Autoantibody and BCR peptide-specific T cells in lupus nephritis

狼疮性肾炎中的自身抗体和 BCR 肽特异性 T 细胞

• 批准号: 8326442
• 负责人: James Ben St Clair
• 金额: $ 2.81万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8326442
• 关键词: Address; Adoptive Transfer; Antibodies; Antibody Formation; Antigen-Antibody Complex; Antigenic Specificity; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autologous; B-Cell Development; B-Lymphocytes; Belief; CD4 Positive T Lymphocytes; Cells; Chimera organism; Complex; Deposition; Development; Disease; Effector Cell; Genes; Heterophile Antibodies; Human; Immunobiology; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunoglobulin Variable Region; Immunoglobulins; Inflammation Mediators; Inflammatory; Interleukin-17; Kidney; Kidney Diseases; Knowledge; Laboratories; Learning; Light; Link; Literature; Lupus; Lupus Nephritis; Lymphatic Diseases; Mediating; Modeling; Monoclonal Antibody Therapy; Mus; Mutate; Mutation; Nature; Nephritis; Nuclear; Pathologic; Pathology; Patients; Peptide antibodies; Peptides; Play; Polysaccharides; Population; Reaction; Receptors, Antigen, B-Cell; Recruitment Activity; Reporting; Research; Role; Specificity; Splenomegaly; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Tissues; Transgenes; Transgenic Organisms; Work; adaptive immunity; clinically significant; glomerular basement membrane; glomerular endothelium; immunogenic; immunogenicity; insight; lupus-like; membrane model; mouse model; neutralizing antibody; novel; peptide V; response; rituximab

DESCRIPTION (provided by applicant): This is a project to test the basic idea that T cells reacting to somatically generated sequences in autoantibody variable regions mediate the development of pathology in lupus nephritis (LN). Many years of research into the immunobiology of LN have demonstrated the pathologic capacity of B cells, infiltrating T cells, and immune complexes in the glomerular endothelium. Inflammatory kidney-infiltrating T cells, both IFN3-secreting Th1 and IL-17-secreting Th17 cells, recruit innate effector cells, which inflict damage upon glomerular cells. However, the mechanisms by which T cells are primed, the specificity of renal T cells, and how autoantibodies are initially elicited are still large unanswered questions. I hypothesize that these questions can be explained by T cells that react to MHC II-presented peptides derived from autoantibodies and that differentiate into inflammatory mediators of kidney pathology. The significance of this hypothesis applies not only to genesis of disease but also to its treatment, as human anti-chimera antibodies (HACA) driven by antibody peptide-specific T cells may play a role in the unexpectedly variable response of LN to monoclonal antibody therapy. To test this hypothesis, I will use an adoptive transfer model of SLE with nephritis in which T cells specific for a V: peptides are introduced into a mouse expressing a corresponding Ig: transgene in B cells. I will determine whether nephritogenic Th1 and Th17 T cells that later arise in mice with LN are V: peptide-specific or instead are derived from an endogenous population via determinant spreading. Both V: peptide-specific and endogenous CD4 T cells will be assessed for microanatomical localization and for their participation in conjugate formation with Ig: transgenic B cells in the kidney. I will extend this analysis to anti-glomerular basement membrane (GBM) models of LN, in which T cell populations in the kidneys may be responsive to either autologous or heterologous antibodies. Finally, I will test the hypothesis that IgG in immune complexes is immunogenic and proinflammatory for V: peptide-specific T cells, and that this is dependent upon Ig glycan content. In contrast, I predict that IgM is immunogenic but noninflammatory. The results of this work will reveal important information about potential antigenic specificities of nephritogenic T cells and provide insight into mechanisms that promote HACA responses in patients that receive monoclonal Ab therapy.

描述（由申请人提供）：这是一个测试基本思想的项目，即T细胞对自身抗体可变区域中体体产生序列的反应介导了狼疮肾炎（LN）中病理学的发展。多年来对LN免疫生物学的研究已经证明了肾小球内皮中B细胞，浸润T细胞和免疫复合物的病理能力。炎症性肾脏浸润的T细胞，分泌Th1和IL-17分泌Th17细胞的IFN3，募集了先天效应细胞，这会损害肾小球细胞。但是，T细胞启动的机制，肾脏T细胞的特异性以及自身抗体最初的引起的方式仍然是很大的未解决问题。我假设这些问题可以用T细胞对自身抗体衍生的MHC II呈现肽的反应，并分化为肾脏病理学的炎症介质。该假设的重要性不仅适用于疾病的起源，而且还适用于其治疗，因为由抗体肽特异性T细胞驱动的人类抗奇异抗体（HACA）可能在LN对单克隆抗体治疗的意外变化反应中起作用。为了检验这一假设，我将使用肾炎的SLE的产物转移模型，其中将特异性的T细胞引入了v：肽中的小鼠中，表达了相应的Ig：在B细胞中的转基因。我将确定后来在LN小鼠中出现的肾病性Th1和Th17 T细胞是V：肽特异性的，还是通过确定性扩散从内源群体中得出。 V：将评估肽特异性和内源性CD4 T细胞的微解剖学定位，并参与与肾脏中的Ig：转基因B细胞共轭形成。我将将此分析扩展到LN的抗斜体基底膜（GBM）模型，其中肾脏中的T细胞种群可能对自体或异源抗体有反应。最后，我将检验以下假设：V：肽特异性T细胞中的IgG是免疫原性和促炎性的，并且这取决于IG糖糖含量。相反，我预测IGM是免疫原性但非炎症的。这项工作的结果将揭示有关肾脏生成T细胞潜在抗原特异性的重要信息，并洞悉促进接受单克隆AB疗法患者的HACA反应的机制。