MECHANISM OF AUTOIMMUNE RESPONSE IN HUMAN LUPUS

人类狼疮的自身免疫反应机制

• 批准号: 6043194
• 负责人: SYAMAL K DATTA
• 金额: $ 17.86万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2000-08-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6043194
• 关键词: B lymphocyte; CD40 molecule; MHC class II antigen; SCID mouse; T cell receptor; antibody formation; antigen presentation; antinuclear autoantibody; autoantigens; biological signal transduction; epitope mapping; helper T lymphocyte; human tissue; ligands; systemic lupus erythematosus; tissue /cell culture; tissue mosaicism

DESCRIPTION (Adapted from Investigator's abstract): The long term objective of this project is to define the fundamental mechanism of the major autoimmune disease, Systemic Lupus Erythematosus (SLE). Analysis of the structure and antigenic specificities of the receptors expressed by the select T helper (TH) cells that induce the production of pathogenic autoantibodies in SLE, may lead to an understanding of the etiologic mechanism of lupus in humans. The goal of the first set of specific aims is to define the antigen receptor mediated signal for the pathogenic autoantibody-inducing Th cells of human lupus. Critical peptide autoepitopes in nucleosomal antigens that trigger lupus Th cells will be identified by eluting naturally processed peptides from MHC molecules and by overlapping peptide synthesis. The disease relevance of the peptide epitopes will be determined in vivo using a SCID-human lupus adoptive transfer system. After fine mapping of MHC and TCR contact residues in the peptide autoepitopes, altered peptide ligands will be designed for blocking pathogenic autoantibody-inducing Th cells from lupus patients. The objective of the second set of specific aims is to define the role of costimulatory signals in the cognate interaction between the select Th and B-cells of lupus that leads to the production of pathogenic autoantibodies. The role of the CD40 ligand molecule (CD40L) in providing the second signal via CD40 on lupus B-cells for production of pathogenic autoantibodies will be studied. The mechanism of hyperexpression of CD40L in the T-cells, and more unexpectedly in the B-cells of lupus patients, will be investigated. Proposed studies on the regulation of CD40L gene expression may reveal an intrinsic defect in lupus which will be important in understanding the basic mechanism of T-cell and B-cell hyperactivity in this disease and will be of diagnostic and prognostic value as well.

描述（改编自研究者摘要）：长期目标

项目成果

Regulatory T cell (Treg) subsets return in patients with refractory lupus following stem cell transplantation, and TGF-beta-producing CD8+ Treg cells are associated with immunological remission of lupus.

• DOI: 10.4049/jimmunol.0901773
• 发表时间: 2009-11-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Zhang L;Bertucci AM;Ramsey-Goldman R;Burt RK;Datta SK
• 通讯作者: Datta SK

Promiscuous presentation and recognition of nucleosomal autoepitopes in lupus: role of autoimmune T cell receptor alpha chain.

狼疮中核小体自身表位的混杂呈现和识别：自身免疫 T 细胞受体 α 链的作用。

• DOI: 10.1084/jem.187.3.367
• 发表时间: 1998
• 期刊: The Journal of experimental medicine
• 作者: Shi,Y;Kaliyaperumal,A;Lu,L;Southwood,S;Sette,A;Michaels,MA;Datta,SK
• 通讯作者: Datta,SK

Lupus: key pathogenic mechanisms and contributing factors.

狼疮：关键致病机制和影响因素。

• DOI: 10.1006/clin.1995.1146
• 发表时间: 1995
• 期刊: Clinical immunology and immunopathology
• 作者: Mohan,C;Datta,SK
• 通讯作者: Datta,SK

T cell receptor alpha-chain repertoire of pathogenic autoantibody-inducing T cells in lupus mice.

狼疮小鼠致病性自身抗体诱导 T 细胞的 T 细胞受体 α 链库。

• 发表时间: 1994
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Mao,C;Osman,GE;Adams,S;Datta,SK
• 通讯作者: Datta,SK

Regulatory defects in Cbl and mitogen-activated protein kinase (extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells.

Cbl 和丝裂原激活蛋白激酶（细胞外信号相关激酶）途径的调节缺陷导致人狼疮 T 细胞中 CD40 配体持续过度表达。

• DOI: 10.4049/jimmunol.165.11.6627
• 发表时间: 2000
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Yi,Y;McNerney,M;Datta,SK
• 通讯作者: Datta,SK