Germinal centres sites of antigendriven clonal expansion of B cells that undergo mutation in their Ig Vregion gene

Germinal centres are present in the first 3 weeks after immunization with protein-based antigens. Figure 20.11 indicates that some of the B blasts generated after cognate interaction with primed T cells migrate to follicles. Some of the antigen-specific T cells also migrate to the follicles. On arrival in the follicles, there is massive clonal expansion of the B cells such that the spaces in the FDC network become filled with blasts. At this stage, changes occur in which the classical germinal centre structures of dark and light zones develop. The dark zone is formed by the blasts moving to the edge of the FDC network next to the T zone. These blasts, now termed centroblasts, activate the somatic hypermutation mechanism that acts on their rearranged im-munoglobulin V-region genes. Centroblasts, like their precursors, have a cell cycle time of 7 h, but their numbers remain relatively constant. The hypermutation mechanism is specifically directed against the immunoglobulin V-region genes but is random in other respects.

The result is that the affinity of surface immunoglobulin for the original antigen may be either decreased or increased. Centroblasts continually give rise to centrocytes, non-dividing cells that migrate into the FDC network that forms the light zone of the germinal centre. Centrocytes either leave the light zone within 12 h or die in situ. They can leave the light zone only if they receive antigen-specific selection signals. The probable sequence of events occurring in fully developed germinal centres is shown in Figure 20.14.

Centrocytes pick up antigen from FDC. Their ability to do this will be determined by the affinity of their surface immuno-globulin for the antigen. In addition, they require signals from local T cells so they must process the antigen they have taken from FDCs and present the resulting peptides with class II MHC molecules to T cells. The T cells in the germinal centre are concentrated in the outer part of the light zone. They are antigen specific in that they were driven to enter the follicle after specific interaction with peptide on B cells in the T zone. This requirement for the B cells to receive T-cell help in the germinal centre protects against potential autoimmune responses, as those B cells that have developed reactivity against autoantigens are unlikely to receive selection signals from germinal centre T cells.

Centrocytes that survive selection within germinal centres leave the light zone as either plasmablasts or memory B cells. The plasmablasts migrate to distant sites of antibody production.

Plasma cell

Memory B cell

Plasma cell

Memory B cell

Figure 20.14 Selection of cells that have undergone Ig V-region gene hypermutation in germinal centres. The hypermutation mechanism is active in centroblasts, which are the rapidly dividing cells of the dark zone that give rise to centrocytes. Centrocytes die by apoptosis unless they (i) pick up and process antigen held on FDC and (ii) find a T cell in the germinal centre that recognizes the peptides from this antigen presented on centrocytes in association with self-class II. The T cell-dependent selection mechanism makes it unlikely that centrocytes with mutated Ig V-region genes that encode self-reactive antibody will be selected. Most B cells that are selected leave the germinal centre (i) to migrate to distant sites of antibody production, the gut or bone marrow, where they differentiate to become plasma cells and (ii) to differentiate into memory B cells. Some selected cells remain within the germinal centre and return to the dark zone as centroblasts.

Figure 20.14 Selection of cells that have undergone Ig V-region gene hypermutation in germinal centres. The hypermutation mechanism is active in centroblasts, which are the rapidly dividing cells of the dark zone that give rise to centrocytes. Centrocytes die by apoptosis unless they (i) pick up and process antigen held on FDC and (ii) find a T cell in the germinal centre that recognizes the peptides from this antigen presented on centrocytes in association with self-class II. The T cell-dependent selection mechanism makes it unlikely that centrocytes with mutated Ig V-region genes that encode self-reactive antibody will be selected. Most B cells that are selected leave the germinal centre (i) to migrate to distant sites of antibody production, the gut or bone marrow, where they differentiate to become plasma cells and (ii) to differentiate into memory B cells. Some selected cells remain within the germinal centre and return to the dark zone as centroblasts.

Plasmablasts from follicles in the spleen or peripheral lymph nodes migrate to the bone marrow. Those activated in the gut or respiratory tract or the lymph nodes that drain these tissues migrate to the corresponding mucosal surfaces. In the bone marrow or the lamina propria of the gut, the plasmablasts differentiate into plasma cells. Unlike the plasma cells generated in T zones, most of these plasma cells have a lifespan of about 1 month.

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