Fig. 10.11The structure of a germinal center. The germinal center is a specialized microenvironment in which B-cell proliferation, somatic hypermutation, and selection for strength of antigen binding all occur. Closely packed centroblasts, which express CXCR4 and CXCR5, form the ‘dark zone’ of the germinal center; the less densely packed ‘light zone’ contains centrocytes, which express only CXCR5. Stromal cells in the dark zone produce CXCL12, which attracts the CXCR4-expressing centroblasts. Cyclic reentry describes the process by which B cells can lose and gain expression of CXCR4 and thus move from the light zone to the dark zone and back again.
In addition, class switching allows the selected B cells to produce antibodies with a variety of effector functions. These B cells will differentiate either into plasma cells that secrete higher-affinity and class-switched antibody in the latter part of the primary immune response, or into memory B cells as described in Chapter 11.
B cells in the germinal center divide rapidly, every 6–8 hours. Initially, these rapidly proliferating B cells, called centroblasts, express the chemokine receptors CXCR4 and CXCR5 but markedly reduce their expression of surface immunoglobulin, particularly of IgD. Centroblasts proliferate in the dark zone of the germinal center, named for its densely packed appearance (Fig. 10.12). Stromal cells in the dark zone produce CXCL12 (SDF-1), a ligand for CXCR4 that acts to retain centroblasts in this region. As time goes on, some centroblasts reduce their rate of cell division, enter the growth phase, pausing at the G2/M phase of the cell cycle, reduce CXCR4 expression, and begin to produce higher levels of surface immunoglobulin. These B cells are termed centrocytes. The loss of CXCR4 allows centrocytes to move into the light zone, a less densely packed area containing abundant FDCs that produce the chemokine CXCL13 (BLC), a ligand for CXCR5 (see Fig. 10.11, right panel). The B cells proliferate in the light zone, but to a lesser extent than in the dark zone.
Fig. 10.12Germinal centers are sites of intense cell proliferation and cell death. The photomicrograph (first panel) shows a section through a human tonsillar germinal center. Closely packed centroblasts, seen in the lower part of this photomicrograph, form the so-called dark zone of the germinal center. Above this region is the less densely packed light zone. The second panel shows immunofluorescent staining of a germinal center. B cells are found in the dark zone, light zone, and mantle zone. Proliferating cells are stained green for Ki67, an antigen expressed in nuclei of dividing cells, revealing the rapidly proliferating centroblasts in the dark zone. The dense network of follicular dendritic cells, stained red, mainly occupies the light zone. Centrocytes in the light zone proliferate to a lesser degree than centroblasts. Small recirculating B cells occupy the mantle zone at the edge of the B-cell follicle. Large masses of CD4 T cells, stained blue, can be seen in the T-cell zones, which separate the follicles. There are also significant numbers of T cells in the light zone of the germinal center; CD4 staining in the dark zone is associated mainly with CD4-positive phagocytes, that digest B cells that die there. Photographs courtesy of I. MacLennan.
Light micrograph of germinal center (high power)
Germinal center stained to show T cells, follicular dendritic cells, and proliferating B cells
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