Target Discovery and Validation Reviews and Protocols

290 Sioud
Fig. 6. A second signal is required for B-cell activation. The interaction of the B-cell
antigen receptor (BCR) with the antigen constitutes the first signal. For thymus-dependent
antigens, the second signal is delivered by the helper cells that recognize the antigen as
peptides bound to major histocompatability complex (MHC) II molecules on B-cells.
The interaction between CD40 ligand (CD40L) on the T-cell and CD40 on the B-cell is
a part of the second signal. For thymus-independent antigens, the antigens or other cells
of the immune system deliver the second signal.
contact with a dense network of follicular dendritic cells (FDCs). B-cells
with mutations that improve affinity for exogenous antigen are positively
selected. However, antigen receptors that fail to bind adequately to low levels
of antigen-presented by FDCs can trigger receptor revision, apoptosis, or
both. Notably, negative selection is an important force in the GC, most likely
eliminating approximately one in every two cells.
The main purpose of the GC reaction is to enhance the later part of the primary
immune response. Some GC cells differentiate first into plasmablasts and then
into plasma cells. These nondividing, terminally differentiated plasma cells are
specialized to secrete antibody at a high rate. Other germinal center cells differentiate
into memory B-cells, which are long-lived descendants of cells that were
once stimulated by antigen and had proliferated in the germinal center. These
cells divide very slowly, if at all. They express surface Ig, but they do not
secrete antibody at a high rate. Signals from both FDCs and T-cells are important
in stimulating a B-cell to become a memory cell.
Notably, the production of highly efficient neutralizing antibodies requires
antibody affinity maturation, which involves two main events (28) (1) immunoglobulin
class-switch recombination (CSR), which directs antibody production
towards the synthesis of IgG, IgA, and IgE; and (2) generation of somatic
hypermutation (SHM) in Ig-variable region (V region), which can result in