Antigen Presentation by B Cells in T Cell Mediated Autoimmunity

T 细胞介导的自身免疫中 B 细胞的抗原呈递

• 批准号: 8379871
• 负责人: VIJAY K. KUCHROO
• 金额: $ 43.64万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8379871
• 关键词: Address; Age; Animal Model; Animals; Antibodies; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Cell Differentiation process; Cells; Central Nervous System Diseases; Clinical; Collaborations; Data; Demyelinations; Development; Disease; Disease Progression; Experimental Autoimmune Encephalomyelitis; Family; Foxes; Gene Expression Profiling; Generations; Human; IL2RA gene; Immune response; In Vitro; Incidence; Inflammatory; Interleukin-10; Interleukin-17; Knock-in Mouse; Laboratories; Lesion; Mediating; Membrane; Multiple Sclerosis; Mus; Myelin; Myelin Proteins; Names; Neuromyelitis Optica; Optic Nerve; Optic Neuritis; Organ; Pathogenesis; Pathogenicity; Peripheral; Play; Population; Process; Production; Property; Receptors, Antigen, B-Cell; Regulation; Regulatory T-Lymphocyte; Reporter; Role; Sclerosis; Severities; Source; Spinal Cord; Surface; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; Testing; Th1 Cells; Transgenic Mice; Transgenic Organisms; Trees; base; cytokine; in vivo; interleukin-22; mouse model; novel; oligodendrocyte-myelin glycoprotein

Experimental autoimmune encephalomyelitis (EAE) is an animal model that reproduces many of the clinical and pathological features of multiple sclerosis (MS). While it is well documented that myelin specific T cells, Th1 and Th17 cells are important for the initiation of the disease, the role of B cells and antibodies in the disease process is not well understood. The development and the progression of EAE, like other autoimmune diseases, results from the pathogenicity of effector T cells and the negative regulation imposed by regulatory T cells (Tregs). However, the lack of a reliable marker for regulatory T cells has made it difficult to study the interplay between myelin specific effector T cells and regulatory T cells. To study the effect of antigen specific B cells in the generation of pathogenic T cells, we have established a mouse model (2D2xTH mice) in which both T and B cells are specific for the same myelin protein, myelin oligodendrocyte glycoprotein (MOG). The majority of 2D2xTH mice (about 59%) develop a very severe form of spontaneous EAE within 6 weeks of age that is similar to a sub-form of MS called Devic disease, characterized by the presence of inflammatory foci restricted to the spinal cord and optic nerve. By gene expression profiling, we have identified IL-22 as a cytokine differentially upregulated in the spinal cord of mice with Devic disease. We have also generated a Foxp3-EGFP knock-in mouse in order to track CD4+CD25+ Treg cells during the course of an ongoing immune response. With the help of l-Ab/MOG35-55 tetramer (developed in collaboration with Kai Wucherpfennig) we are able to track development and effector functions of MOG specific pathogenic and regulatory T cells. Based on our results, we propose that antigen presentation by MOG-specific B cells generates highly pathogenic T cells and limits the generation and function of MOG specific CD4+CD25+ regulatory T cells which results in the development of a very severe EAE. We will test whether: 1) MOG specific B cells participate in disease progression by the secretion of MOG specific pathogenic antibodies and /or by preferential antigen presentation to MOG-specific T cells; 2) T cells generated in the presence of cognate antigen specific B cells are more encephalitogenic and produce more IL-17 and IL-22; 3) MOG specific B cells limit the expansion and/or function of regulatory T cells responsible for keeping pathogenic T cells under check. The role of IL-22 in generating highly pathogenic T cells and development of Devic-like disease in mice will be evaluated by using IL-22 deficient mice. The proposed studies will allow us to better characterize the mechanism by which autoantigen specific B cells induce autopathogenic T cells and how they regulate the expansion and function of antigen specific regulatory T cells. Furthermore, our proposed studies will allow us to study how antigen specific B cells might control the development of an organ specific T cell mediated autoimmune disease.

实验性自身免疫性脑脊髓炎(EAE)是一种复制许多临床 多发性硬化症(MS)的病理特点。虽然有充分的证据证明髓鞘特异的T细胞， Th1和Th17细胞在疾病的发病过程中起重要作用，B细胞和抗体在 疾病过程还没有被很好地理解。与其他疾病一样，EAE的发展和进展 自身免疫性疾病，由效应性T细胞的致病性和施加的负调节引起 通过调节性T细胞(Tregs)。然而，缺乏可靠的调节性T细胞标记物使这一点变得困难 研究髓鞘特异性效应T细胞与调节性T细胞之间的相互作用。研究……的影响 抗原特异性B细胞中致病T细胞的产生，我们建立了小鼠模型 (2D2xTH小鼠)T和B细胞对同一髓鞘蛋白--髓鞘少突胶质细胞有特异性 糖蛋白(MOG)。大多数2D2xTH小鼠(约59%)发展为非常严重的自发性 6周龄内的EAE，类似于一种称为设备病的MS亚型，其特征是 仅限于脊髓和视神经的炎性病灶。通过基因表达谱，我们 已经确定IL-22是一种在患有设备病的小鼠的脊髓中差异上调的细胞因子。 我们还培育了一只Foxp3-EGFP敲入小鼠，以跟踪CD4+CD25+Treg细胞 一种持续的免疫反应过程。借助于L抗体/MOG35-55四聚体(开发于 与KAI Wucherpfennig合作)我们能够跟踪MOG的开发和效应器功能 特异性致病和调节性T细胞。基于我们的结果，我们建议通过以下方式呈现抗原 MOG特异性B细胞产生高致病性T细胞并限制MOG的产生和功能 特异性的CD4+CD25+调节性T细胞，导致非常严重的EAE。我们将测试 是否：1)MOG特异性B细胞通过分泌MOG特异性B细胞参与疾病进展 致病抗体和/或优先提呈MOG特异性T细胞；2)T细胞 在同源抗原存在的情况下产生的特异性B细胞更具脑源性，并产生更多 IL-17和IL-22；3)MOG特异性B细胞限制调节性T细胞的增殖和/或功能 用来控制致病T细胞。IL-22在产生高致病性T细胞中的作用 将使用IL-22缺陷小鼠来评估小鼠设备样疾病的发展。建议数 研究将使我们能够更好地描述自身抗原特异性B细胞诱导 自发性T细胞及其如何调节抗原特异性调节性T细胞的扩增和功能 细胞。此外，我们提议的研究将使我们能够研究抗原特异性B细胞如何控制 器官特异性T细胞介导的自身免疫性疾病的发展。