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CELLULAR MECHANISMS OF GERMINAL CENTER REACTION IN AGING

衰老过程中生发中心反应的细胞机制

基本信息

批准号：
6372376
负责人：
ANDRAS K. SZAKAL
金额：
$ 23.67万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2004-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6372376
关键词：
B lymphocyte SCID mouse age difference animal old age antigen presentation athymic mouse bone marrow bone marrow transplantation cellular immunity dendritic cells developmental immunology helper T lymphocyte hematopoietic stem cells immunologic memory immunosenescence juvenile animal laboratory mouse monoclonal antibody

项目摘要

In aging, deficient de novo germinal center developments results in the complete loss of memory B cells and recall antibody responses. Clinically, this correlates with the decreased secondary antibody responses to tetanus toxoid and flu vaccines. Germinal center development depends on antigen transport by antigen transport (ATC) cells to lymph node follicles where the antigen is trapped and retained on follicular dendritic cells (FDC). The dendrites of the FDCs produce iccosomes (immune-complex-coated bodies) which deliver the antigen to follicular B cells for endocytosis, Ag processing and presentation to T helper cells-a sequence described as the "alternative Ag-transport pathway." Senescence results in atrophic FDCs, which retain little antigen, produce few iccosomes, and induce no germinal centers and beta memory cells. Our recent publication provides new evidence for Antigen transport cells and follicular dendritic cells being derived from bone marrow. Preliminary evidence of the extra follicular origin of FDCs was obtained by showing that ATCs are pre-FDCs. Thus, we examined the blood and bone marrow for the presence of FDC precursors. Data in agreement with the bone marrow derivation of ATCs and FDCs were obtained by identifying a large mononuclear blood cell and a bone marrow cell using the FDC-specific monoclonal Ab. Bone marrow reconstitution studies of Fdc and GCs in old, immunodeficient mice further support the bone marrow derivation of ATCs and FDCs. Therefore, we hypothesize that, in aged individuals, depressed secondary Ab response and GC paucity is due at lest in part to a reduced capacity for Ag transport and defective FDCs, which may in turn be due to a decrease or defects in ATC/FDC bone marrow precursors. Alternatively, the explanation for these age-related deficits may depend on defects in DC functions such as signal 1 (Ag presentation to B cells) and signal 2 (co-stimulatory function of FDCs). To test these hypotheses, we will study the germinal center response and bone marrow deficits in old mice and the accessory functions of isolated old FDCs.

在衰老过程中，从头发育的缺陷导致记忆B细胞和回忆抗体反应的完全丧失。在临床上，这与破伤风类毒素和流感疫苗的二次抗体应答降低有关。生发中心的发育依赖于抗原转运（ATC）细胞将抗原转运至淋巴结滤泡，在淋巴结滤泡中抗原被捕获并保留在滤泡树突状细胞（FDC）上。FDC的树突产生iccosomes（免疫复合物包被体），其将抗原递送至滤泡B细胞以进行内吞作用、Ag加工并呈递至T辅助细胞-一种被描述为“替代Ag转运途径”的序列。衰老导致萎缩的FDC，其保留很少的抗原，产生很少的iccosome，并且不诱导生发中心和β记忆细胞。我们最近发表的文章为抗原转运细胞和滤泡树突状细胞来源于骨髓提供了新的证据。初步证据表明，额外的卵泡起源的FDCs获得的显示，ATC是前FDCs。因此，我们检查了血液和骨髓中FDC前体的存在。通过使用FDC特异性单克隆抗体鉴定大单核血细胞和骨髓细胞，获得了与ATC和FDC的骨髓来源一致的数据。Fdc和GC在老年免疫缺陷小鼠中的骨髓重建研究进一步支持ATC和FDC的骨髓衍生。因此，我们假设，在老年人中，抑制的继发性Ab反应和GC缺乏至少部分是由于Ag转运能力降低和FDC缺陷，这可能又是由于ATC/FDC骨髓前体减少或缺陷。或者，对这些年龄相关缺陷的解释可能取决于DC功能的缺陷，如信号1（Ag呈递给B细胞）和信号2（FDC的共刺激功能）。为了验证这些假设，我们将研究老年小鼠的生发中心反应和骨髓缺陷以及孤立的老年FDC的辅助功能。