Antibody Affinity Maturation in the Aging Bone Marrow

老化骨髓中抗体亲和力的成熟

• 批准号: 7389516
• 负责人: FERENC LIVAK
• 金额: $ 14.92万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7389516
• 关键词: Adoptive Transfer; Affect; Affinity; Age; Aged, 80 and over; Aging; Animals; Antibodies; Antibody Affinity; Antibody Formation; Antibody Repertoire; Antibody-Producing Cells; Antigens; Area; B-Lymphocytes; Bone Marrow; Cells; Characteristics; Data; Effector Cell; Elderly; Exhibits; Future; Generations; Genes; Genetic; Goals; Home environment; Homing; Host Defense; Humoral Immunities; Immunity; Immunization; Immunoglobulin G; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Impairment; In Situ; Individual; Infection; Kinetics; Lymphoid; Lymphoid Tissue; Mature B-Lymphocyte; Measures; Modeling; Molecular; Mus; Mutation; Nature; Organ; Pathway interactions; Pattern; Peripheral; Phase; Population; Predisposition; Process; Rate; Research; Role; Site; Somatic Mutation; Specificity; Spleen; Staging; Structure of germinal center of lymph node; Testing; Thinking; activation-induced cytidine deaminase; age effect; age related; aged; base; day; improved; lymph nodes; middle age; novel; research study; response; vaccination strategy

DESCRIPTION (provided by applicant): High affinity antigen-specific antibodies form the basis of protective humoral immunity. Defective generation of such antibodies is a major cause of the increased susceptibility of the elderly to common infections. Antibody affinity maturation is the result of the selection of high affinity immunoglobulin (Ig)-expressing B-lymphocytes. Most Ig genes undergo antigen-driven somatic hypermutation (SHM) in specialized lymphoid germinal centers to generate higher affinity antibodies. Our preliminary data in mice with the model antigen nitrophenyl (NP) suggest that antibody affinity maturation continues in the late phase of the primary response (35-70 days post immunization) well after the involution of lymphoid germinal centers. Surprisingly, the highest affinity antibody producing cells are found predominantly in the bone marrow. Because the same bone marrow B-cells also exhibited higher rate of SHM in the canonical anti-NP Ig variable genes, we hypothesized that SHM may take place in situ in the bone marrow. SHM is absolutely dependent on the activation-induced cytidine deaminase (AICDA) which is thought to be expressed almost exclusively in germinal center B-cells. Our analysis indicate that bone marrow-derived, IgG-positive, mature B-cells also express substantial level of AICDA, supporting the possibility of in situ Ig hypermutation in bone marrow. Because reduced antibody affinity maturation in the elderly is due to low level AICDA expression and poor SHM we compared the level of AICDA expression in splenic and bone marrow B-cells from young (2 month old) and old (22 month old) mice. While AICDA expression was significantly lower in the old spleen, it was comparable between young and old in bone marrow IgG-positive B-cells. Based on these findings we propose that the bone marrow is an alternative site of antibody affinity maturation which may, potentially, be better preserved during aging than the other, peripheral lymphoid sites. In this exploratory application we will test this hypothesis by comparing the characteristics of affinity maturation in young and old bone marrow, by identifying the candidate B-cell population that migrates to the bone marrow and by performing reciprocal, adoptive transfers to establish the step(s) where translocation of the humoral response to the bone marrow may be impaired in aging. With these studies we hope to open a new area of research which we could pursue in subsequent larger applications to understand the cellular and molecular mechanisms of bone marrow-associated humoral response in both young and aged individuals and test novel vaccination strategies that would improve antibody responses in the elderly.

描述（由申请人提供）：高亲和力抗原特异性抗体构成了保护性体液免疫的基础。这种抗体的有缺陷的产生是老年人对常见感染敏感性增加的主要原因。抗体亲和力成熟是选择高亲和力免疫球蛋白（IG）表达B淋巴细胞的结果。大多数IG基因在专门的淋巴生发中心中经历抗原驱动的体细胞超突变（SHM），以产生较高的亲和力抗体。我们使用模型抗原亚硝基苯基（NP）在小鼠中的初步数据表明，抗体亲和力成熟在淋巴样生发中心的主要反应（免疫后35-70天）的后期继续进行。出乎意料的是，产生最高亲和力的产生细胞主要在骨髓中发现。由于相同的骨髓B细胞在规范抗NP Ig变量基因中也表现出更高的SHM速率，因此我们假设SHM可能在骨髓中发生。 SHM绝对取决于激活诱导的胞苷脱氨酶（AICDA），该酶（AICDA）几乎仅在生发中心B细胞中表达。我们的分析表明，骨髓衍生的，IgG阳性，成熟的B细胞也表达了大量的AICDA水平，这支持了在骨髓中原位IG超孕的可能性。由于老年人的抗体亲和力成熟降低是由于AICDA表达低，因此SHM较差，我们比较了来自Young（2个月大）和老年（22个月大）小鼠的脾和骨髓B细胞中AICDA表达的水平。尽管旧脾脏的AICDA表达显着降低，但在骨髓IgG阳性B细胞中，年轻人和老年人之间的表达相当。根据这些发现，我们建议骨髓是抗体亲和力成熟的替代部位，在衰老期间，可能比其他外周淋巴部位更好地保存。在此探索性应用中，我们将通过比较年轻人和老年骨髓中亲和力成熟的特征来检验这一假设，通过识别迁移到骨髓的候选B细胞种群，并通过进行相互接收的，产卵的转移来建立对骨骼骨髓易感响应的易位，以建立对骨骼的易位响应的步骤。通过这些研究，我们希望开设一个新的研究领域，我们可以在随后的更大应用中追求，以了解年轻人和老年人的骨髓相关的体液反应的细胞和分子机制，并测试新的疫苗接种策略，以改善老年人的抗体反应。