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: 8316143
• 负责人: VIJAY K. KUCHROO
• 金额: $ 39.18万
• 依托单位: DANA-FARBER CANCER INST
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316143
• 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）是一种动物模型，其再现了许多临床表现， 和多发性硬化症（MS）的病理特征。虽然有充分的证据表明髓磷脂特异性T细胞， Th 1和Th 17细胞对于疾病的起始是重要的，B细胞和抗体在Th 1和Th 17细胞中的作用是重要的。 疾病的过程还不太清楚。EAE的发展和进步，与其他一样 自身免疫性疾病，由效应T细胞的致病性和施加的负调节引起 调节性T细胞（Regulatory T cells，Tcells）然而，由于缺乏一种可靠的调节性T细胞标志物， 研究髓鞘特异性效应T细胞和调节性T细胞之间的相互作用。探讨蛋白酶体抑制剂 抗原特异性B细胞在致病性T细胞的产生，我们建立了小鼠模型 （2D 2 xTH小鼠），其中T细胞和B细胞对相同的髓鞘蛋白（髓鞘少突胶质细胞）具有特异性 糖蛋白（MOG）。大多数2D 2xTH小鼠（约59%）发生非常严重的自发性 6周龄内的EAE，类似于MS的一种亚型，称为Devic病，其特征是 存在局限于脊髓和视神经的炎性病灶。通过基因表达谱分析，我们 已经将IL-22鉴定为在患有Devic病的小鼠的脊髓中差异上调的细胞因子。 我们还产生了Foxp 3-EGFP基因敲入小鼠，以便在细胞周期中追踪CD 4 + CD 25 + Treg细胞。 持续免疫反应的过程在I-Ab/M0 G 35 -55四聚体（在1999年开发的）的帮助下， 与Kai Wucherpfennig合作），我们能够跟踪MOG的发育和效应器功能 特异性致病性和调节性T细胞。基于我们的研究结果，我们提出，抗原呈递， 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CD 4 + CD 25+调节性T细胞，其导致非常严重的EAE的发展。我们将测试 是否：1）MOG特异性B细胞通过分泌MOG特异性 病原性抗体和/或通过向MOG特异性T细胞的优先抗原呈递; 2）T细胞 在存在同源抗原特异性B细胞的情况下产生的抗体更易致脑炎， IL-17和IL-22; 3）MOG特异性B细胞限制调节性T细胞的扩增和/或功能 来控制致病性T细胞IL-22在产生高致病性T细胞中的作用， 将通过使用IL-22缺陷型小鼠来评价小鼠中Devic样疾病的发展。拟议 研究将使我们能够更好地表征自身抗原特异性B细胞诱导免疫应答的机制。 自体致病性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，我们提出的研究将使我们能够研究抗原特异性B细胞如何控制免疫反应。 器官特异性T细胞介导的自身免疫性疾病的发展。