Selection of B cell repertoire in senescence

衰老过程中 B 细胞库的选择

• 批准号: 8134867
• 负责人: RICHARD L RILEY
• 金额: $ 29.41万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134867
• 关键词: Address; Adoptive Transfer; Affect; Age; Aging; Antibodies; Antibody Formation; Antibody Repertoire; Antigens; Autoantigens; B cell repertoire; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; Bone Marrow; Bromodeoxyuridine; CXCL12 gene; Cell Aging; Communicable Diseases; Complex; DNA Sequence Rearrangement; Defect; Development; Disease; Down-Regulation; Effector Cell; Family; Genes; Home environment; Homeostasis; Homing; Immune; Immunoglobulin Idiotypes; Immunoglobulins; Interleukin-1; Interleukin-6; Label; Light; Lymphopoiesis; Measures; Mediating; Molecular; Mus; Natural Killer Cells; Nuclear Antigens; Pathway interactions; Peripheral; Phosphorylation; Phosphorylcholine; Production; Receptor Signaling; Role; Serum; Signal Transduction; Spleen; Staging; Streptococcus pneumoniae; Stromal Cells; TCF3 gene; Testing; Vaccination; aged; anergy; autoreactivity; cell age; cohort; cytokine; in vivo; insight; migration; pathogen; peripheral blood; pre-B cell receptor; prevent; public health relevance; receptor; receptor function; release of sequestered calcium ion into cytoplasm; response; senescence; surrogate light chain; transcription factor; Address; Adoptive Transfer; Affect; Age; Aging; Antibodies; Antibody Formation; Antibody Repertoire; Antigens; Autoantigens; B cell repertoire; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; Bone Marrow; Bromodeoxyuridine; CXCL12 gene; Cell Aging; Communicable Diseases; Complex; DNA Sequence Rearrangement; Defect; Development; Disease; Down-Regulation; Effector Cell; Family; Genes; Home environment; Homeostasis; Homing; Immune; Immunoglobulin Idiotypes; Immunoglobulins; Interleukin-1; Interleukin-6; Label; Light; Lymphopoiesis; Measures; Mediating; Molecular; Mus; Natural Killer Cells; Nuclear Antigens; Pathway interactions; Peripheral; Phosphorylation; Phosphorylcholine; Production; Receptor Signaling; Role; Serum; Signal Transduction; Spleen; Staging; Streptococcus pneumoniae; Stromal Cells; TCF3 gene; Testing; Vaccination; aged; anergy; autoreactivity; cell age; cohort; cytokine; in vivo; insight; migration; pathogen; peripheral blood; pre-B cell receptor; prevent; public health relevance; receptor; receptor function; release of sequestered calcium ion into cytoplasm; response; senescence; surrogate light chain; transcription factor

DESCRIPTION (provided by applicant): B lymphopoiesis is severely compromised in murine senescence. While there are defects at several distinct stages in the B lymphopoietic pathway in old age, down-regulation at the pro-B to pre-B cell transition likely has a major role in altering the composition of the B cell antibody repertoire. This transition is particularly dependent upon expression of and signaling by the pre-B cell receptor (preBCR), a complex of immunoglobulin 5 heavy chain associated with the surrogate light chains l5 and VpreB. Aged mice have significantly reduced expression of surrogate light chains and poor preBCR function. This results in progressive alteration of the 5 heavy chain repertoire in newly formed B cells in aged mice. However, rather than a random loss of pre-B cells in old age, we propose that the aged pre-B compartment will become skewed in favor of those pre-B cells that undergo positive selection even when surrogate light chain is highly reduced. Moreover, we propose that increases in autoreactivity as well as detrimental changes in the availability of protective antibody responses to pathogens, e.g., S. pneumoniae, are, in part, due to a compromised preBCR checkpoint. To address this hypothesis, we propose 3 integrated Specific Aims. In Specific Aim 1, we ask "Does compromise of the preBCR checkpoint in old age 'reshape' the Vh repertoire and promote autoreactivity"? Here, the effects of diminished preBCR function on 5 heavy chain usage, and capacity to signal when surrogate light chain is low, will be determined together with impact on autoreactivity. Specific Aim 2 addresses the fate of autoreactive immature B cells within the bone marrow of aged mice and their contribution to the peripheral B cell pools. Tolerance among immature B cells in aged mice, their capacity to home to the spleen, and, importantly, the expression of protective versus non-protective clonotypes in response to the S. pneumoniae antigen phosphorylcholine will be assessed. Specific Aim 3 focuses upon the importance of proinflammatory cytokines (TNFa) and effector cells (NK) in triggering the down-regulation of preBCR, altering both B lymphopoiesis and antibody repertoires in aged mice. These studies will advance understanding of the immune defects that accompany old age and their cellular and molecular mechanisms. PUBLIC HEALTH RELEVANCE: The development of new antibody producing B cells is compromised in old age. This may result in both poor antibody protective responses to pathogens in disease as well as to vaccination. Our studies focus on the mechanisms that affect antibody producing B cell production in old age, primarily the role of the pre-B cell receptor complex. Insight into the defects in B cell production in old age may reveal their influence on developing and maintaining effective immune barriers to infectious disease.

描述（由申请人提供）：B淋巴细胞在鼠衰老中受到严重损害。尽管在老年B淋巴管途径的几个不同阶段存在缺陷，但在Pro-B到B PER-B细胞转变的下调可能在改变B细胞抗体库的组成方面具有重要作用。这种过渡特别取决于Pre-B细胞受体（PREBCR）的表达和信号传导，这是一种与替代光链L5和VPREB相关的免疫球蛋白5重链。老年小鼠的替代光链的表达显着降低，而PREBCR功能差。这导致在老年小鼠新形成的B细胞中的5个重链曲目进行了逐步改变。但是，我们建议，即使在高度降低替代光链的情况下，也将偏向于那些接受阳性选择的前B细胞，而不是在老年内随机丧失前B细胞。此外，我们提出，保护性抗体对病原体的可用性的增加以及有害的变化，例如肺炎链球菌，部分原因是受损的prebcr检查点。为了解决这一假设，我们提出了3个集成的特定目标。在特定的目标1中，我们问“在老年人“重塑” VH曲目中妥协并促进自动反应性的prebcr检查站吗？在这里，PrebCR功能降低对5个重链使用的影响以及在替代光链较低时发出信号的能力将与对自动反应性的影响一起确定。具体目标2解决了老年小鼠骨髓内自动反应性不成熟B细胞的命运及其对外围B细胞池的贡献。年龄小鼠中未成熟的B细胞之间的耐受性，它们可以回家脾脏的能力，并且将评估保护性与非保护性克隆型的表达，以响应肺炎链球菌抗原磷酸胆碱。具体目标3的重点是促炎细胞因子（TNFA）和效应细胞（NK）在触发prebCR下调的重要性，从而改变了老年小鼠的B淋巴细胞和抗体库。这些研究将提高人们对老年伴随的免疫缺陷及其细胞和分子机制的了解。 公共卫生相关性：新抗体产生B细胞的开发在老年时受到损害。这可能导致对疾病中病原体以及疫苗接种的病原体的抗体保护性差。我们的研究重点是影响老年产生B细胞产生的抗体的机制，主要是前B细胞受体复合物的作用。对老年B细胞产生缺陷的洞察力可能揭示其对发展和维持有效的免疫障碍的影响。