Not all B cells activated by TFH cells will migrate to the outer follicle and eventually establish a primary focus. Instead, some move into a primary lymphoid follicle together with their associated TFH cells (Fig. 10.10), where they continue to proliferate and ultimately form a germinal center; follicles with germinal centers are also called secondary lymphoid follicles. Downregulating EBI2 by B cells appears to favor germinal center formation. In mice lacking EBI2 expression in B cells, antigen-activated B cells remain near the border with the T-cell zone and are able to form germinal centers, but generate fewer plasmablasts.
Germinal centers are composed mainly of proliferating B cells, but antigen-specific T cells make up about 10% of germinal center lymphocytes and provide indispensable help to the B cells. The germinal center is an area of active cell division that forms within a surrounding region of resting B cells in the primary follicle. Proliferating germinal center B cells displace the resting B cells toward the periphery of the follicle, forming a mantle zone of resting cells around the two distinguishable areas of activated B cells, called the light zone and the dark zone (Fig. 10.11, left panel). The germinal center grows in size as the immune response proceeds, and then shrinks and finally disappears when the infection is cleared. Germinal centers are present for about 3–4 weeks after initial antigen exposure.
The primary focus and the germinal center reaction differ in the quality of antibody that they produce. Plasmablasts, germinal center B cells, and early memory B cells begin to emerge during the first 4–5 days of an immune response. Plasmablasts in primary foci primarily secrete antibodies of the IgM isotype that offer some immediate protection. In contrast, B cells in the germinal center reaction undergo several processes that produce antibodies that are more effective in eliminating infections. These processes include somatic hypermutation, which alters the V regions of immunoglobulin genes (see below), and which enables a process called affinity maturation, which selects for the survival of mutated B cells that have a high affinity for the antigen.
Fig. 10.10 Activated B cells form germinal centers in lymphoid follicles. Activation of B cells in a lymph node is shown here. Top panel: naive circulating B cells enter lymph nodes from the blood via high endothelial venules (HEV) and are attracted by chemokines into the primary lymphoid follicle; if these B cells do not encounter antigen in the follicle, they leave via the efferent lymphatic vessel. Second panel: B cells that have bound antigen move to the border with the T-cell area, where they may encounter activated helper T cells specific for the same antigen; these T cells interact with the B cells and activate them to start proliferation and differentiation into plasmablasts. Some B cells activated at the T-cell–B-cell border migrate to form a primary focus of antibody-secreting plasmablasts in the interfollicular regions (spleen) or medullary cords (lymph nodes), whereas others move back into the follicle, where they continue to proliferate and form a germinal center. Germinal centers are sites of sustained B-cell proliferation and differentiation. Follicles in which germinal centers have formed are known as secondary follicles. Within the germinal center, B cells begin their differentiation into either antibody-secreting plasma cells or memory B cells. Third and fourth panels: plasma cells leave the germinal center and migrate to the medullary cords, or leave the lymph node altogether via the efferent lymphatics and migrate to the bone marrow.
Schematic representation of a follicle Cyclic reentry of cells into the dark zone with a germinal center is dependent on reexpression of CXCR4 on centrocytes