Selection of the B Cell Repertoire in Senescence

衰老过程中 B 细胞库的选择

基本信息

批准号：
9029541
负责人：
RICHARD L RILEY
金额：
$ 21.49万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029541
关键词：
2 year old Adoptive Transfer Affect Affinity Age Antibodies Antibody Repertoire Antibody Response Antibody Specificity Antibody-Producing Cells Apoptosis B cell repertoire B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Back Biological Assay Bone Marrow Cell Count Cell Maintenance Cell physiology Cells Common Lymphoid Progenitor Communicable Diseases Defect Development Elderly Epitopes Feeds Frequencies Generations Genes Growth Hematopoietic stem cells Human Immunity Immunoglobulin Class Switching Immunoglobulin Idiotypes Immunoglobulin Somatic Hypermutation In Vitro Infection Inflammation Inflammatory Lymphoid Lymphopoiesis Maintenance Mature B-Lymphocyte Mus Myelogenous Pathway interactions Peripheral Phosphorylcholine Production Reading Recovery Rejuvenation Role Spleen Staging Stem Cell Development Streptococcus pneumoniae TCF3 gene TNF gene Testing age related aged cell growth humoral immunity deficiency in vivo inhibitor/antagonist novel pre-B cell receptor progenitor public health relevance receptor expression repaired response restoration senescence surrogate light chain

项目摘要

DESCRIPTION (provided by applicant): In old age, in both mice and humans, B lymphopoiesis is compromised and intrinsic B cell defects contribute to poor Ig isotype switch and somatic hypermutation. Old age causes poor B lymphopoiesis by interfering with: 1) pro-B/pre-B cell function; 2) development of common lymphoid progenitors (CLP); and 3) maintenance of lymphoid-biased hematopoietic stem cells (L-HSC). This contributes to alterations in B cell numbers and composition in the periphery and also changes the "read-out" of B cell antibody specificities. The latter can result in poor protection to infectious diseases. cells in old mice (and humans) are pro-inflammatory and express TNFa. In particular, the Age-associated B cells (ABC) in old mice are pro-inflammatory and represent a novel B cell subset which expands extensively in old age. By 2 years of age, ABC can constitute up to one- half of mature B cells in spleen and bone marrow. In old mice, TNFa diminishes peripheral B cell function by interfering with Ig isotype switching. In the bone marrow of old mice, ABC, via TNFa, induce apoptosis in B cell precursors. Moreover, those B cell precursors which are less affected by ABC in old mice express lower levels of the surrogate light chain (SLC). The SLC is a key constituent of the pre-B cell receptor (preBCR); compromise of the preBCR in old mice affects the "read-out" of the B cell antibody repertoire. This is seen as an increased frequency of B cells which are reactive with the bacterial epitope phosphorylcholine, are negative for the T15 idiotype, and are of low affinity. These "old-age" related anti-PC B cells produce less protective antibodies to pneumococci. In this proposal, we will test the role of pro-inflammatory B cells, including ABC, in down-regulating B lymphopoiesis at relatively late stages (pro-B/pre-B) as well as early stages (Common Lymphoid Progenitors [CLP]; hematopoietic stem cells [HSC]) of development (Specific Aims 1 and 2). Furthermore, we will determine effects of pro-inflammatory B cells, including ABC, in both altering the "read- out" of the B cell repertoire and inhibiting Ig isotype switch and somatic hypermutation in mature B cells (Specific Aim 3). Finally, we will test whether depletion of pro-inflammatory B cells and their subsets in old mice "rejuvenates" B cell development and "repairs" the functional B cell deficiencies seen in old age.

描述（由适用提供）：在老年中，在小鼠和人类中，B淋巴细胞受到损害，内在的B细胞缺陷有助于较差的Ig同型开关和体细胞超变量。老年通过干扰：1）pro-B/pre-b细胞功能会导致较差的B淋巴细胞。 2）开发普通淋巴祖细胞（CLP）； 3）维持淋巴偏见的造血干细胞（L-HSC）。这有助于B细胞数量和周围的组成改变，并改变B细胞抗体特异性的“读出”。后者可能导致对传染病的保护不良。老鼠（和人类）中的细胞具有促炎和表达TNFA。特别是，旧小鼠中与年龄相关的B细胞（ABC）是促炎性的，代表了一种新型的B细胞子集，该子群在老年时广泛扩展。到2岁时，ABC可以构成脾和骨髓中成熟的B细胞一半。在旧小鼠中，TNFA通过干扰Ig同种型切换来减少外围B细胞功能。在ABC的老鼠的骨髓中，通过TNFA诱导B细胞前体的凋亡。此外，那些在旧小鼠中受ABC影响较小的B细胞前体表达了替代光链（SLC）的较低水平。 SLC是PRE-B细胞受体（PREBCR）的关键；旧小鼠的PreBCR妥协会影响B细胞抗体库的“读出”。这被视为B细胞的频率增加这些“老年”相关的抗PC B细胞产生对肺炎球菌的受保护较少的抗体。在该提案中，我们将测试包括ABC在内的促炎B细胞在相对较晚（Pro-B/Pre-B）和早期阶段下调BC淋巴细胞中的作用（常见的淋巴样祖细胞[CLP]; Clpoietic Stempoletic干细胞[HSC]）的作用（特定于发育目标1和2）。此外，我们将确定包括ABC在内的促炎性B细胞的影响，既改变了B细胞库的读数”，并在成熟的B细胞中抑制Ig同型开关和体细胞超女性（特定AIM 3）。最后，我们将测试促炎性B细胞及其子集的耗竭，以“恢复” B细胞的发育和“修复”在老年时看到的功能性B细胞缺陷。