Kinetics of GC Development



LEFT PANEL: Illustrates the changes in the kinetics of the germinal center (GC) response in the 'draining' lymph node of young immune mice [REF]. As the antigen transport mechanism brings the antigen (Ag) into the lymphoid nodule (follicle), the FDC network develops and peaks in size by Day 3 after antigenic challenge (red graph). By this time ICCOSOMEs are formed and by Day 3 they are dispersed in the edematous FDC network for endocytosis by Ag-specific B cells. Concomitantly with the ICCOSOME-induced stimulation of B cells, B cells proliferate and the germinal center (made up of these B cells) rapidly increases and reaches its peak size around 10 days (see yellow graph). The FDC network in contrast, once released its iccosomes, decreases in size (volume occupied) and becomes condensed to a small fraction of its size at day 3. The blue graph represents the change in the size (volume) of the axillary lymph node from the time of antigen injection through the 10th day. Although the peak size of the AXLN corresponds to the peak size of the FDC Network, the increased size of the FDC network does not Account for the size increase alone. There is increase in cellularity of the lymph node at that time in other compartments an this adds to the AXLN size increase. By the time of the reduction in the size of the FDC Network the lymph node returns to its starting volume.

RIGHT PANEL: Illustrates the changes in the kinetics of the germinal center response in the 'draining' lymph node of aged immune mice. In old mice, in agreement with the consensus that the FDC network plays an important role in the initiation of GC development, the observed minimal development of the FDC network (see red graph), the observed lack of ICCOSOME production and reduced retention of Ag-Ab complexes result in a minimal GC development (i.e., occasional GCs) (see yellow graph). The initial 'large' compartment size of GCs in old mice at the time of Ag injection reflect a number of preexisting GCs (induced by environmental antigens). The rapid decrease in the volume of these GCs reflects the so called "germinal center dissociation" that rapidly follows antigenic challenge [REF]. Note the accompanying size changes in lymph node size and contrast it to that in the young animal. AXLN size drops at the time of "germinal center dissociation"and levels off nearly parallel with the rest of the events.

Please scroll up to see the actual FDC Network as visualized by histochemical localization of the antigen HRP. These micrographs correspond to the "red" graph line above.

These micrographs show a sequence of changes in the development of the FDC Network (or antigen retaining reticulum; ARR) in both young and old popliteal lymph nodes (PLN). Similar changes were observed for axillary lymph nodes. The ARR development begins with the development of antigen transport mechanisms (ATM) from the subcapsular sinus (SS) to the cortex. The lines indicate the size of the bases of these pyramid- shaped structures. In the old PLN these ATM have globular (degenerate) structures. Degenerate development of ARR follows these globular ATM. Contrast the robust ARR in the young PLN with the old. Times are: 1a/b, 15 min; 1c/d, 1 day; 1e/f, 3 day; and 1g/h, 5 days after challenge in the feet with HRP.

Diagrammatic Interpretation:


LEGEND: The two panels of this chart illustrate the working models of the alternative antigen transport pathway in young and aged mice. These cartoons were based on presently available data. For references on the transport path in old mice: [REF1] [REF2] It is essential for the viewer to be familiar with the chart presented under the heading Humoral Immune Response, The Alternative Antigen Transport Pathway (See front page of this website).

A brief interpretation of the observed age-related changes is the following: Since antigen transport is for the most part defective (e.g., antigen transport cells become phagocytic rather than become transporters of antigens from the afferent lymph to the follicles in the lymph node cortex ) very little antigen is retained on the dendrites of FDCs in the follicles. FDCs also become atrophic and do not develop the normal numbers of dendrites that are typically seen on FDCs from young individuals. Consequently, no iccosomes are produced which typically function in delivering antigen for endocytosis to germinal center B cells. This results in reduced numbers of germinal centers where B memory cells are formed. Therefore, very few B memory cells develop. This will lead to a deficit in antibody secreting plasma cells which begin their development in germinal centers and migrate to the medullary cords of lymph nodes and then to the bone marrow for antibody production. Since the old system is deficient in these plasma cells no feedback occurs and the cycling of the alternative antigen transport pathway is disrupted. The result is a seriously depressed, if not absent, anamnestic immune response. In other words the system thought to be functional in maintaining immunity became defective with aging.