CELLULAR MECHANISMS OF GERMINAL CENTER REACTION IN AGING

衰老过程中生发中心反应的细胞机制

• 批准号: 6169447
• 负责人: ANDRAS K. SZAKAL
• 金额: $ 23.16万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6169447
• 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

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，新生生发中心发育不足导致记忆B细胞和回忆抗体反应的完全丧失。临床上，这与破伤风类毒素和流感疫苗的二次抗体反应降低有关。生发中心的发育依赖于抗原转运(ATC)细胞将抗原转运到淋巴滤泡，在那里抗原被捕获并保留在滤泡树突状细胞(FDC)上。FDC的树突产生冰小体(免疫复合体)，将抗原运送到滤泡B细胞进行内吞、Ag加工和呈递给T辅助细胞-这一序列被描述为“替代的Ag运输途径”。衰老导致萎缩的FDCs，其保留的抗原很少，产生的冰小体很少，并且不会诱导生发中心和β记忆细胞。我们最近发表的文章为抗原运输细胞和滤泡树突状细胞来源于骨髓提供了新的证据。通过显示ATCs是前FDCs，获得了FDCs来自毛囊外的初步证据。因此，我们检查了血液和骨髓中是否存在FDC前体。通过使用FDC特异性单抗鉴定一个大的单核血细胞和一个骨髓细胞，获得了与ATCs和FDCs的骨髓来源一致的数据。老年免疫缺陷小鼠的FDC和GCs的骨髓重建研究进一步支持ATCs和FDC的骨髓来源。因此，我们假设，在老年人中，次级抗体反应和GC缺乏至少部分是由于Ag运输能力降低和FDCs缺陷，这可能反过来是由于ATC/FDC前体细胞减少或缺陷。或者，这些与年龄相关的缺陷的解释可能取决于DC功能的缺陷，如信号1(向B细胞提呈抗原)和信号2(FDCs的共刺激功能)。为了验证这些假说，我们将研究老年小鼠的生发中心反应和骨髓缺陷，以及分离的老年FDCs的辅助功能。