases Peptide/MHC Complex Peptides Physiologic pulse Pneumonia Population Process Production Progress Reports Protease Inhibitor Pulse taking Research Role T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte Testing antigen processing base cathepsin F cytokine in vivo invariant chain macrophage mast cell reconstitution research study response trafficking

项目摘要

The endosomal cysteine protease, cathepsin S, has a key role in MHC class II (MHCII)-dependent immunity through its role in degradation of the MHCII-associated chaperone, the invariant chain (Ii). But studies of cathepsin S -/- mice also reveal unexpected findings. Cathepsin S deficiency predominantly affects Thl- dependent immunity. IgE responses and Th2-driven pulmonary inflammation, while dependent on cysteine proteases, are normal or increased in cathepsin S -/- mice. Indeed baseline IgE levels and lung mRNA of proinflammatory cytokines in these mice are elevated. Surprisingly, high IgE levels and cytokines are mast cell-dependent. These observations imply additional proteases, and perhaps additional antigen presenting cells (APC), are important to MHCII function and that protease dysregulation can skew, not just block, MHCII-dependent immune responses. Experiments are directed toward understanding how proteases can effect polarization of T and B cell development relevant to lung disease. Mechanisms of peptide loading in cathepsin S-deficient APC will be defined. Mice deficient in the Ii-degrading APC protease cathepsin F have been recently generated and will be used to test the hypothesis that cathepsin F rescues MHC class II peptide display in myeloid APCs, thereby favoring Th2 polarization. Selective protease inhibitors will be used to determine if a set of protease activities in human APC are required for Th2 cytokine production by allergen- stimulated T cells. The mechanisms by which mast cells promote APC-dependent IgE production will be explored by reconstitution of mast cell deficient mice (Wsh) with mast cells cultured from S-/- or cytokine- deficient mice. The overall goal of this application is to understand the molecular basis for protease- dependent polarization of T cell and B cell immune responses and to learn how to exploit this process to ameliorate CD4+ T cell driven disorders such as autoimmunity and asthma.

内体半胱氨酸蛋白酶，组织蛋白酶S，在MHC II类（MHCII）依赖性免疫中具有关键作用通过其在MHCII相关的分子伴侣不变链（Ii）的降解中的作用。但是，组织蛋白酶S -/-小鼠也揭示了意想不到的发现。组织蛋白酶S缺乏主要影响Thl- 依赖性免疫IgE反应和Th 2驱动的肺部炎症，同时依赖于半胱氨酸蛋白酶在组织蛋白酶S -/-小鼠中是正常的或增加的。事实上，基线IgE水平和肺mRNA的这些小鼠中的促炎细胞因子升高。令人惊讶的是，高IgE水平和细胞因子是肥大细胞，依赖细胞的这些观察结果意味着额外的蛋白酶，可能还有额外的抗原呈递细胞（APC），对MHCII功能很重要，蛋白酶失调可以扭曲，而不仅仅是阻断， MHCII依赖性免疫反应。实验旨在了解蛋白酶如何影响与肺部疾病相关T和B细胞发育的极化。肽负载机制将定义组织蛋白酶S缺陷型APC。Ii降解APC蛋白酶组织蛋白酶F缺陷的小鼠具有最近产生的，并将用于测试假设，组织蛋白酶F拯救MHC II类肽在骨髓APC中显示，从而有利于Th 2极化。选择性蛋白酶抑制剂将用于确定人APC中的一组蛋白酶活性是否是过敏原产生Th 2细胞因子所需的，刺激T细胞。肥大细胞促进APC依赖性IgE产生的机制将是通过用从S-/-或细胞因子- 缺陷小鼠本申请的总体目标是了解蛋白酶的分子基础- T细胞和B细胞免疫应答的依赖性极化，并学习如何利用这一过程，改善CD 4 + T细胞驱动的疾病，如自身免疫和哮喘。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Interferon gamma induction of pulmonary emphysema in the adult murine lung.

成年鼠肺中肺肺气肿的干扰素γ诱导。

DOI：
10.1084/jem.192.11.1587
发表时间：
2000-12-04
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Wang Z;Zheng T;Zhu Z;Homer RJ;Riese RJ;Chapman HA Jr;Shapiro SD;Elias JA
通讯作者：
Elias JA

Importance of lysosomal cysteine proteases in lung disease.

DOI：
10.1186/rr29
发表时间：
2000
期刊：
Respiratory research
影响因子：
5.8
作者：
Wolters PJ;Chapman HA
通讯作者：
Chapman HA

Murine cathepsin F deficiency causes neuronal lipofuscinosis and late-onset neurological disease.

鼠组织蛋白酶 F 缺乏会导致神经元脂褐质沉着症和迟发性神经系统疾病。

DOI：
10.1128/mcb.26.6.2309-2316.2006
发表时间：
2006
期刊：
Molecular and cellular biology
影响因子：
5.3
作者：
Tang,Chi-Hui;Lee,Je-Wook;Galvez,MichaelG;Robillard,Liliane;Mole,SaraE;Chapman,HaroldA
通讯作者：
Chapman,HaroldA