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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细胞在中枢神经系统自身免疫性疾病的发病机制中可能具有多种作用。虽然数据表明髓磷脂特异性抗体（Ab）促进实验性自身免疫性脑脊髓炎（EAE）和MS的脱髓鞘，但B细胞在CNS自身免疫性疾病中抗原（Ag）呈递中的作用尚不清楚。与其他APC群体相比，当B细胞表达针对应答T细胞识别的Ag特异性B细胞受体（BCR）时，B细胞是高效的Ag蛋白APC。我们假设B细胞，特别是髓磷脂特异性B细胞在髓磷脂特异性T细胞的激活中具有重要的APC作用。我们建议(1)评估髓磷脂特异性B细胞作为APC在EAE中的作用，并将其功能与髓磷脂特异性Ab在EAE中的作用区分开来。我们正在创建两种转基因（Tg）模型，一种含有只表达mog特异性BCR的B细胞，另一种含有表达mog特异性BCR并能分泌mog特异性IgM的B细胞。我们将比较这些小鼠与B细胞缺陷小鼠和mog特异性BCR敲入小鼠的EAE易感性，这些小鼠可以分泌所有Ig同种型。我们建议(2)研究B细胞MHC II表达和髓磷脂BCR特异性在EAE中髓磷脂Ag呈递中的作用。我们假设B细胞，特别是髓鞘特异性B细胞，在EAE和ms中MHC II限制性Ag呈递和髓鞘特异性T细胞激活中作为APC发挥关键作用(a)。我们将通过创建混合bm嵌合体小鼠来测试MHC II限制性B细胞Ag呈递到T细胞的作用，其中B细胞区室选择性地缺乏MHC II表达。并比较mog特异性T细胞的活化和EAE对含有表达MHC II分子的B细胞的bm嵌合体小鼠的易感性。(b)为了阐明BCR特异性在EAE中MHC II限制性Ag呈递中的作用，我们将检测混合bm嵌合体小鼠，其中b细胞表达mog特异性BCR或硝基苯（NP）特异性BCR，并表达或不表达MHC II分子。最近的临床结果表明，抗cd20b细胞清除可能在多发性硬化症治疗中有效。我们的初步数据表明，B细胞耗竭对rmog诱导的EAE有益，但会加剧MOG p35- 55诱导的EAE。我们假设rmog诱导的EAE的临床获益是由于B细胞Ag呈递减少或髓鞘特异性Ab分泌减少。我们还假设MOG p35-55诱导的EAE（一种较少依赖B细胞和Ab的模型）的恶化代表了B细胞调节功能的丧失。为了评估这些可能性，我们将(3)研究抗cd20 B细胞耗竭如何影响急性和慢性EAE外周和中枢神经系统中mog特异性T细胞反应，并研究mog特异性Ab反应是否与抗cd20 B细胞耗竭小鼠的临床改善相关。这些研究应该提供关于中枢神经系统自身免疫中B细胞消耗的机制见解，并解决在MS临床试验中不易接近的关于B细胞消耗的问题。

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

B cells in multiple sclerosis: connecting the dots.