B cells in CNS autoimmunity

B细胞在中枢神经系统自身免疫中的作用

基本信息

批准号：
8414832
负责人：
SCOTT S ZAMVIL
金额：
$ 35.45万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8414832
关键词：
Acute Address Animal Model Antibodies Antibody Formation Antigen Presentation Antigen-Presenting Cells Antigens Area Autoimmune Diseases B-Lymphocytes CNS autoimmunity Cell physiology Cells Chimera organism Chronic Clinical Clinical Trials Data Demyelinations Dendritic Cells Disease model Experimental Autoimmune Encephalomyelitis Goals Health Human Immune Immune system Immunoglobulin Isotypes Immunoglobulin M Immunoglobulins Inflammation Knock-in Mouse MS4A1 gene Mediating Membrane Modeling Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Neuraxis Neuromyelitis Optica Optic Nerve Pathogenesis Peripheral Plasma Cells Population Predisposition Proteins Receptors, Antigen, B-Cell Regulation Regulatory T-Lymphocyte Relapse Relative (related person)Research Role Severities Source Specificity Spinal Cord Staging T cell response T-Cell Receptor T-Lymphocyte Testing Therapeutic Time Transgenic Mice Transgenic Model antigen processing base insight interest programs response

项目摘要

DESCRIPTION (provided by applicant): B cells may have multiple roles in pathogenesis of CNS autoimmune disease. While data indicate that myelin-specific antibodies (Ab) promote demyelination in experimental autoimmune encephalomyelitis (EAE) and MS, the role of B cells in antigen (Ag) presentation in CNS autoimmune disease is not clear. When compared to other APC populations, B cells are efficient APC in presentation of protein Ag when they express the B cell receptor (BCR) specific for the Ag recognized by responding T cells. We hypothesize that B cells, in particular, myelin-specific B cells have an important role as APC in activation of myelin-specific T cells. We propose (1) to evaluate the contribution of myelin-specific B cells as APC in EAE and distinguish this function from the role of myelin-specific Ab in EAE. We are creating two transgenic (Tg) models, one containing B cells that express membrane MOG-specific BCR only, and one containing B cells that express membrane MOG-specific BCR and can secrete MOG-specific IgM. We will compare EAE susceptibility in these mice to B cell-deficient and MOG-specific BCR knock-in mice that can secrete all Ig isotypes. We propose (2) to examine the roles of B cell MHC II expression and myelin BCR specificity in presentation of myelin Ag in EAE. We hypothesize that B cells, in particular myelin-specific B cells, have a key role as APC in MHC II-restricted Ag presentation and activation of myelin-specific T cells in EAE and MS. (a) We will test the role of MHC II-restricted B cell Ag presentation to T cells by creating mixed bm chimera mice in which the B cell compartment is selectively deficient in MHC II expression, and compare activation of MOG-specific T cells and EAE susceptibility to bm chimera mice containing B cells that express MHC II molecules. (b) To clarify the role of BCR specificity in MHC II-restricted Ag presentation in EAE, we will examine mixed bm chimera mice in which B cells express either the MOG-specific BCR or nitrophenyl (NP)-specific BCR and do, or do not, express MHC II molecules. Recent clinical results suggest that anti-CD20 B cell depletion may be effective in MS treatment. Our preliminary data suggest that B cell depletion is beneficial in rMOG-induced EAE, but exacerbates MOG p35- 55-induced EAE. We hypothesize that the clinical benefit in rMOG-induced EAE results from reduced B cell Ag presentation or decreased secretion of myelin-specific Ab. We also hypothesize that exacerbation of MOG p35-55-induced EAE, a model that is less dependent upon B cells and Ab, represents loss of regulatory B cell function. In order to evaluate these possibilities, we will (3) examine how anti-CD20 B cell depletion influences MOG-specific T cell responses in the periphery and in the CNS in acute and chronic EAE, and examine whether MOG-specific Ab responses correlate with clinical improvement in anti-CD20 B cell-depleted mice. These studies should provide mechanistic insight regarding B cell depletion in CNS autoimmunity and address questions regarding B cell depletion that are not easily approached in MS clinical trials.

描述（由申请人提供）：B细胞在CNS自身免疫性疾病的发病机理中可能具有多重作用。虽然数据表明髓磷脂特异性抗体（AB）促进了实验性自身免疫性脑脊髓炎（EAE）和MS中的脱髓鞘，但B细胞在CNS自身免疫性疾病中B细胞中的作用尚不清楚。与其他APC群体相比，B细胞在蛋白质Ag表达B细胞受体（BCR）时对通过反应T细胞识别的Ag特异的AG时是有效的APC。我们假设B细胞，特别是髓磷脂特异性B细胞在激活髓磷脂特异性T细胞中具有重要作用。我们建议（1）评估髓磷脂特异性B细胞作为APC在EAE中的贡献，并将该功能与髓磷脂特异性AB在EAE中的作用区分开。我们正在创建两个转基因（TG）模型，一种包含仅表达膜MOG特异性BCR的B细胞，一个包含一个表达膜MOG特异性BCR的B细胞，可以分泌MOG特异性IgM。我们将将这些小鼠的EAE敏感性与B细胞缺陷型和MOG特异性BCR敲入小鼠进行比较，该小鼠可以分泌所有Ig同型。我们建议（2）检查B细胞MHC II表达和髓鞘BCR特异性在EAE中呈髓磷脂Ag中的作用。我们假设B细胞，尤其是髓磷脂特异性B细胞，在EAE和MS中髓磷脂特异性T细胞的MHC II限制性AG表现和激活中具有APC的关键作用。（a）我们将通过创建混合BM嵌合小鼠对MHC II限制的B细胞Ag呈递对T细胞的作用，其中B细胞室在MHC II表达中有选择性缺陷，并比较MOG特异性T细胞的激活和EAE对含有BM嵌合体的敏感性激活，表达了含有MHC II分解MHC II分解的BM Chimera小鼠。（b）为了阐明BCR特异性在EAE中MHC II限制的AG表现中的作用，我们将检查B细胞表达MOG特异性BCR或硝基苯基（NP）特定BCR的混合BM嵌合小鼠，并且不做或不进行表达MHC II分子。最近的临床结果表明，抗CD20 B细胞耗竭可能在MS治疗中有效。我们的初步数据表明，B细胞的耗竭对RMOG诱导的EAE有益，但加剧了MOG P35-55诱导的EAE。我们假设RMOG诱导的EAE的临床益处是由于B细胞AG表现减少或髓磷脂特异性AB的分泌减少而导致的。我们还假设MOG P35-55诱导的EAE加剧，该模型较少依赖B细胞，而AB则代表了调节B细胞功能的丧失。为了评估这些可能性，我们将（3）检查抗CD20 B细胞耗竭如何影响急性和慢性EAE中周围和CNS中MOG特异性T细胞反应，并检查MOG特异性AB反应与抗C-CD20 B细胞耗尽的小鼠的临床改善是否相关。这些研究应提供有关CNS自身免疫性B细胞耗竭的机械洞察力，并解决有关B细胞耗竭的问题，这些问题在MS临床试验中很难解决。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Translational research in neurology and neuroscience 2010: multiple sclerosis.

2010 年神经病学和神经科学转化研究：多发性硬化症。

DOI：
10.1001/archneurol.2010.158
发表时间：
2010
期刊：
Archives of neurology
影响因子：
0
作者：
Stuve,Olaf;Kieseier,BerndC;Hemmer,Bernhard;Hartung,Hans-Peter;Awad,Amer;Frohman,ElliotM;Greenberg,BenjaminM;Racke,MichaelK;Zamvil,ScottS;Phillips,JTheodore;Gold,Ralf;Chan,Andrew;Zettl,Uwe;Milo,Ron;Marder,Ellen;Khan,Oma
通讯作者：
Khan,Oma

FTY720 and central memory: out of sight, out of mind.

FTY720 和中央存储器：眼不见心不烦。

DOI：
10.1212/wnl.0b013e3181eee298
发表时间：
2010
期刊：
Neurology
影响因子：
9.9
作者：
Slavin,AnthonyJ;Zamvil,ScottS
通讯作者：
Zamvil,ScottS

Lymph node-derived donor encephalitogenic CD4+ T cells in C57BL/6 mice adoptive transfer experimental autoimmune encephalomyelitis highly express GM-CSF and T-bet.

DOI：
10.1186/1742-2094-8-73
发表时间：
2011-06-24
期刊：
Journal of neuroinflammation
影响因子：
9.3
作者：
Cravens PD;Hussain RZ;Zacharias TE;Ben LH;Herndon E;Vinnakota R;Lambracht-Washington D;Nessler S;Zamvil SS;Eagar TN;Stüve O
通讯作者：
Stüve O

Laquinimod, an up-and-coming immunomodulatory agent for treatment of multiple sclerosis.