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）：该项目旨在测试 T 细胞对自身抗体可变区中体细胞生成的序列作出反应介导狼疮性肾炎 (LN) 病理学发展的基本想法。多年对 LN 免疫生物学的研究已经证明了肾小球内皮中 B 细胞、浸润性 T 细胞和免疫复合物的病理能力。炎症性肾浸润 T 细胞（分泌 IFN3 的 Th1 细胞和分泌 IL-17 的 Th17 细胞）会募集先天效应细胞，对肾小球细胞造成损伤。然而，T 细胞启动的机制、肾 T 细胞的特异性以及最初如何引发自身抗体仍然是尚未解答的重大问题。我假设这些问题可以通过 T 细胞来解释，T 细胞对源自自身抗体的 MHC II 呈递肽发生反应，并分化为肾脏病理学的炎症介质。这一假设的重要性不仅适用于疾病的发生，也适用于其治疗，因为由抗体肽特异性 T 细胞驱动的人类抗嵌合抗体 (HACA) 可能在 LN 对单克隆抗体治疗的意外可变反应中发挥作用。为了验证这一假设，我将使用 SLE 合并肾炎的过继转移模型，其中将针对 V: 肽的特异性 T 细胞引入到在 B 细胞中表达相应 Ig: 转基因的小鼠中。我将确定后来在患有 LN 的小鼠中出现的肾炎性 Th1 和 Th17 T 细胞是否是 V: 肽特异性的，或者是通过决定簇扩散源自内源性细胞群。将评估 V：肽特异性和内源性 CD4 T 细胞的显微解剖定位以及它们参与与 Ig：肾脏中转基因 B 细胞形成缀合物的情况。我将把这一分析扩展到 LN 的抗肾小球基底膜 (GBM) 模型，其中肾脏中的 T 细胞群可能对自体或异源抗体有反应。最后，我将检验以下假设：免疫复合物中的 IgG 对 V: 肽特异性 T 细胞具有免疫原性和促炎性，并且这取决于 Ig 聚糖含量。相反，我预测 IgM 具有免疫原性但非炎症性。这项工作的结果将揭示有关肾炎性 T 细胞潜在抗原特异性的重要信息，并深入了解在接受单克隆抗体治疗的患者中促进 HACA 反应的机制。