Target Discovery and Validation Reviews and Protocols

Overview of Immune System 291
amino acid replacements in immunoglobulin V regions that affect the fate of
B-cells. Because not all IgGs or IgAs carry somatic hypermutations and some
IgMs have such mutations (28), neither CSR nor SHM is a prerequisite of the
other. However, both processes require close cooperation between T- and B-cells.
The best known form of such cooperation is the interaction between CD40
ligand transiently expressed on activated Th cells and CD40 molecules constitutively
expressed by B-cells (Fig. 6). Defect in this interaction can lead to
hyper-IgM syndromes (29). Because of somatic hypermutations, tolerance must be
induced on B-cells both during their development and after antigenic stimulation
in the secondary lymphoid tissues. Then, useful IgG molecules require a higher
affinity binding to exogenous antigens, whereas useful TCRs must bind their
MHC-self peptide with a lower affinity.
3.3. Receptor Revision
BCRs that fail to bind adequately to low levels of exogenous antigens presented
by FDCs within the GC can trigger yet another mechanism for optimizing
the B-cell affinity, receptor revision, which refers to secondary rearrangements
in peripheral cells (30). This process is initiated by the absence of signaling
through the BCR and results in secondary RAG-mediated rearrangement at the
IgL locus, leading to the expression of a surface Ig molecule that binds antigen
with affinity higher than that of the parent Ig molecule (Fig. 5). Importantly,
BCR signaling results in a variety of cellular events, including activation, cell
cycling, survival, differentiation, apoptosis, and induction or suppression of Ig
gene rearrangement, depending on the developmental state and interaction with
their microenvironments.
Although antibody response to most protein antigens is dependent on Th cells,
humans and mice with T-cell deficiencies nevertheless make antibodies to many
bacterial antigens. Such antigens are known as thymus-independent antigens
because they stimulate strong antibody responses in athymic individuals. These
antigens are often called mitogens, a mitogen being a substance that induces cells
to undergo mitosis (e.g., LPS). This immunity is an important component of the
humoral immune response to nonprotein antigens that do not engage peptidespecific
T-cell help.
4. Peripheral Tolerance
After development and selection in the thymus or the bone marrow, respectively,
naive T- and B-cells migrate to the secondary lymphoid organs (e.g.,
lymph nodes, tonsils, and spleen). These lymphoid tissues, in addition to bringing
T- and B-cells together, contain professional APCs and microenvironments
(e.g., cytokines) that are crucial for T- and B-cell function and survival (8).
APCs include DCs, B-cells, and macrophages.