Target Discovery and Validation Reviews and Protocols

Overview of Immune System 289
soluble, monovalent antigens mainly induce anergy. Anergic B-cells exhibit a
shortened half-life in the periphery (24).
Once nonautoreactive B-cells are generated, they can leave the bone marrow
for the spleen where they further mature into naive B-cells, which express both
IgM and IgD molecules, by alternative splicing. However, it is not yet clear how,
in the absence of binding to specific antigen in the bone marrow, an immature
B-cell senses that a functional IgM has been made and subsequently receives
signals for further maturation. There are three mature B-cell subsets: follicular
(FO) or B-2 cells, marginal zone (MZ) B-cells, and B1 cells. FO B-cells contain
the bulk of the peripheral B-cell pool and are the main cellular constituent of
the spleenic and lymph node follicles and the bone marrow as recirculating
cells. MZ B-cells constitute a small fraction (5%) of all peripheral B-cells and
are located in the marginal zones of the spleen and are responsible for the early
antibody response to blood-borne pathogens. B1 cells are located principally in
the peritoneal and pleural cavities. They provide protection against antigen of
the gut and peritoneum. Both MZ and B1 cells are often autoreactive, a property
that enhance their survival and rapid responses to foreign antigens. Upon
antigen encounter, FO naive B-cells differentiate into plasma cells or memory
cells in secondary lympoid organs, in particular the spleen (Fig. 4). It is worth
noting that in the bone marrow, IgM+ immature B-cells that interact strongly
with self-antigen either are eliminated by apoptosis (negative selection) or
undergo further rearrangement at the IgL loci to alter their specificity, whereas
stimulation via the IgM BCR induces proliferation of mature naive B-cells.
Thus, both cell populations differ in their signaling downstream of the BCR.
Indeed, the BCR is recruited to lipid rafts, an important structure in cell signaling,
in mature B-cells but not in immature B-cells.
3.2. Somatic Hypermutation
B-cells, which express a self-tolerant BCR, exit the bone marrow to join
the peripheral B-cell population. In contrast to TCRs, the BCRs mature antigenically.
Upon encountering exogenous antigens, which they recognize
specifically by means of the IgM BCR, mature naive B-lymphocytes are activated,
proliferate, and form germinal centers. B-cells are first activated outside
the follicles by antigen and T-cells (Fig. 5). Then, they migrate into a
primary lymphoid follicle where they continue to proliferate and subsequently
form the germinal center (GC). Proliferating B-cells reduce the
expression of surface immunoglobulin. These cells are termed centroblasts,
which first proliferate in the dark zone of the GC (Fig. 5). Subsequently,
some cells reduce their rate of cell division and express higher levels of surface
immunoglobulin. These cells are termed centrocytes, which are mostly
found in the light zone of the GC. Within the light zone, centrocytes make