Fig. 10.17 Immune complexes bound to FDCs form iccosomes, which are released and can be taken up by B cells in the germinal center. FDCs have a prominent cell body and many dendritic processes. Immune complexes, bound to complement receptors and Fc receptors on the FDC surface, become clustered, forming prominent ‘beads’ along the dendrites (a). An intermediate form of FDC is shown, which has both straight filiform dendrites and others that are becoming beaded. These beads are shed from the cell as iccosomes (immune complex-coated bodies), which can bind to a B cell in the germinal center (b) and be taken up by it (c). In panels b and c, the iccosome has been formed with immune complexes containing horseradish peroxidase, which is electron-dense and therefore appears dark in the transmission electron micrographs. Photographs courtesy of A.K. Szakal.
antigen, in competition with the other clonally related centrocytes harboring different mutations. Centrocytes whose receptors bind antigen better will capture and present more peptides on their surface MHC class II molecules. TFH cells in the germinal center recognize these peptides and, as before, are activated to deliver signals to the B cell that promote survival. Centrocytes whose mutations reduce antigen-binding affinity will take up less antigen, and so will receive weaker survival signals from TFH cells. Successful B cells will reexpress CXCR4 and return to the dark zone, where they will undergo additional rounds of division, in effect becoming centroblasts again. Germinal center B cells that fail to acquire sufficient antigen from FDCs to engage TFH cells will become apoptotic and be lost. This process of B-cell migration within the germinal center is known as the cyclic reentry model (see Fig. 10.11, right panel). In this way, the affinity and specificity of B cells are continually refined during the germinal center response, through affinity maturation (see Section 10-6). The selection process can be quite stringent: although 50–100 B cells may seed the germinal center, most of them leave no progeny, and by the time the germinal center reaches maximum size, it is typically composed of the descendants of only one or a few B cells.
In the germinal center, TFH cells and B cells interact to deliver signals that are important for both cells (see Section 10-4). Mice that lack ICOS are deficient in the germinal center reaction and have severely reduced class-switched antibody responses due to defective TFH-cell function. CD40 signaling in B cells is activated by CD40L on TFH cells and increases expression of the survival molecule Bcl-XL, a relative of Bcl-2. These interactions also include signaling by SLAM family receptors through the adapter protein SAP, as discussed above. Two-photon intravital microscopy has revealed that mice lacking the SLAM receptor CD84 have reduced numbers of conjugates between antigen-specific T cells and B cells in germinal centers, and these mice also have a reduced humoral response to antigen.
10-9 Activation-induced cytidine deaminase (AID) introduces mutations into genes transcribed in B cells.
Now that we have discussed the cellular processes involved in somatic hypermutation and affinity maturation, we will delve into the details of the mutation process itself. The enzyme AID is important for both somatic hyper-mutation and class switch recombination, as mice lacking AID have defects in both processes. People with mutations in the AID gene that inactivate the enzyme—that is, have activation-induced cytidine deaminase deficiency, or AID deficiency—also lack both somatic hypermutation and class switching. This condition leads to the production of predominantly IgM antibodies and the absence of affinity maturation, a syndrome known as hyper IgM type 2 immunodeficiency (discussed in Chapter 13).