CELLULAR MECHANISMS OF GERMINAL CENTER REACTION IN AGING

在衰老过程中，缺乏新生生发中心的发育导致记忆性B细胞和回忆性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抗反应降低有关。生发中心的发育取决于抗原转运（ATC）细胞到淋巴结滤泡的抗原转运，在那里抗原被捕获并保留在滤泡树突状细胞（FDC）上。fdc的树突产生糖蛋白小体（免疫复合物包裹的小体），将抗原传递给滤泡B细胞进行内吞、银加工并呈递给T辅助细胞——这一序列被描述为“替代银运输途径”。衰老导致萎缩的fdc，保留很少的抗原，产生很少的糖原体，没有生发中心和β记忆细胞。我们最近的出版物提供了抗原转运细胞和滤泡树突状细胞来源于骨髓的新证据。通过显示ATCs是前FDCs，获得了FDCs起源于卵泡外的初步证据。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一个大的单核血细胞和一个骨髓细胞，获得了与ATCs和Fdc的骨髓来源一致的数据。在老年免疫缺陷小鼠中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，继发性Ab反应下降和GC缺乏至少部分是由于Ag转运能力下降和FDC缺陷，这可能是由于ATC/FDC骨髓前体减少或缺陷。另外，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（向B细胞呈递Ag）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分离的老年fdc的辅助功能。

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.