Studies of human B cell tolerance, from a humanized mouse model to human beings

从人源化小鼠模型到人类的人类 B 细胞耐受性研究

• 批准号: 9119354
• 负责人: Roberta Pelanda
• 金额: $ 42.76万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-05 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119354
• 关键词: Affect; Antibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B cell repertoire; B-Cell Development; B-Lymphocytes; Binding; Blood Circulation; Bone Marrow; Bypass; Cell model; Cells; Data; Defect; Development; Disease; Employee Strikes; Ensure; Environment; Flare; Generations; Genetic Predisposition to Disease; Hematopoietic; Human; Immune system; Immunoglobulin Genes; Immunologic Deficiency Syndromes; Individual; Insulin-Dependent Diabetes Mellitus; Knowledge; Lead; Lupus; Mediating; Membrane; Molecular; Mus; PTPN22 gene; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenotype; Physiological; Play; Population; Process; Research; Rheumatoid Arthritis; Role; Side; Specificity; Testing; Ursidae Family; Variant; Work; autoreactive B cell; autoreactivity; base; central tolerance; guided inquiry; humanized mouse; innovation; mouse model; novel; public health relevance; receptor; systemic autoimmune disease

 DESCRIPTION (provided by applicant): In both mice and humans, the majority of newly generated B cells are autoreactive and a selection process - tolerance - exists to ensure that most of these cells do not enter the peripheral B cell population. Recent data indicate that in individuals affected by systemic autoimmunity such as lupus, a large fraction of the B cells participating in disease bear germline immunoglobulin genes and are, therefore, the product of a central selection process gone awry. While in the mouse the understanding of how newly generated B cells are centrally selected in the bone marrow is quite sophisticated, there remains a surprising dearth of knowledge about this process in humans. Given the role primary B cells play in autoimmune diseases, it is of critical importance to correct this gap in knowledge. The overall objective of this application is to determine how human immature B cells are selected to enter or not the primary B cell population. The central hypothesis is that a fraction of human autoreactive B cells undergoes tolerance via receptor editing, but that this process is compromised in immune systems prone to the development of systemic autoimmune diseases. This hypothesis has been formulated on the basis of preliminary studies developed with a unique humanized mouse model of human B cell tolerance. The results of these studies have provided us a direct way to investigate directly human B cells undergoing central tolerance to natural self-antigens. We plan to test our hypothesis and attain the objective of this application by pursuing the following specific aims: 1) Determine the phenotype of human B cells undergoing central tolerance to synthetic and natural self-antigens in humanized mice and humans; 2) Determine use and efficiency of receptor editing in human B cells responding to natural self-antigens; and 3) Identify defects in central B cell tolerance in human immune systems genetically predisposed to autoimmunity. The major innovation of this project resides in the ability to investigate human autoreactive B cells directly while they undergo central tolerance. These studies are significant because they provide direct information on mechanisms human B cells utilize during central selection and because they contribute to understanding why and how autoreactive B cells are generated at higher numbers in some individuals predisposed or suffering from autoimmunity. Ultimately, such knowledge has the potential of guiding us toward novel treatments for autoimmune diseases.

 描述（由申请方提供）：在小鼠和人类中，大多数新生成的B细胞是自身反应性的，存在一个选择过程-耐受性-以确保大多数这些细胞不会进入外周B细胞群。最近的数据表明，在受系统性自身免疫（如狼疮）影响的个体中，参与疾病的大部分B细胞携带生殖系免疫球蛋白基因，因此是中央选择过程出错的产物。虽然在小鼠中对新产生的B细胞如何在骨髓中集中选择的理解是相当复杂的，但关于人类中这一过程的知识仍然令人惊讶地缺乏。鉴于原代B细胞在自身免疫性疾病中的作用，纠正这一知识差距至关重要。 本申请的总体目的是确定如何选择人未成熟B细胞进入或不进入原代B细胞群。核心假设是一部分人自身反应性B细胞通过受体编辑经历耐受，但这一过程在易于发展成系统性自身免疫疾病的免疫系统中受到损害。这一假设是基于用人B细胞耐受性的独特人源化小鼠模型开发的初步研究而提出的。这些研究结果为我们直接研究人B细胞对天然自身抗原的中枢耐受提供了一条直接的途径。我们计划通过追求以下具体目标来检验我们的假设并达到本申请的目的：1）确定在人源化小鼠和人中经历对合成和天然自身抗原的中枢耐受的人B细胞的表型; 2）确定在响应天然自身抗原的人B细胞中受体编辑的使用和效率;和3）鉴定在遗传上易患自身免疫的人免疫系统中中央B细胞耐受性的缺陷。 该项目的主要创新在于能够直接研究人类自身反应性B细胞，同时它们经历中枢耐受。这些研究是重要的，因为它们提供了关于人类B细胞在中心选择过程中利用的机制的直接信息，并且因为它们有助于理解为什么以及如何在一些易患或患有自身免疫的个体中以较高数量产生自身反应性B细胞。最终，这些知识有可能指导我们寻找治疗自身免疫性疾病的新方法。